RNAi-mediated inhibition of ocular hypertension targets

Abstract

RNA interference is provided for inhibition of ocular hypertension target mRNA expression for lowering elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Ocular hypertension targets include carbonic anhydrase II, IV, and XII; .beta.1- and .beta.2 adrenergic receptors; acetylcholinesterase; Na.sup.+/K.sup.+-ATPase; and Na--K-2Cl cotransporter. Ocular hypertension is treated by administering interfering RNAs of the present invention.

Description

[0001] The present application claims the benefit of co-pending U.S. Provisional Patent Applications having Ser. Nos. 60/648,926 filed Feb. 1, 2005, and 60/753,364 filed Dec. 22, 2005, the texts of which are specifically incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to the field of interfering RNA compositions for inhibition of expression of ocular hypertension targets in glaucoma, particularly for primary open angle glaucoma.

BACKGROUND OF THE INVENTION

[0003] Glaucoma is a heterogeneous group of optic neuropathies that share certain clinical features. The loss of vision in glaucoma is due to the selective death of retinal ganglion cells in the neural retina that is clinically diagnosed by characteristic changes in the visual field, nerve fiber layer defects, and a progressive cupping of the optic nerve head (ONH). One of the main risk factors for the development of glaucoma is the presence of ocular hypertension (elevated intraocular pressure, IOP). An adequate intraocular pressure is needed to maintain the shape of the eye and to provide a pressure gradient to allow for the flow of aqueous humor to the avascular cornea and lens. IOP levels may also be involved in the pathogenesis of normal tension glaucoma (NTG), as evidenced by patients benefiting from IOP lowering medications. Once adjustments for central corneal thickness are made to IOP readings in NTG patients, many of these patients may be found to be ocular hypertensive.

[0004] The elevated IOP associated with glaucoma is due to elevated aqueous humor outflow resistance in the trabecular meshwork (TM), a small specialized tissue located in the iris-corneal angle of the ocular anterior chamber. Glaucomatous changes to the TM include a loss in TM cells and the deposition and accumulation of extracellular debris including proteinaceous plaque-like material. In addition, there are also changes that occur in the glaucomatous ONH. In glaucomatous eyes, there are morphological and mobility changes in ONH glial cells. In response to elevated IOP and/or transient ischemic insults, there is a change in the composition of the ONH extracellular matrix and alterations in the glial cell and retinal ganglion cell axon morphologies.

[0005] Primary glaucomas result from disturbances in the flow of intraocular fluid that has an anatomical or physiological basis. Secondary glaucomas occur as a result of injury or trauma to the eye or a preexisting disease. Primary open angle glaucoma (POAG), also known as chronic or simple glaucoma, represents ninety percent of all primary glaucomas. POAG is characterized by the degeneration of the trabecular meshwork, resulting in abnormally high resistance to fluid drainage from the eye. A consequence of such resistance is an increase in the IOP that is required to drive the fluid normally produced by the eye across the increased resistance.

[0006] Current anti-glaucoma therapies include lowering IOP by the use of suppressants of aqueous humor formation or agents that enhance uveoscleral outflow, laser trabeculoplasty, or trabeculectomy, which is a filtration surgery to improve drainage. Pharmaceutical anti-glaucoma approaches have exhibited various undesirable side effects. For example, miotics such as pilocarpine can cause blurring of vision and other negative visual side effects. Systemically administered carbonic anhydrase inhibitors (CAIs) can also cause nausea, dyspepsia, fatigue, and metabolic acidosis. Further, certain beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics cause tachycardia, arrhythmia and hypertension. Such negative side effects may lead to decreased patient compliance or to termination of therapy. In addition, the efficacy of current IOP lowering therapies is relatively short-lived requiring repeated dosing during each day and, in some cases, the efficacy decreases with time.

[0007] In view of the importance of ocular hypertension in glaucoma, and the inadequacies of prior methods of treatment, it would be desirable to have an improved method of treating ocular hypertension that would address the underlying causes of its progression.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to interfering RNAs that silence ocular hypertension target mRNA expression, thus lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Ocular hypertension targets include carbonic anhydrase II, IV, and XII; .beta.1- and .beta.2 adrenergic receptors; acetylcholinesterase; Na.sup.+/K.sup.+-ATPase; and Na--K-2Cl cotransporter. The interfering RNAs of the invention are useful for treating patients with open-angle glaucoma or ocular hypertension.

[0009] An embodiment of the present invention provides a method of attenuating expression of an ocular hypertension target mRNA such as carbonic anhydrase II, IV, or XII; .beta.1- or .beta.2 adrenergic receptors; acetylcholinesterase; Na.sup.+/K.sup.+-ATPase; or Na--K-2Cl cotransporter mRNA in a subject. The method comprises administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier. Administration is to the eye of the subject for attenuating expression of an ocular hypertension target in a human.

[0010] In one embodiment of the invention, the interfering RNA comprises a sense nucleotide strand, an antisense nucleotide strand and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides. Further, the antisense strand hybridizes under physiological conditions to a portion of an mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134 which are sense cDNA sequences encoding carbonic anhydrase II and IV; .beta.1- and .beta.2 adrenergic receptors; acetylcholinesterase (ACHE) variant E4-E5; Na.sup.+/K.sup.+-ATPase .alpha.2 polypeptide; Na--K-2Cl cotransporter NKCC2 (SLC12A1), carbonic anhydrase XII variant 1, acetylcholinesterase variant E4-E6, Na.sup.+/K.sup.+-ATPase al polypeptide variant 1 and variant 2, Na.sup.+/K.sup.+-ATPase .alpha.3 polypeptide, Na.sup.+/K.sup.+-ATPase .alpha.4 polypeptide variant 1 and variant 2, Na.sup.+/K.sup.+-ATPase .beta.1 polypeptide variant 1 and 2, Na.sup.+/K.sup.+-ATPase .beta.2 polypeptide, Na.sup.+/K.sup.+-ATPase .beta.3 polypeptide, Na--K-2Cl cotransporter NKCC1 (SLC12A2), and carbonic anhydrase XII variant 2, respectively. The antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, respectively. The administration of such a composition attenuates the expression of an ocular hypertension target mRNA of the subject.

[0011] In one embodiment, the ocular hypertension target mRNA encodes carbonic anhydrase II, IV or XII, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:101, or SEQ ID NO:134 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:101, or SEQ ID NO:134, respectively.

[0012] In another embodiment, the ocular hypertension target mRNA encodes a .beta.1- or .beta.2-adrenergic receptor, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively.

[0013] In a further embodiment, the ocular hypertension target mRNA encodes an acetylcholinesterase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123, respectively.

[0014] In yet another embodiment, the ocular hypertension target mRNA encodes a subunit of Na.sup.+/K.sup.+-ATPase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132, respectively.

[0015] In a further embodiment, the ocular hypertension target mRNA encodes a Na--K-2Cl cotransporter, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133, respectively.

[0016] In one embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:1 comprising nucleotide 232, 527, 721, 728, 809, 810, 855, 856, 921, 1139, 506, 547, 548, 740, 911, 1009, 1140, 1149, 1150, 1151, 1188, 1194, 1195, 1223, 1239, 1456, 1457, 1458, 100, 158, 166, 247, 286, 318, 322, 328, 371, 412, 482, 504, 505, 541, 734, 772, 777, 814, 972, 998, 1232, 317, or 401.

[0017] In another embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:2 comprising nucleotide 213, 252, 258, 266, 399, 457, 463, 490, 595, 1064, 109, 112, 125, 126, 150, 261, 265, 280, 398, 453, 459, 462, 467, 492, 534, 785, 801, 825, 827, 876, 1003, or 1012.

[0018] In a further embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:101 comprising nucleotide 191, 239, 274, 275, 341, 389, 412, 413, 423, 687, 689, 695, 710, 791, 792, 794, 983, 993, 994, 995, 691, 1039, 1568, 2326, 2332, 2425, 2433, 2844, 2845, 2880, 2884, 2891, 2954, 2955, 2956, 2957, 2964, 2965, 3006, 3007, 3012, or 3026.

[0019] In another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:134 comprising nucleotide 687, 1535, 2293, 2299, 2392, 2400, 2811, 2812, 2847, 2851, 2858, 2921, 2922, 2923, 2924, 2931, 2932, 2973, 2974, 2979, or 2993.

[0020] Another embodiment of the invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:3 comprising nucleotide 468, 523, 799, 1563, 1565, 1569, 1593, 1613, 1614, 1626, 310, 322, 726, 769, 772, 801, 802, 1501, 1576, 1577, 1579, 1580, 1581, 1586, 1590, 1592, 1594, 1615, 1616, 1632, 1633, or 1654.

[0021] A further embodiment of the invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:4 comprising nucleotide 329, 375, 1031, 1046, 1149, 1163, 1371, 1401, 1426, 1880, 283, 607, 608, 609, 619, 623, 722, 857, 1037, 1091, 1115, 1124, 1136, 1137, 1151, 1164, 1393, 1394, 1395, 1406, 1407, 1427, 1428, 1429, 1442, 1725, 1726, 1756, 1757, 1758, 1767, 1790, 1791, 1792, 1793, 1803, 1861, 1869, 1971, 1972, or 1979.

[0022] In another method of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:123 comprising nucleotide 1875, 1890, 1891, 2011, 2012, 2133, or 2134.

[0023] Another embodiment of the invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:5 comprising nucleotide 366, 370, 384, 385, 525, 588, 768, 1045, 1046, 1061, 1090, 1232, 1314, 1316, 1460, 1461, 1462, 1528, 1607, 1705, 1713, 382, 393, 397, 622, 1131, 1459, 1530, 2251, 2885, 2886, 386, 1231, 1315, 2047, 2049, 2053, 2055, 2057, 2125, 2126, 2127, 2250, 2253, 2258, 2260, 2318, 2395, 2397, 2404, 2405, 2643, 2645, or 2887.

[0024] In a further embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:124 comprising nucleotide 2208, 2275, 2307, 2526, 2538, 2592, 2628, 2979, 2985, 3093, 3474, 3504, 3505, 3506, 3518, 343, 442, 700, 707, 811, 907, 1059, 1363, 1594, 1662, 1758, 1760, 1896, 2037, or 2147.

[0025] In yet another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:125 comprising nucleotide 436, 441, 443, 552, 617, 701, 702, 832, 2204, 2291, or 2495.

[0026] A further embodiment of the present invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:6 comprising nucleotide 471, 1990, 3080, 3797, 4037, 4093, 4225, 4323, 5213, 5285, 214, 467, 470, 472, 473, 632, 825, 946, 1693, 1767, 1768, 2157, 2263, 2589, 2590, 2765, 2988, 3094, 3144, 3145, 3344, 3345, 3418, 3666, 3828, 3850, 4040, 4041, 4061, 4882, 4894, 4900, 5040, 5114, 5115, 5128, 5129, 5253, 5296, 5375, 5384, or 5385.

[0027] In another embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:126 comprising nucleotide 240, 272, 362, 1836, 1851, 2103, 2137, 2138, 2139, 2157, 2158, 2160, 2425, 2580, 2601, 2646, 2650, 2794, 2803, 3116, 3124, 3126, 3129, or 3377.

[0028] In yet another embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:127 comprising nucleotide 113, 612, 702, 833, 1101, 1732, 1733, 1836, 2070, 2071, 2143, 2328, 2475, 2861, 2862, 2952, 3203, 3281, 3377, 3379, 3470, 3471, 3554, 3614, 3615, 3616, 3617, 3625, 3626, 3642, 3646, 3647, 3653, 3655, 3797, 3801, 3803, 3809 or 3810.

[0029] In another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:128 comprising nucleotide 126, 251, 252, 253, 331, 427, 429, 520, 521, 530, 601, 602, 603, 604, 664, 665, 666, 667, 675, 676, 692, 696, 697, 702, 703, 705, 707, 847, 851, 853, 859, or 860.

[0030] In yet another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:129 comprising nucleotide 1096, 1099, 1130, 1131, 1167, 1299, 1441, 1450, 1451, 1452, 1564, 1746, 1750, 1751, 1752, 1795, 203, 204, 214, 222, 224, 225, 226, 380, 525, 591, 612, 613, 615, 635, 636, 663, 664, 669, 699, 765, 790, 839, 840, 841, 900, 909, 933, or 947.

[0031] In another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:130 comprising nucleotide 1063, 1102, 1106, 1107, 1108, 1109, 1111, or 1151.

[0032] In another embodiment, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:131 comprising nucleotide 653, 654, 771, 773, 841, 849, 853, 917, 918, 926, 927, 931, 981, 983, 984, 996, 998, 1022, 1023, 1160, 1214, 1355, 1356, 1381, 1394, 1425, 1474, 1550, 1620, 1707, 1740, 1753, 1825, 1956, 1965, 2598, 2599, 2608, 2828, 2829, 2888, 3012, or 3251.

[0033] In another embodiment of the invention, an interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:132 comprising nucleotide 292, 434, 438, 457, 459, 488, 490, 498, 499, 592, 639, 723, 774, 775, 788, 857, 858, 910, 911, 930, 931, 932, 1009, 1010, 1023, 1024, 1111, 1146, 1147, 1220, 1246, 1321, 1325, 1326, 1327, 1331, 1437, 1548, 1571, 1785, 1786, or 1787.

[0034] Another embodiment of the present invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:7 comprising nucleotide 675, 974, 1373, 1780, 2102, 2151, 2315, 2542, 2609, 3197, 67, 71, 73, 353, 405, 864, 911, 912, 913, 1409, 1748, 1811, 1935, 1937, 1993, 2012, 2346, 2388, 2437, 2586, 3007, 3008, 3022, 3130, 3210, 3237, or 3271.

[0035] Another embodiment of the present invention provides an interfering RNA designed to target an mRNA corresponding to SEQ ID NO:133 comprising nucleotide 748, 749, 753, 1119, 1169, 1499, 1509, 1820, 2081, 2118, 2147, 2615, 2644, 2659, 2663, 2671, 2672, 2793, 2812, 2914, 2948, 3044, 3334, 3391, 3480, 3520, 3549, 3639, 3840, 3941, 3944, 4001, 4995, 4997, 5141, 5143, 5249, 5375, 5834, 5852, 5981, or 6678.

[0036] The present invention further provides for administering a second interfering RNA to a subject in addition to a first interfering RNA. The method comprises administering to the subject a second interfering RNA having a length of 19 to 49 nucleotides and comprising a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides; wherein the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, respectively. The second interfering RNA may target the same mRNA as the first interfering RNA or may target a different mRNA. Further, a third, fourth, or fifth, etc. interfering RNA may be administered in a similar manner.

[0037] A further embodiment of the invention is a method of treating ocular hypertension in a subject in need thereof. The method comprises administering to the eye of the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides. The antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, respectively. The ocular hypertension is treated thereby.

[0038] Another embodiment of the invention is a method of attenuating expression of an ocular hypertension target mRNA in a subject comprising administering to the subject a composition comprising an effective amount of single-stranded interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier. For attenuating expression of an ocular hypertension target, the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to the sequence identifiers and nucleotide positions cited supra for antisense strands.

[0039] Another embodiment of the invention is a method of attenuating expression of an ocular hypertension target mRNA in a subject, comprising administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, where the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:8, SEQ ID NO:14-SEQ ID NO:100, SEQ ID NO:102-SEQ ID NO:122, SEQ ID NO:135-SEQ ID NO:717, SEQ ID NO:720, and SEQ ID NO:721, as follows.

[0040] When the ocular hypertension target mRNA encodes carbonic anhydrase mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:8, SEQ ID NO:14-SEQ ID NO:32, SEQ ID NO:83-SEQ ID NO:100, SEQ ID NO:102-SEQ ID NO:122, SEQ ID NO:135-SEQ ID NO:219, SEQ ID NO:720, and SEQ ID NO:721.

[0041] When the ocular hypertension target mRNA encodes a .beta.-adrenergic receptor mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:33-SEQ ID NO:52, and SEQ ID NO:220-SEQ ID NO:282.

[0042] When the ocular hypertension target mRNA encodes ACHE mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:53-SEQ ID NO:62 and SEQ ID NO:283-333.

[0043] When the ocular hypertension target mRNA encodes ATP1A1 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:334-SEQ ID NO:374.

[0044] When the ocular hypertension target mRNA encodes ATP1A2 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:63-SEQ ID NO:72 and SEQ ID NO:375-SEQ ID NO:416.

[0045] When the ocular hypertension target mRNA encodes ATP1A3 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:417-SEQ ID NO:440.

[0046] When the ocular hypertension target mRNA encodes ATP1A4 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:441-SEQ ID NO:511.

[0047] When the ocular hypertension target mRNA encodes ATP1B1 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:512-SEQ ID NO:563.

[0048] When the ocular hypertension target mRNA encodes ATP1B2 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:564-SEQ ID NO:606.

[0049] When the ocular hypertension target mRNA encodes ATP1B3 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:607-SEQ ID NO:648.

[0050] When the ocular hypertension target mRNA encodes SLC12A1 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:73-SEQ ID NO:82 and SEQ ID NO:649-SEQ ID NO:675.

[0051] When the ocular hypertension target mRNA encodes SLC12A2 mRNA, the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:676-SEQ ID NO:717.

[0052] In a further embodiment of the present invention, the region of contiguous nucleotides is a region of at least 14 contiguous nucleotides having at least 85% sequence complementarity to, or at least 85% sequence identity with, the penultimate 14 nucleotides of the 3' end of the sequence of the sequence identifier. In yet another embodiment of the invention, the region of contiguous nucleotides is a region of at least 15, 16, 17, or 18 contiguous nucleotides having at least 80% sequence complementarity to, or at least 80% sequence identity with, the penultimate 15, 16, 17, or 18 nucleotides, respectively, of the 3' end of the sequence of the sequence identifier.

[0053] A composition comprising interfering RNA having a length of 19 to 49 nucleotides and having a nucleotide sequence of any one of SEQ ID NO's: 8, SEQ ID NO:14-SEQ ID NO:100, SEQ ID NO:102-SEQ ID NO:122, SEQ ID NO:135-SEQ ID NO:717, SEQ ID NO:720, and SEQ ID NO:721, or a complement thereof, and a pharmaceutically acceptable carrier is an embodiment of the present invention. In one embodiment, the interfering RNA is isolated. The term "isolated" means that the interfering RNA is free of its total natural mileau.

[0054] Another embodiment of the invention is a method of treating ocular hypertension in a subject in need thereof, the method comprising administering to an eye of the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:8, SEQ ID NO:14-SEQ ID NO:100, SEQ ID NO:102-SEQ ID NO:122, SEQ ID NO:135-SEQ ID NO:717, SEQ ID NO:720, and SEQ ID NO:721, wherein the ocular hypertension is treated thereby.

[0055] A method of attenuating expression of an ocular hypertension target mRNA first variant without attenuating expression of an ocular hypertension target mRNA second variant in a subject is a further embodiment of the invention. The method comprises administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of the first variant, wherein the expression of the first variant mRNA is attenuated without attenuating expression of the second variant mRNA, and wherein the first variant target mRNA is SEQ ID NO:101, SEQ ID NO:5, SEQ ID NO:124, SEQ ID NO:127, or SEQ ID NO:129, and the second variant target mRNA is SEQ ID NO:134, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:128, or SEQ ID NO:130, respectively.

[0056] In a further embodiment of the above-cited method, the first variant target mRNA is SEQ ID NO:134, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:128, or SEQ ID NO:130, and the second variant target mRNA is SEQ ID NO:101, SEQ ID NO:5, SEQ ID NO:124, SEQ ID NO:127, or SEQ ID NO:129, respectively.

[0057] Use of any of the embodiments as described herein in the preparation of a medicament for attenuating expression of an ocular hypertension mRNA is also an embodiment of the present invention.

BRIEF DESCRIPTION OF THE DRAWING

[0058] FIG. 1 provides a western blot, probed with antibodies against CA2 and actin, of HeLa cells transfected with CA2 siRNAs #1, #3, #4, and #5; a non-targeting control siRNA; and a buffer control (-siRNA). The siRNAs were at a concentration of 100 nM or 1 nM. The arrows indicate the positions of the .about.30-kDa CA2 protein and 42-kDa actin protein bands.

DETAILED DESCRIPTION OF THE INVENTION

[0059] RNA interference (RNAi) is a process by which double-stranded RNA (dsRNA) is used to silence gene expression. While not wanting to be bound by theory, RNAi begins with the cleavage of longer dsRNAs into small interfering RNAs (siRNAs) by an RNaseIII-like enzyme, dicer. SiRNAs are dsRNAs that are usually about 19 to 28 nucleotides, or 20 to 25 nucleotides, or 21 to 22 nucleotides in length and often contain 2-nucleotide 3' overhangs, and 5' phosphate and 3' hydroxyl termini. One strand of the siRNA is incorporated into a ribonucleoprotein complex known as the RNA-induced silencing complex (RISC). RISC uses this siRNA strand to identify mRNA molecules that are at least partially complementary to the incorporated siRNA strand, and then cleaves these target mRNAs or inhibits their translation. Therefore, the siRNA strand that is incorporated into RISC is known as the guide strand or the antisense strand. The other siRNA strand, known as the passenger strand or the sense strand, is eliminated from the siRNA and is at least partially homologous to the target mRNA. Those of skill in the art will recognize that, in principle, either strand of an siRNA can be incorporated into RISC and function as a guide strand. However, siRNA design (e.g., decreased siRNA duplex stability at the 5' end of the antisense strand) can favor incorporation of the antisense strand into RISC.

[0060] RISC-mediated cleavage of mRNAs having a sequence at least partially complementary to the guide strand leads to a decrease in the steady state level of that mRNA and of the corresponding protein encoded by this mRNA. Alternatively, RISC can also decrease expression of the corresponding protein via translational repression without cleavage of the target mRNA. Other RNA molecules and RNA-like molecules can also interact with RISC and silence gene expression. Examples of other RNA molecules that can interact with RISC include short hairpin RNAs (shRNAs), single-stranded siRNAs, microRNAs (mRNAs), and dicer-substrate 27-mer duplexes. The term "siRNA" as used herein refers to a double-stranded interfering RNA unless otherwise noted. Examples of RNA-like molecules that can interact with RISC include RNA molecules containing one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages. For purposes of the present discussion, all RNA or RNA-like molecules that can interact with RISC and participate in RISC-mediated changes in gene expression will be referred to as "interfering RNAs." SiRNAs, shRNAs, mRNAs, and dicer-substrate 27-mer duplexes are, therefore, subsets of "interfering RNAs."

[0061] Interfering RNA of embodiments of the invention appear to act in a catalytic manner for cleavage of target mRNA, i.e., interfering RNA is able to effect inhibition of target mRNA in substoichiometric amounts. As compared to antisense therapies, significantly less interfering RNA is required to provide a therapeutic effect under such cleavage conditions.

[0062] The present invention relates to the use of interfering RNA to inhibit the expression of ocular hypertension target mRNA, thus lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Ocular hypertension targets include carbonic anhydrase II, IV, and XII; .beta.1- and .beta.2 adrenergic receptors; acetylcholinesterase; Na.sup.+/K.sup.+-ATPase subunits; and Na--K-2Cl cotransporter. According to the present invention, interfering RNAs provided exogenously or expressed endogenously effect silencing of ocular hypertension target mRNA in ocular tissue(s).

[0063] Carbonic anhydrase catalyzes reversible hydration of carbon dioxide and appears to play a role in the regulation of aqueous humor formation. Carbonic anhydrase inhibitors lower pressure in the eye by reducing the amount of fluid produced. Carbonic anhydrase inhibitors are available as eyedrops (dorzolamide, brinzolamide) or tablets/capsules (acetazolamide, methazolamide). The eyedrops are associated with fewer side effects than the tablets or capsules and are better tolerated by many patients. AZOPT.RTM. (brinzolamide) ophthalmic suspension 1% is a topical carbonic anhydrase inhibitor (Alcon Laboratories, Inc., Fort Worth, Tex.).

[0064] Ophthalmic .beta.-blockers lower pressure in the eye by reducing the amount of fluid produced in the eye. These drugs are divided into two classes: the nonselective beta-blockers (timolol, levobunolol, metipranolol, carteolol) and the .beta.-1 selective blockers (betaxolol). The usual dosage is one drop in each eye once or twice a day, depending on the drug used. An example of this product is BETOPTIC S.RTM. (betaxolol HCl) ophthalmic suspension 0.25% (Alcon Laboratories, Inc., Fort Worth, Tex.).

[0065] Inhibitors of acetylcholinesterase preserve acetylcholine at the receptor site by blocking the enzyme responsible for its hydrolysis, acetylcholinesterase. Acetylcholine accumulates at the receptor, producing a reduction in intraocular pressure by contraction of the ciliary muscle, similar to the action of direct-acting cholinergic agonists.

[0066] Na.sup.+/K.sup.+-ATPase inhibitors such as ouabain, nitric oxide donors, and endothelin decrease the activity of Na.sup.+/K.sup.+-ATPase, the driving force for aqueous humour formation by the ciliary process.

[0067] Chloride transport inhibitors such as ethacrynic acid alter trabecular meshwork cell volume to increase outflow facility.

[0068] Nucleic acid sequences cited herein are written in a 5' to 3' direction unless indicated otherwise. The term "nucleic acid," as used herein, refers to either DNA or RNA or a modified form thereof comprising the purine or pyrimidine bases present in DNA (adenine "A," cytosine "C," guanine "G," thymine "T") or in RNA (adenine "A," cytosine "C," guanine "G," uracil "U"). Interfering RNAs provided herein may comprise "T" bases, particularly at 3' ends, even though "T" bases do not naturally occur in RNA. "Nucleic acid" includes the terms "oligonucleotide" and "polynucleotide" and can refer to a single-stranded molecule or a double-stranded molecule. A double-stranded molecule is formed by Watson-Crick base pairing between A and T bases, C and G bases, and between A and U bases. The strands of a double-stranded molecule may have partial, substantial or full complementarity to each other and will form a duplex hybrid, the strength of bonding of which is dependent upon the nature and degree of complementarity of the sequence of bases.

[0069] An mRNA sequence is readily deduced from the sequence of the corresponding DNA sequence. For example, SEQ ID NO:1 provides the sense strand sequence of DNA corresponding to the mRNA for carbonic anhydrase II. The mRNA sequence is identical to the DNA sense strand sequence with the "T" bases replaced with "U" bases.

[0070] Therefore, the mRNA sequence of carbonic anhydrase II is known from SEQ ID NO:1, the mRNA sequence of carbonic anhydrase IV is known from SEQ ID NO:2, the mRNA sequence of .beta.1-adrenergic receptor is known from SEQ ID NO:3, the mRNA sequence of .beta.2-adrenergic receptor is known from SEQ ID NO:4, the mRNA sequence of acetylcholinesterase splice variant E4-E5 is known from SEQ ID NO:5, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .alpha.2 is known from SEQ ID NO:6, the mRNA sequence of Na--K-2Cl cotransporter A1 is known from SEQ ID NO:7, the mRNA sequence of carbonic anhydrase XII, variant 1 is known from SEQ ID NO:101, the mRNA sequence of acetylcholinesterase splice variant E4-E6 is known from SEQ ID. NO:123, the mRNA sequence of Na.sup.+/K.sup.+-ATPase al, variant 1, is known from SEQ ID NO:124, the mRNA sequence of Na.sup.+/K.sup.+-ATPase al, variant 2, is known from SEQ ID NO:125, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .alpha.3 is known from SEQ ID NO:126, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .alpha.4, variant 1, is known from SEQ ID NO:127, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .alpha.4, variant 2, is known from SEQ ID NO:128, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .beta.1, variant 1, is known from SEQ ID NO:129, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .beta.1, variant 2, is known from SEQ ID NO:130, the mRNA sequence of Na.sup.+/K.sup.+-ATPase p2, is known from SEQ ID NO:131, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .beta.3 is known from SEQ ID NO:132, the mRNA sequence of Na--K-2Cl cotransporter A2 is known from SEQ ID NO:133, and the mRNA sequence of carbonic anhydrase XII, variant 2, is known from SEQ ID NO:134.

[0071] Carbonic anhydrases II, IV, and XII mRNA (CA2, CA4, and CA12): Carbonic anhydrases (CAs) II, IV and XII are members of a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide as described by the GenBank database of the National Center for Biotechnology Information at ncbi.nlm.nih.gov. Carbonic anhydrases are involved in crucial physiological processes such as respiration and transport of CO.sub.2/bicarbonate between metabolizing tissues and the lungs, pH and CO.sub.2 homeostasis, electrolyte secretion in a variety of tissues and organs, biosynthetic reactions (such as gluconeogenesis, lipogenesis and ureagenesis), bone resorption, calcification, and tumorigenicity.

[0072] Fourteen different carbonic anhydrase isozymes have been identified with different subcellular localizations and tissue distributions. Carbonic anhydrase II is a cytosolic isozyme, whereas carbonic anhydrases IV and XII are membrane-bound. Two transcript variants encoding different isoforms have been identified for the CA-XII gene; variant 1 encodes the longer isoform while variant 2 is lacking one of the internal coding exons compared to transcript variant 1 thereby missing an 11 amino acid segment compared to isoform 1. Systemic carbonic anhydrase inhibitors (CAIs) are useful in reducing the elevated intraocular pressure (IOP) that is characteristic of glaucoma. Inhibition of the isozymes present in the ciliary process (the sulfonamide susceptible isozymes CA II and CA IV) reduces the rate of bicarbonate and aqueous humor secretion, which leads to a 25-30% decrease in IOP. However, inhibition of various CA isozymes present in extraocular tissues leads to side effects including numbness and tingling of extremities, metallic taste, depression, fatigue, malaise, weight loss, decreased libido, gastrointestinal irritation, metabolic acidosis, renal calculi, and transient myopia.

[0073] The GenBank database provides the DNA sequence for CA2 as accession no. NM.sub.--000067, provided in the "Sequence Listing" as SEQ ID NO:1. SEQ ID NO:1 provides the sense strand sequence of DNA that corresponds to the mRNA encoding CAII (with the exception of "T" bases for "U" bases). The coding sequence for CAII is from nucleotides 66-848.

[0074] Equivalents of the above cited CA2 mRNA sequence are alternative splice forms, allelic forms, isozymes, or a cognate thereof. A cognate is a CA2 mRNA from another mammalian species that is homologous to SEQ ID NO:1 (i.e., an ortholog). CA2 nucleic acid sequences related to SEQ ID NO:1 include those having GenBank accession numbers M77181, X03251, BC011949, BC035424, CR536526, CR541875, J03037, M36532, S69526, and Y00339.

[0075] The GenBank database provides the DNA sequence for CA4 as accession no. NM.sub.--000717, provided in the "Sequence Listing" as SEQ ID NO:2. SEQ ID NO:2 provides the sense strand sequence of DNA that corresponds to the mRNA encoding CAIV (with the exception of "T" bases for "U" bases). The coding sequence for CAIV is from nucleotides 47-985.

[0076] Equivalents of the above cited CA4 mRNA sequence are alternative splice forms, allelic forms, isozymes, or a cognate thereof. A cognate is a CA4 mRNA from another mammalian species that is homologous to SEQ ID NO:2 (i.e., an ortholog). CA4 nucleic acid sequences related to SEQ ID NO:2 include those having GenBank accession numbers L10955, BC057792, BC069649, BC074768, CR541766, and M83670.

[0077] The GenBank database provides the DNA sequence for CA12, variant 1, as accession no. NM.sub.--001218, provided in the "Sequence Listing" as SEQ ID NO:101. SEQ ID NO:101 provides the sense strand sequence of DNA that corresponds to the mRNA encoding CAXII, variant 1 (with the exception of "T" bases for "U" bases). The coding sequence for CAXII, variant 1, is from nucleotides 157-1221.

[0078] Equivalents of the above cited CA12, variant 1 mRNA sequence are alternative splice forms, allelic forms, isozymes, or a cognate thereof. A cognate is a CA12 mRNA from another mammalian species that is homologous to SEQ ID NO:101 (i.e., an ortholog).

[0079] The GenBank database provides the DNA sequence for CA12, variant 2, as accession no. NM.sub.--206925, provided in the "Sequence Listing" as SEQ ID NO:134. SEQ ID NO:134 provides the sense strand sequence of DNA that corresponds to the mRNA encoding CAXII, variant 2 (with the exception of "T" bases for "U" bases). The coding sequence for CAXII, variant 2, is from nucleotides 157-1188. Variant 2 lacks an internal coding exon compared to variant 1.

[0080] Equivalents of the above cited CA12, variant 2 mRNA sequence are alternative splice forms, allelic forms, isozymes, or a cognate thereof. A cognate is a CA12 mRNA from another mammalian species that is homologous to SEQ ID NO:134 (i.e., an ortholog).

[0081] Adrenergic Receptors-.beta.1 and .beta.2 mRNA (ADRB1 and ADRB2): The adrenergic receptors (subtypes .alpha.1, .alpha.2, .beta.1, and .beta.2) are a prototypic family of G protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine as described by the GenBank database of the National Center for Biotechnology Information at ncbi.nlm.nih.gov.

[0082] The GenBank database provides the DNA sequence for ADRB1 as accession no. NM.sub.--000684, provided in the "Sequence Listing" as SEQ ID NO:3. SEQ ID NO:3 provides the sense strand sequence of DNA that corresponds to the mRNA encoding .beta.1-adrenergic receptor (with the exception of "T" bases for "U" bases). The coding sequence for .beta.1-adrenergic receptor is from nucleotides 87-1520.

[0083] Equivalents of the above cited ADRB1 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ADRB1 mRNA from another mammalian species that is homologous to SEQ ID NO:3 (i.e., an ortholog). ADRB1 nucleic acid sequences related to SEQ ID NO:3 include those having GenBank accession numbers AF169006, AF169007, AY567837, and J03019.

[0084] The GenBank database provides the DNA sequence for ADRB2 as accession no. NM.sub.--000024, provided below as SEQ ID NO:4. SEQ ID NO:4 provides the sense strand sequence of DNA that corresponds to the mRNA encoding .beta.2-adrenergic receptor (with the exception of "T" bases for "U" bases). The coding sequence for .beta.2-adrenergic receptor is from nucleotides 220-1461.

[0085] Equivalents of the above cited ADRB2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ADRB2 mRNA from another mammalian species that is homologous to SEQ ID NO:4 (i.e., an ortholog). ADRB2 nucleic acid sequences related to SEQ ID NO:4 include those having GenBank accession numbers AF022953, AF022954, AF022955, AF022956, AF169225, AF202305, AF203386, AY011291, J02960, Y00106, AY136741, BC012481, BC063486, BC073856, M15169, and X04827.

[0086] Acetylcholinesterase mRNA splice variants E4-E6 and E4-E5 (ACHE): As described by the GenBank database of the National Center for Biotechnology Information at ncbi.nlm.nih.gov, acetylcholinesterase hydrolyzes the neurotransmitter acetylcholine at neuromuscular junctions and brain cholinergic synapses, and thus terminates signal transmission. It is also found on red blood cell membranes, where it constitutes the Yt blood group antigen. Acetylcholinesterase exists in multiple molecular forms which possess similar catalytic properties, but differ in their oligomeric assembly and mode of cell attachment to the cell surface. It is encoded by the single ACHE gene, and the structural diversity in the gene products arises from alternative mRNA splicing, and post-translational associations of catalytic and structural subunits. The major form of acetylcholinesterase found in brain, muscle and other tissues is the hydrophilic species, which forms disulfide-linked oligomers with collagenous, or lipid-containing structural subunits. The other, alternatively spliced form, expressed primarily in the erythroid tissues, differs at the C-terminal end, and contains a cleavable hydrophobic peptide with a GPI-anchor site. It associates with the membranes through the phosphoinositide (PI) moieties added post-translationally. The splice variant E4-E6 is the major transcript and results from the splicing of exon 4 to exon 6. The splice variant E4-E5 results from alternative splicing of exon 4 to exon 5.

[0087] The GenBank database provides the DNA sequence for ACHE splice variant E4-E5 as accession no. NM.sub.--015831, provided in the "Sequence Listing" as SEQ ID NO:5. SEQ ID NO:5 provides the sense strand sequence of DNA that corresponds to the mRNA encoding acetylcholinesterase E4-E5 (with the exception of "T" bases for "U" bases). The coding sequence for acetylcholinesterase E4-E5 is from nucleotides 95-1948.

[0088] Equivalents of the above cited ACHE mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ACHE mRNA from another mammalian species that is homologous to SEQ ID NO:5 (i.e., an ortholog). ACHE nucleic acid sequences related to SEQ ID NO:5 include those having GenBank accession numbers AC011895, AF002993, AF312032, AY750146, CH236956, L06484, L42812, S71129, AF334270, BC026315, BC036813, M55040 and NM.sub.--000665.

[0089] The GenBank database provides the DNA sequence for ACHE splice variant E4-E6 as accession no. NM.sub.--000665, provided in the "Sequence Listing" as SEQ ID NO:123. SEQ ID NO:123 provides the sense strand sequence of DNA that corresponds to the mRNA encoding acetylcholinesterase E4-E6 variant (with the exception of "T" bases for "U" bases). The coding sequence for acetylcholinesterase E4-E6 is from nucleotides 95-1939.

[0090] Equivalents of the above cited ACHE mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ACHE mRNA from another mammalian species that is homologous to SEQ ID NO:123 (i.e., an ortholog). ACHE nucleic acid sequences related to SEQ ID NO:123 include those having GenBank accession numbers NM.sub.--015831, AC011895, AF002993, AF312032, AY750146, CH236956, L06484, L42812, S71129, AF334270, BC026315, BC036813, and M55040.

[0091] Na.sup.+/K.sup.+-ATPase a and .beta. mRNA (ATP1-A1 variant 1, -A1 variant 2, -A2, -A3, -A4 variant 1, -A4 variant 2, -B1 variant 1, -B1 variant 2, -B2, and -B3): As described by the GenBank database, the proteins encoded by these genes belong to the family of P-type cation transport ATPases, and to the subfamily of Na.sup.+/K.sup.+-ATPases. Na.sup.+/K.sup.+-ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (a or A) and a smaller glycoprotein subunit (.beta. or B). The catalytic subunit of Na.sup.+/K.sup.+-ATPase is encoded by multiple genes.

[0092] The GenBank database provides the DNA sequence for ATP1A1 variant 1 as accession no. NM.sub.--000701, provided in the "Sequence Listing" as SEQ ID NO:124. SEQ ID NO:124 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase subunit A1 variant 1 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase subunit A1 variant 1 is from nucleotides 299-3370.

[0093] Equivalents of the above cited ATP1A1 variant 1 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A1 variant 1 mRNA from another mammalian species that is homologous to SEQ ID NO:124 (i.e., an ortholog).

[0094] The GenBank database provides the DNA sequence for ATP1A1 variant 2 as accession no. NM.sub.--001001586, provided in the "Sequence Listing" as SEQ ID NO:125. SEQ ID NO:125 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase subunit A1 variant 2 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase subunit A1 variant 2 is from nucleotides 299-2344.

[0095] Equivalents of the above cited ATP1A1 variant 2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A1 variant 2 mRNA from another mammalian species that is homologous to SEQ ID NO:125 (i.e., an ortholog).

[0096] The GenBank database provides the DNA sequence for ATP1A2 as accession no. NM.sub.--000702, provided in the "Sequence Listing" as SEQ ID NO:6. SEQ ID NO:6 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase A2 subunit (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase A2 subunit is from nucleotides 105-3167.

[0097] Equivalents of the above cited ATP1A2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A2 mRNA from another mammalian species that is homologous to SEQ ID NO:6 (i.e., an ortholog). ATP1A2 nucleic acid sequences related to SEQ ID NO:6 include those having GenBank accession numbers J05096, M27578, AB018321, AK091617, AK124581, AK126573, AL831991, AL831997, BC013680, BC047533, BC052271, M16795, and Y07494.

[0098] The GenBank database provides the DNA sequence for ATP1A3 as accession no. NM.sub.--152296, provided in the "Sequence Listing" as SEQ ID NO:126. SEQ ID NO:126 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase A3 subunit (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase A3 subunit is from nucleotides 155-3196.

[0099] Equivalents of the above cited ATP1A3 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A3 mRNA from another mammalian species that is homologous to SEQ ID NO:126 (i.e., an ortholog).

[0100] The GenBank database provides the DNA sequence for ATP1A4 variant 1 as accession no. NM.sub.--144699, provided in the "Sequence Listing" as SEQ ID NO:127. SEQ ID NO:127 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase A4 subunit variant 1 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase A4 subunit variant 1 is from nucleotides 469-3558.

[0101] Equivalents of the above cited ATP1A4 variant 1 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A4 variant 1 mRNA from another mammalian species that is homologous to SEQ ID NO:127 (i.e., an ortholog).

[0102] The GenBank database provides the DNA sequence for ATP1A4 variant 2 as accession no. NM.sub.--001001734, provided in the "Sequence Listing" as SEQ ID NO:128. SEQ ID NO:128 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase A4 subunit variant 2 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase A4 subunit variant 2 is from nucleotides 111-608.

[0103] Equivalents of the above cited ATP1A4 variant 2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1A4 variant 2 mRNA from another mammalian species that is homologous to SEQ ID NO:128 (i.e., an ortholog).

[0104] The GenBank database provides the DNA sequence for ATP1B1 variant 1 as accession no. NM.sub.--001677, provided in the "Sequence Listing" as SEQ ID NO:129. SEQ ID NO:129 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase B1 subunit variant 1 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase B1 subunit variant 1 is from nucleotides 122-1033.

[0105] Equivalents of the above cited ATP1B1 variant 1 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1B1 variant 1 mRNA from another mammalian species that is homologous to SEQ ID NO:129 (i.e., an ortholog).

[0106] The GenBank database provides the DNA sequence for ATP1B1 variant 2 as accession no. NM.sub.--001001787, provided in the "Sequence Listing" as SEQ ID NO:130. SEQ ID NO:130 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase B1 subunit variant 2 (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase B1 subunit variant 2 is from nucleotides 122-1027.

[0107] Equivalents of the above cited ATP1B1 variant 2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1B1 variant 2 mRNA from another mammalian species that is homologous to SEQ ID NO:130 (i.e., an ortholog).

[0108] The GenBank database provides the DNA sequence for ATP1B2 as accession no. NM.sub.--001678, provided in the "Sequence Listing" as SEQ ID NO:131. SEQ ID NO:131 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase B2 subunit (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase B2 subunit is from nucleotides 584-1456.

[0109] Equivalents of the above cited ATP1B2 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1B2 mRNA from another mammalian species that is homologous to SEQ ID NO:131 (i.e., an ortholog).

[0110] The GenBank database provides the DNA sequence for ATP1B3 as accession no. NM.sub.--001679, provided in the "Sequence Listing" as SEQ ID NO:132. SEQ ID NO:132 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na.sup.+/K.sup.+-ATPase B3 subunit (with the exception of "T" bases for "U" bases). The coding sequence for Na.sup.+/K.sup.+-ATPase B3 subunit is from nucleotides 175-1014.

[0111] Equivalents of the above cited ATP1B3 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is an ATP1B3 mRNA from another mammalian species that is homologous to SEQ ID NO:132 (i.e., an ortholog).

[0112] Na--K-2Cl cotransporter mRNA (SLC12A1 and SLC12A2): The sodium-potassium-chloride cotransporter (Na--K-2Cl cotransporter or NKCC) facilitates the coupled cotransport of Na.sup.+, K.sup.+, and Cl. ions across the plasma membrane. There are two isoforms: NKCC1 and NKCC2. NKCC1 is expressed in most tissues, including the eye. In contrast, NKCC2 is expressed primarily in the kidney, however, there is evidence for lower level expression of this isoform in the eye as well. NKCC1 is encoded by the SLC12A2 gene (solute carrier family 12, member 2) and NKCC2 is encoded by the SLC12A1 gene. Trabecular meshwork cells possess a robust Na--K-2Cl cotransporter. The activity of this cotransporter is modulated by neurotransmitters and hormones such as norepinephrine, which reduces cotransport activity, or vasopressin, which increases cotransport activity.

[0113] The GenBank database provides the DNA sequence for SLC12A1 as accession no. NM.sub.--000338, provided in the "Sequence Listing" as SEQ ID NO:7. SEQ ID NO:7 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na--K-2Cl cotransporter NKCC2 (with the exception of "T" bases for "U" bases). The coding sequence for Na--K-2Cl cotransporter NKCC2 is from nucleotides 20-3319.

[0114] Equivalents of the above cited Na--K-2Cl NKCC2 cotransporter mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is a Na--K-2Cl cotransporter NKCC2 mRNA from another mammalian species that is homologous to SEQ ID NO:7 (i.e., an ortholog). SLC12A1 nucleic acid sequences related to SEQ ID NO:7 include those having GenBank accession numbers AJ005332, AJ005333, AB032525, AB032527, BC040138, BX647067, BX647484, and U58130.

[0115] The GenBank database provides the DNA sequence for SLC12A2 as accession no. NM.sub.--001046, provided in the "Sequence Listing" as SEQ ID NO:133. SEQ ID NO:133 provides the sense strand sequence of DNA that corresponds to the mRNA encoding Na--K-2Cl cotransporter NKCC1 (with the exception of "T" bases for "U" bases). The coding sequence for Na--K-2Cl cotransporter NKCC1 is from nucleotides 165-3803.

[0116] Equivalents of the above cited Na--K-2Cl cotransporter NKCC1 mRNA sequence are alternative splice forms, allelic forms, or a cognate thereof. A cognate is a Na--K-2Cl cotransporter NKCC1 mRNA from another mammalian species that is homologous to SEQ ID NO:133 (i.e., an ortholog).

[0117] Attenuating expression of an mRNA: The phrase, "attenuating expression of an mRNA," as used herein, means administering or expressing an amount of interfering RNA (e.g., an siRNA) to reduce translation of the target mRNA into protein, either through mRNA cleavage or through direct inhibition of translation. The reduction in expression of the target mRNA or the corresponding protein is commonly referred to as "knock-down" and is reported relative to levels present following administration or expression of a non-targeting control RNA (e.g., a non-targeting control siRNA). Knock-down of expression of an amount including and between 50% and 100% is contemplated by embodiments herein. However, it is not necessary that such knock-down levels be achieved for purposes of the present invention. In one embodiment, a single interfering RNA targeting one of the ocular hypertension targets is administered to lower IOP. In other embodiments, two or more interfering RNAs targeting the same ocular hypertension target (e.g., CA2) are administered to lower IOP. In still other embodiments, two or more interfering RNAs targeting multiple hypertension targets (e.g., CA2 and ADRB2) are administered to lower IOP.

[0118] Knock-down is commonly assessed by measuring the mRNA levels using quantitative polymerase chain reaction (qPCR) amplification or by measuring protein levels by western blot or enzyme-linked immunosorbent assay (ELISA). Analyzing the protein level provides an assessment of both mRNA cleavage as well as translation inhibition. Further techniques for measuring knock-down include RNA solution hybridization, nuclease protection, northern hybridization, gene expression monitoring with a microarray, antibody binding, radioimmunoassay, and fluorescence activated cell analysis.

[0119] Inhibition of targets cited herein is also inferred in a human or mammal by observing an improvement in a glaucoma symptom such as improvement in intraocular pressure, improvement in visual field loss, or improvement in optic nerve head changes, for example.

[0120] Interfering RNA of embodiments of the invention appear to act in a catalytic manner for cleavage of target mRNA, i.e., interfering RNA is able to effect inhibition of target mRNA in substoichiometric amounts. As compared to antisense therapies, significantly less interfering RNA is required to provide a therapeutic effect under such cleavage conditions.

[0121] Interfering RNA: In one embodiment of the invention, interfering RNA (e.g., siRNA) has a sense strand and an antisense strand, and the sense and antisense strands comprise a region of at least near-perfect contiguous complementarity of at least 19 nucleotides. In a further embodiment of the invention, the interfering RNA comprises a region of at least 13, 14, 15, 16, 17, or 18 contiguous nucleotides having percentages of sequence complementarity to or, having percentages of sequence identity with, the penultimate 13, 14, 15, 16, 17, or 18 nucleotides, respectively, of the 3' end of the corresponding target sequence within an mRNA.

[0122] The length of each strand of the interfering RNA comprises 19 to 49 nucleotides, and may comprise a length of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 nucleotides.

[0123] The antisense strand of an siRNA is the active guiding agent of the siRNA in that the antisense strand is incorporated into RISC, thus allowing RISC to identify target mRNAs with at least partial complementarity to the antisense siRNA strand for cleavage or translational repression.

[0124] In the present invention, interfering RNA target sequences (e.g., siRNA target sequences) within a target mRNA sequence are selected using available design tools. Interfering RNAs corresponding to these target sequences are then tested by transfection of cells expressing the target mRNA followed by assessment of knockdown as described above. Interfering RNAs that produce a knockdown in expression of between 50% and 100% are selected for further analysis.

[0125] Techniques for selecting target sequences for siRNAs are provided by Tuschl, T. et al., "The siRNA User Guide," revised May 6, 2004, available on the Rockefeller University web site; by Technical Bulletin #506, "siRNA Design Guidelines," Ambion Inc. at Ambion's web site; and by other web-based design tools at, for example, the Invitrogen, Dharmacon, Integrated DNA Technologies, Genscript, or Proligo web sites. Initial search parameters can include G/C contents between 35% and 55% and siRNA lengths between 19 and 27 nucleotides. The target sequence may be located in the coding region or in the 5' or 3' untranslated regions of the mRNA.

[0126] An embodiment of a 19-nucleotide DNA target sequence for carbonic anyhdrase II is present at nucleotides 232 to 250 of SEQ ID NO:1:

[0127] 5'-CCCTGAGGATCCTCAACAA-3' SEQ ID NO:8.

[0128] An siRNA of the invention for targeting a corresponding mRNA sequence of SEQ ID NO:8 and having 21-nucleotide strands and a 2-nucleotide 3' overhang is: TABLE-US-00001 5'-CCCUGAGGAUCCUCAACAANN-3' SEQ ID NO:9 3'-NNGGGACUCCUAGGAGUUGUU-5'. SEQ ID NO:10

Each "N" residue can be any nucleotide (A, C, G, U, T) or modified nucleotide. The 3' end can have a number of "N" residues between and including 1, 2, 3, 4, 5, and 6. The "N" residues on either strand can be the same residue (e.g., UU, AA, CC, GG, or TT) or they can be different (e.g., AC, AG, AU, CA, CG, CU, GA, GC, GU, UA, UC, or UG). The 3' overhangs can be the same or they can be different. In one embodiment, both strands have a 3'UU overhang.

[0129] An siRNA of the invention for targeting a corresponding mRNA sequence of SEQ ID NO:8 and having 21-nucleotide strands and a 3'UU overhang on each strand is: TABLE-US-00002 5'-CCCUGAGGAUCCUCAACAAUU-3' SEQ ID NO:11 3'-UUGGGACUCCUAGGAGUUGUU-5'. SEQ ID NO:12

[0130] The interfering RNA may also have a 5' overhang of nucleotides or it may have blunt ends. An siRNA of the invention for targeting a corresponding mRNA sequence of SEQ ID NO:8 and having 19-nucleotide strands and blunt ends is: TABLE-US-00003 5'-CCCUGAGGAUCCUCAACAA-3' SEQ ID NO:722 3'-GGGACUCCUAGGAGUUGUU-5'. SEQ ID NO:723

[0131] The strands of a double-stranded interfering RNA (e.g., an siRNA) may be connected to form a hairpin or stem-loop structure (e.g., an shRNA). An shRNA of the invention targeting a corresponding mRNA sequence of SEQ ID NO:8 and having a 19 bp double-stranded stem region and a 3'UU overhang is: TABLE-US-00004 NNN / \ 5'-CCCUGAGGAUCCUCAACAA N 3'-UUGGGACUCCUAGGAGUUGUU N SEQ ID NO:13 \ \ NNN.

[0132] N is a nucleotide A, T, C, G, U, or a modified form known by one of ordinary skill in the art. The number of nucleotides N in the loop is a number between and including 3 to 23, or 5 to 15, or 7 to 13, or 4 to 9, or 9 to 11, or the number of nucleotides N is 9. Some of the nucleotides in the loop can be involved in base-pair interactions with other nucleotides in the loop. Examples of oligonucleotide sequences that can be used to form the loop include 5'-UUCAAGAGA-3' (Brummelkamp, T. R. et al. (2002) Science 296: 550) and 5'-UUUGUGUAG-3' (Castanotto, D. et al. (2002) RNA 8:1454). It will be recognized by one of skill in the art that the resulting single chain oligonucleotide forms a stem-loop or hairpin structure comprising a double-stranded region capable of interacting with the RNAi machinery.

[0133] The siRNA target sequence identified above can be extended at the 3' end to facilitate the design of dicer-substrate 27-mer duplexes. Extension of the 19-nucleotide DNA target sequence (SEQ ID NO:8) identified in the carbonic anhydrase II DNA sequence (SEQ ID NO:1) by 6 nucleotides yields a 25-nucleotide DNA target sequence present at nucleotides 232 to 256 of SEQ ID NO:1:

[0134] 5'-CCCTGAGGATCCTCAACAATGGTCA-3' SEQ ID NO:724.

[0135] A dicer-substrate 27-mer duplex of the invention for targeting a corresponding mRNA sequence of SEQ ID NO:724 is: TABLE-US-00005 5'-CCCUGAGGAUCCUCAACAAUGGUCA-3' SEQ ID NO:718 3'-UUGGGACUCCUAGGAGUUGUUACCAGU-5'. SEQ ID NO:719

The two nucleotides at the 3' end of the sense strand (i.e., the CA nucleotides of SEQ ID NO:718) may be deoxynucleotides for enhanced processing. Design of dicer-substrate 27-mer duplexes from 19-21 nucleotide target sequences, such as provided herein, is further discussed by the Integrated DNA Technologies (IDT) website and by Kim, D.-H. et al., (February, 2005) Nature Biotechnology 23:2; 222-226.

[0136] When interfering RNAs are produced by chemical synthesis, phosphorylation at the 5' position of the nucleotide at the 5' end of one or both strands (when present) can enhance siRNA efficacy and specificity of the bound RISC complex but is not required since phosphorylation can occur intracellularly.

[0137] Table 1 lists examples of siRNA target sequences within the CA2, CA4, and CA12 variant 1 and variant 2 DNA sequences (SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:101, and SEQ ID NO:134, respectively) from which siRNAs of the present invention are designed in a manner as set forth above. CA2, CA4, and CA12 variant 1 and variant 2 encode carbonic anhydrase II, IV, and XII variant 1 and 2, respectively. TABLE-US-00006 TABLE 1 CA2, CA4, and CA12 Target Sequences for siRNAs # of Starting Nucleotide with SEQ reference to ID CA2 Target Sequence SEQ ID NO:1 NO: CCCTGAGGATCCTCAACAA 232 8 GGGCCTTCAGAAAGTTGTT 527 14 GCGAGCAGGTGTTGAAATT 721 15 GGTGTTGAAATTCCGTAAA 728 16 GCCACTGAAGAACAGGCAA 809 17 CCACTGAAGAACAGGCAAA 810 18 CCCATAGTCTGTATCCAAA 855 19 CCATAGTCTGTATCCAAAT 856 20 GGTGATTTGGACCCTGGTT 921 21 GGGTGATGAGCACTCACAA 1139 22 GAAGGTTGGCAGCGCTAAA 506 83 ATGTGCTGGATTCCATTAA 547 84 TGTGCTGGATTCCATTAAA 548 85 CCGTAAACTTAACTTCAAT 740 86 GATCTACCTTGGTGATTTG 911 87 GACCAATTGTCATGCTTGA 1009 88 GGTGATGAGCACTCACAAT 1140 89 CACTCACAATTGTTGACTA 1149 90 ACTCACAATTGTTGACTAA 1150 91 CTCACAATTGTTGACTAAA 1151 92 AGGAAAGTAGAATGGTTGA 1188 93 GTAGAATGGTTGAGTGCAA 1194 94 TAGAATGGTTGAGTGCAAA 1195 95 CAAGATAAATTGAGCTAGT 1223 96 AGTTAAGGCAAATCAGGTA 1239 97 GAGTTGTGATACAGAGTAT 1456 98 AGTTGTGATACAGAGTATA 1457 99 GTTGTGATACAGAGTATAT 1458 100 GACCTGAGCACTGGCATAA 100 135 TGACATCGACACTCATACA 158 136 ACACTCATACAGCCAAGTA 166 137 ACAATGGTCATGCTTTCAA 247 138 AGGACAAAGCAGTGCTCAA 286 139 GATGGCACTTACAGATTGA 318 140 GCACTTACAGATTGATTCA 322 141 ACAGATTGATTCAGTTTCA 328 142 ACAAGGTTCAGAGCATACT 371 143 CAGAACTTCACTTGGTTCA 412 144 ACTGGCCGTTCTAGGTATT 482 145 TTGAAGGTTGGCAGCGCTA 504 146 TGAAGGTTGGCAGCGCTAA 505 147 TTGTTGATGTGCTGGATTC 541 148 GAAATTCCGTAAACTTAAC 734 149 CCGAAGAACTGATGGTGGA 772 150 GAACTGATGGTGGACAACT 777 151 TGAAGAACAGGCAAATCAA 814 152 CTTACTTGATAGACTTACT 972 153 TGTGAAGACTAGACCAATT 998 154 TTGAGCTAGTTAAGGCAAA 1232 155 GGATGGCACTTACAGATTG 317 720 GAAATATGCTGCAGAACTT 401 721 # of Starting Nucleotide with SEQ reference to ID CA4 Target Sequence SEQ ID NO:2 NO: TCGTCACCACCAAGGCAAA 213 23 GCTTCTTCTTCTCTGGCTA 252 24 TCTTCTCTGGCTACGATAA 258 25 GGCTACGATAAGAAGCAAA 266 26 GGTCCGACTTGCCATATAA 399 27 GGAGATGCACATAGTACAT 457 28 GCACATAGTACATGAGAAA 463 29 GACATCGAGGAATGTGAAA 490 30 GGTGGAGGCACTGTCTAAT 595 31 GGGACTTTAGGCATGATTA 1064 32 ACACTGGTGCTACGAGGTT 109 156 CTGGTGCTACGAGGTTCAA 112 157 GTTCAAGCCGAGTCCTCCA 125 158 TTCAAGCCGAGTCCTCCAA 126 159 CCTGCTTGGTGCCAGTCAA 150 160 TCTCTGGCTACGATAAGAA 261 161 TGGCTACGATAAGAAGCAA 265 162 GCAAACGTGGACTGTCCAA 280 163 TGGTCCGACTTGCCATATA 398 164 CCATGGAGATGCACATAGT 453 165 AGATGCACATAGTACATGA 459 166 TGCACATAGTACATGAGAA 462 167 ATAGTACATGAGAAAGAGA 467 168 CATCGAGGAATGTGAAAGA 492 169 TTGCGGTGCTGGCCTTTCT 534 170 GAACAGATCCTGGCATTCT 785 171 TCTCTCAGAAGCTGTACTA 801 172 AGGAACAGACAGTGAGCAT 825 173 GAACAGACAGTGAGCATGA 827 174 GGCAGCGCACGGTGATAAA 876 175 CAGCCTCTCTGTTGCCTCA 1003 176 TGTTGCCTCAGCTCTCCAA 1012 177 # of Starting CA12, variant 1 Nucleotide with SEQ and 2 Common reference to ID Target Sequences SEQ ID NO:101 NO: TCCTGCTGGTGATCTTAAA 191 102 ACGGTTCCAAGTGGACTTA 239 103 GAGAATAGCTGGTCCAAGA 274 104 AGAATAGCTGGTCCAAGAA 275 105 GTGACATCCTCCAGTATGA 341 106 GCTACAATCTGTCTGCCAA 389 107 CAGTTTCTCCTGACCAACA 412 108 AGTTTCTCCTGACCAACAA 413 109 GACCAACAATGGCCATTCA 423 110 CTCCTTCAATCCGTCCTAT 687 111 CCTTCAATCCGTCCTATGA 689 112 ATCCGTCCTATGACAAGAT 695 113 AGATCTTCAGTCACCTTCA 710 114 CGGAGAGGACCGCTGAATA 791 115 GGAGAGGACCGCTGAATAT 792 116 AGAGGACCGCTGAATATTA 794 117 AGGTCCAGAAGTTCGATGA 983 118 GTTCGATGAGAGGCTGGTA 993 119 TTCGATGAGAGGCTGGTAT 994 120 TCGATGAGAGGCTGGTATA 995 121 TTCAATCCGTCCTATGACA 691 178 # of Starting CA12, Nucleotide with SEQ variant 1 Target reference to ID Sequence SEQ ID NO:101 NO: TGTACTGCGGCAGGACTGA 1039 122 AGAGCGTGCTTTCAAGTGT 1568 179 GATGTCAAATCGTGGTTTA 2326 180 AAATCGTGGTTTAGATCAA 2332 181 ATGGAATGCTACTAAGATA 2425 182 CTACTAAGATACTCCATAT 2433 183 ACAACGATGGCAAGCCTTA 2844 184 CAACGATGGCAAGCCTTAT 2845 185 TTGCTAGGCAAAGTTACAA 2880 186 TAGGCAAAGTTACAAGTGA 2884 187 AGTTACAAGTGACCTAATG 2891 188 TGTGCACTCAAGACCTCTA 2954 189 GTGCACTCAAGACCTCTAA 2955 190 TGCACTCAAGACCTCTAAC 2956 191 GCACTCAAGACCTCTAACA 2957 192 AGACCTCTAACAGCCTCGA 2964 193 GACCTCTAACAGCCTCGAA 2965 194 TGCCATTAGCATGCCTCAT 3006 195 GCCATTAGCATGCCTCATG 3007 196 TAGCATGCCTCATGCATCA 3012 197 CATCATCAGATGACAAGGA 3026 198 # of Starting CA12, Nucleotide with SEQ variant 2 Target reference to ID Sequence SEQ ID NO:134 NO: CTCCTTCAATCCGTCCTAT 687 199 AGAGCGTGCTTTCAAGTGT 1535 200 GATGTCAAATCGTGGTTTA 2293 201 AAATCGTGGTTTAGATCAA 2299 202 ATGGAATGCTACTAAGATA 2392 203 CTACTAAGATACTCCATAT 2400 204 ACAACGATGGCAAGCCTTA 2811 205 CAACGATGGCAAGCCTTAT 2812 206 TTGCTAGGCAAAGTTACAA 2847 207 TAGGCAAAGTTACAAGTGA 2851 208 AGTTACAAGTGACCTAATG 2858 209 TGTGCACTCAAGACCTCTA 2921 210 GTGCACTCAAGACCTCTAA 2922 211 TGCACTCAAGACCTCTAAC 2923 212 GCACTCAAGACCTCTAACA 2924 213 AGACCTCTAACAGCCTCGA 2931 214 GACCTCTAACAGCCTCGAA 2932 215 TGCCATTAGCATGCCTCAT 2973 216 GCCATTAGCATGCCTCATG 2974 217 TAGCATGCCTCATGCATCA 2979 218 CATCATCAGATGACAAGGA 2993 219

[0138] Table 2 lists examples of siRNA target sequences within the ADRB1 and ADRB2 DNA sequences (SEQ ID NO:3 and SEQ ID NO:4, respectively) from which siRNAs of the present invention are designed in a manner as set forth above. As noted above, ADRB1 and ADRB2 encode the .beta.1- and .beta.2-adrenergic receptors, respectively. TABLE-US-00007 TABLE 2 ADRE1 and ADRE2 Target Sequences for siRNAs # of Starting Nucleotide with SEQ reference to ID ADRE1 Target Sequence SEQ ID NO:3 NO: TCCTTCTTCTGCGAGCTGT 468 33 TCGAGACCCTGTGTGTCAT 523 34 GCATCATGGCCTTCGTGTA 799 35 GAACGAGGAGATCTGTGTT 1563 36 ACGAGGAGATCTGTGTTTA 1565 37 GGAGATCTGTGTTTACTTA 1569 38 GATAGCAGGTGAACTCGAA 1593 39 CCCACAATCCTCGTCTGAA 1613 40 CCACAATCCTCGTCTGAAT 1614 41 TCTGAATCATCCGAGGCAA 1626 42 GCAATGTGCTGGTGATCGT 310 220 TGATCGTGGCCATCGCCAA 322 221 AAGTGCTGCGACTTCGTCA 726 222 CGTCCGTAGTCTCCTTCTA 769 223 CCGTAGTCTCCTTCTACGT 772 224 ATCATGGCCTTCGTGTACC 801 225 TCATGGCCTTCGTGTACCT 802 226 CCTCGGAATCCAAGGTGTA 1501 227 TGTGTTTACTTAAGACCGA 1576 228 GTGTTTACTTAAGACCGAT 1577 229 GTTTACTTAAGACCGATAG 1579 230 TTTACTTAAGACCGATAGC 1580 231 TTACTTAAGACCGATAGCA 1581 232 TAAGACCGATAGCAGGTGA 1586 233 ACCGATAGCAGGTGAACTC 1590 234 CGATAGCAGGTGAACTCGA 1592 235 ATAGCAGGTGAACTCGAAG 1594 236 CACAATCCTCGTCTGAATC 1615 237 ACAATCCTCGTCTGAATCA 1616 238 TCATCCGAGGCAAAGAGAA 1632 239 CATCCGAGGCAAAGAGAAA 1633 240 CCACGGACCGTTGCACAAA 1654 241 # of Starting Nucleotide with SEQ reference to ID ADRE2 Target Sequence SEQ ID NO:4 NO: GCATCGTCATGTCTCTCAT 329 43 GCTGGTCATCACAGCCATT 375 44 CCCTCAAGACGTTAGGCAT 1031 45 GCATCATCATGGGCACTTT 1046 46 CCTAAATTGGATAGGCTAT 1149 47 GCTATGTCAATTCTGGTTT 1163 48 GGAAGACTTTGTGGGCCAT 1371 49 GCCTAGCGATAACATTGAT 1401 50 GGGAGGAATTGTAGTACAA 1426 51 GCTGTGAACATGGACTCTT 1880 52 CACGACGTCACGCAGCAAA 283 242 GATCGCTACTTTGCCATTA 607 243 ATCGCTACTTTGCCATTAC 608 244 TCGCTACTTTGCCATTACT 609 245 GCCATTACTTCACCTTTCA 619 246 TTACTTCACCTTTCAAGTA 623 247 CCATTCAGATGCACTGGTA 722 248 TGATCATGGTCTTCGTCTA 857 249 AGACGTTAGGCATCATCAT 1037 250 TCGTTAACATTGTGCATGT 1091 251 AGGATAACCTCATCCGTAA 1115 252 TCATCCGTAAGGAAGTTTA 1124 253 AAGTTTACATCCTCCTAAA 1136 254 AGTTTACATCCTCCTAAAT 1137 255 TAAATTGGATAGGCTATGT 1151 256 CTATGTCAATTCTGGTTTC 1164 257 GGTACTGTGCCTAGCGATA 1393 258 GTACTGTGCCTAGCGATAA 1394 259 TACTGTGCCTAGCGATAAC 1395 260 GCGATAACATTGATTCACA 1406 261 CGATAACATTGATTCACAA 1407 262 GGAGGAATTGTAGTACAAA 1427 263 GAGGAATTGTAGTACAAAT 1428 264 AGGAATTGTAGTACAAATG 1429 265 CAAATGACTCACTGCTGTA 1442 266 GACCTGAGTCTGCTATATT 1725 267 ACCTGAGTCTGCTATATTT 1726 268 CCATGTATCTACCTCACTA 1756 269 CATGTATCTACCTCACTAT 1757 270 ATGTATCTACCTCACTATT 1758 271 CCTCACTATTCAAGTATTA 1767 272 TAATATATTGCTGCTGGTA 1790 273 AATATATTGCTGCTGGTAA 1791 274 ATATATTGCTGCTGGTAAT 1792 275 TATATTGCTGCTGGTAATT 1793 276 CTGGTAATTTGTATCTGAA 1803 277 GAGTATCTCGGACCTTTCA 1861 278 CGGACCTTTCAGCTGTGAA 1869 279 CGAGCAAAGGTCTAAAGTT 1971 280 GAGCAAAGGTCTAAAGTTT 1972 281 GGTCTAAAGTTTACAGTAA 1979 282

[0139] Table 3 lists examples of siRNA target sequences within the ACHE DNA sequences for splice variants E4-E5 and E4-E6 (SEQ ID NO:5 and SEQ ID NO:123, respectively) from which siRNAs of the present invention are designed in a manner as set forth above. As noted above, ACHE encodes acetylcholinesterase. TABLE-US-00008 TABLE 3 ACHE Target Sequences for siRNAs # of Starting Nucleotide with SEQ ACHE E4-E5 reference to ID Target Sequence SEQ ID NO:5 NO: CCAGAGTGTCTGCTACCAA 382 53 GCTACCAATATGTGGACAC 393 54 CCAATATGTGGACACCCTA 397 55 GCTGGTGTCCATGAACTAC 622 56 TCATCAACGCGGGAGACTT 1131 57 GGTCTACGCCTACGTCTTT 1459 58 GCTACGAGATCGAGTTCAT 1530 59 GCTATAACGGTCAACCATT 2251 60 GGCTGCAAATAAACTGTTA 2885 61 GCTGCAAATAAACTGTTAC 2886 62 AGTGTCTGCTACCAATATG 386 283 AGACAACGAGTCTCTCATC 1231 284 GGCTGTGGTCCTGCATTAC 1315 285 CTTCCTCCTCAAACCGAGA 2047 286 TCCTCCTCAAACCGAGAGA 2049 287 CCTCAAACCGAGAGACTCA 2053 288 TCAAACCGAGAGACTCACA 2055 289 AAACCGAGAGACTCACACT 2057 290 CCACGCCTTTGTTGTTTGA 2125 291 CACGCCTTTGTTGTTTGAA 2126 292 ACGCCTTTGTTGTTTGAAT 2127 293 GGCTATAACGGTCAACCAT 2250 294 TATAACGGTCAACCATTTC 2253 295 CGGTCAACCATTTCTGTCT 2258 296 GTCAACCATTTCTGTCTCT 2260 297 CCGTCTTCCGGTCATTCTT 2318 298 CCTCTCGTCTTTCGCACAT 2395 299 TCTCGTCTTTCGCACATTC 2397 300 TTTCGCACATTCTCCTGAT 2404 301 TTCGCACATTCTCCTGATC 2405 302 AGAACCAGTTCGACCACTA 2643 303 AACCAGTTCGACCACTACA 2645 304 CTGCAAATAAACTGTTACA 2887 305 # of Starting ACHE E4-E5 and E4-E6 Nucleotide with SEQ Target Sequences reference to ID in Common SEQ ID NO:5 NO: TAGACGCTACAACCTTCCA 366 306 CGCTACAACCTTCCAGAGT 370 307 AGAGTGTCTGCTACCAATA 384 308 GAGTGTCTGCTACCAATAT 385 309 CTGTCCTCGTCTGGATCTA 525 310 ATGGCCGCTTCTTGGTACA 588 311 CGACATCAGTGACGCTGTT 768 312 GCACGTGCTGCCTCAAGAA 1045 313 CACGTGCTGCCTCAAGAAA 1046 314 GAAAGCGTCTTCCGGTTCT 1061 315 TGTGGTAGATGGAGACTTC 1090 316 GACAACGAGTCTCTCATCA 1232 317 AGGCTGTGGTCCTGCATTA 1314 318 GCTGTGGTCCTGCATTACA 1316 319 GTCTACGCCTACGTCTTTG 1460 320 TCTACGCCTACGTCTTTGA 1461 321 CTACGCCTACGTCTTTGAA 1462 322 CGGCTACGAGATCGAGTTC 1528 323 CAGCGACTGATGCGATACT 1607 324 GGCTCAGCAGTACGTTAGT 1705 325 AGTACGTTAGTCTGGACCT 1713 326 # of Starting Nucleotide with SEQ ACHE E4-E6 Target reference to ID Sequence SEQ ID NO:123 NO: ACATGGTGCACTGGAAGAA 1875 327 AGAACCAGTTCGACCACTA 1890 328 GAACCAGTTCGACCACTAC 1891 329 GGCTATAACACAGACGAGC 2011 330 GCTATAACACAGACGAGCC 2012 331 GCTGCAAATAAACTGTTAC 2133 332 CTGCAAATAAACTGTTACA 2134 333

[0140] Table 4 lists examples of siRNA target sequences within the Na.sup.+/K.sup.+-ATPase A and B subunit DNA sequences (ATP1A1 variant 1, SEQ ID NO:124; ATP1A1 variant 2, SEQ ID NO:125; ATP1A2, SEQ ID NO:6; ATP1A3, SEQ ID NO:126; ATP1A4 variant 1, SEQ ID NO:127; ATP1A4 variant 2, SEQ ID NO:128; ATP1B1 variant 1, SEQ ID NO:129; ATP1B1 variant 2, SEQ ID NO:130; ATP1B2, SEQ ID NO:131; and ATP1B3, SEQ ID NO:132) from which siRNAs of the present invention are designed in a manner as set forth above. TABLE-US-00009 TABLE 4 ATP1A and ATP1B Target Sequences for siRNAs # of Starting Nucleotide with SEQ ATP1A1 variant 1 reference to ID Target Sequence SEQ ID NO:124 NO: GCAATGAGACCGTGGAAGA 2208 334 TGCCAAGQCCTGCGTAGTA 2275 335 TAAAGGACATGACCTCCGA 2307 336 AGCAAGCTGCTGACATGAT 2526 337 ACATGATTCTTCTGGATGA 2538 338 GTCGTCTGATCTTTGATAA 2592 339 CTTATACCTTAACCAGTAA 2628 340 GGATCAACGATGTGGAAGA 2979 341 ACGATGTGGAAGACAGCTA 2985 342 CCGACTTGGTCATCTGTAA 3093 343 TAGGAAAGCACCGCAGCAT 3474 344 AGACGTCCTGGAATGAAGC 3504 345 GACGTCCTGGAATGAAGCA 3505 346 ACGTCCTGGAATGAAGCAT 3506 347 GAAGCATGTAGCTCTATGG 3518 348 # of Starting ATP1A1 variant 1 Nucleotide with SEQ and variant 2 Common reference to ID Target Sequences SEQ ID NO:124 NO: TTCAGAACAAGGTGATAAA 343 349 TGATGAACTTCATCGTAAA 442 350 GGTGCTATCAGCCGTTGTA 700 351 TCAGCCGTTGTAATCATAA 707 352 GATTCGAAATGGTGAGAAA 811 353 CAGAATCATATCTGCAAAT 907 354 CACGTGGTATTGTTGTCTA 1059 355 CTGCTTAGTGAAGAACTTA 1363 356 GTTTCAGGCTAACCAGGAA 1594 357 CACTCTTAAAGTGCATAGA 1662 358 AGTACCAGTTGTCTATTCA 1758 359 TACCAGTTGTCTATTCATA 1760 360 AGCTGAAAGACGCCTTTCA 1896 361 TCGATAATCTGTGCTTTGT 2037 362 ACAGGAGACCATCCAATCA 2147 363 # of Starting Nucleotide with SEQ ATP1A1 variant 2 reference to ID Target Sequence SEQ ID NO:125 NO: TAGCCTTGATGAACTTCAT 436 364 TTGATGAACTTCATCGTAA 441 365 GATGAACTTCATCGTAAAT 443 366 CTACTCCTGAATGGATCAA 552 367 GGAGCGATTCTTTGTTTCT 617 368 GTGCTATCAGCCGTTGTAA 701 369 TGCTATCAGCCGTTGTAAT 702 370 GAGCATAAATGCGGAGGAA 832 371 GAAGGCAATGGACCTATGA 2204 372 CCGACTTGGTCATCTGTAA 2291 373 TATATGACGAAGTCAGAAA 2495 374 # of Starting Nucleotide with SEQ ATP1A2 reference to ID Target Sequence SEQ ID NO:6 NO: CCATCCAACGACAATCTAT 471 63 GCATCATATCAGAGGGTAA 1990 64 CCTCCTCATCTTCATCTAT 3080 65 GGAAGTGAGGTAGTGCCAA 3797 66 GGATGTCACTCATGTACTT 4037 67 GCTCCATGCTGTTCTGAAA 4093 68 GCTGGCCATTGGCTAGAAT 4225 69 GGTCAGAACCTTTGGACAA 4323 70 GCTAGAGGTGGCATGTTTA 5213 71 GCGAGTGCATGGGCTAATT 5285 72 TGGCAATGGATGACCACAA 214 375 TGAACCATCCAACGACAAT 467 376 ACCATCCAACGACAATCTA 470 377 CATCCAACGACAATCTATA 472 378 ATCCAACGACAATCTATAT 473 379 GCAGATCAACGCAGAGGAA 632 380 TGTTTCTTCTCCACCAACT 825 381 CCATAGCAATGGAGATTGA 946 382 AGATGCAAGATGCCTTTCA 1693 383 CTGAATCTGCCATCTGGAA 1767 384 TGAATCTGCCATCTGGAAA 1768 385 ATCGTCTTTGCTCGAACGT 2157 386 CTGCATTGAAGAAGGCTGA 2263 387 ATGAAGCGGCAGCCACGAA 2589 388 TGAAGCGGCAGCCACGAAA 2590 389 GGATGACCGGACCATGAAT 2765 390 GCTGCCTTTCTCTCTTACT 2988 391 TCTATGATGAGGTCCGAAA 3094 392 GTGGAGAAGGAGACATACT 3144 393 TGGAGAAGGAGACATACTA 3145 394 TAGACCTAACTGTGAACAA 3344 395 AGACCTAACTGTGAACAAT 3345 396 TCCACTATGTTGTCTATTT 3418 397 TGAGTGCAAGAGCCTGAGA 3666 398 TGACATGAGTCTCCAGATA 3828 399 GTCGTGGACTCCAGCTCTA 3850 400 TGTCACTCATGTACTTAAT 4040 401 GTCACTCATGTACTTAATA 4041 402 CACTTCACCTTCTGTAATA 4061 403 GTAGAGAGAGACCTAGATA 4882 404 CTAGATAGGTCATGCAAGT 4894 405 AGGTCATGCAAGTGAGAAA 4900 406 TATCAGAAGCAAGGAAGTA 5040 407 TCCGATTAATTGGAGATTA 5114 408 CCGATTAATTGGAGATTAC 5115 409 GATTACTAACTGTGGACAA 5128 410 ATTACTAACTGTGGACAAA 5129 411 TCAGGCACTTTAGAAATAT 5253 412 GGCTAATTATCATCAATCT 5296 413 AGTTTGAGGTACTACCTAT 5375 414 TACTACCTATGTACTTGAA 5384 415 ACTACCTATGTACTTGAAA 5385 416 # of Starting Nucleotide with SEQ ATP1A3 reference to ID Target Sequence SEQ ID NO:126 NO: TGGCTATGACAGAGCACAA 240 417 GAGGTCTGCCGGAAATACA 272 418 CTCACGCCACCGCCTACCA 362 419 TCGACTGTGATGACGTGAA 1836 420 TGAACTTCACCACGGACAA 1851 421 CCAAGGCCTGCGTGATCCA 2103 422 GGACTTCACCTCCGAGCAA 2137 423 GACTTCACCTCCGAGCAAA 2138 424 ACTTCACCTCCGAGCAAAT 2139 425 TCGACGAGATCCTGCAGAA 2157 426 CGACGAGATCCTGCAGAAT 2158 427 ACGAGATCCTGCAGAATCA 2160 428 GATCTTCGACAACCTAAAG 2425 429 CCATCTCACTGGCGTACGA 2580 430 CTGCCGAAAGCGACATCAT 2601 431 CGGACAAATTGGTCAATGA 2646 432 CAAATTGGTCAATGAGAGA 2650 433 GGATGACCGCACCGTCAAT 2794 434 CACCGTCAATGACCTGGAA 2803 435 ATCTTCGTCTACGACGAAA 3116 436 CTACGACGAAATCCGCAAA 3124 437 ACGACGAAATCCGCAAACT 3126 438 ACGAAATCCGCAAACTCAT 3129 439 CCAAACCTCTCTCCTCTCT 3377 440 # of Starting Nucleotide with SEQ ATP1A4 variant 1 reference to ID Target Sequence SEQ ID NO:127 NO: GGCACCTGGTTACGCTTCA 113 441 CATGGATGATCACAAATTA 612 442 AATCCTGACTCGAGATGGA 702 443 CCTACAGCATCCAGATATA 833 444 CCGGCTTATCTCTGCACAA 1101 445 AGCTCTGATACCTGGTTTA 1732 446 GCTCTGATACCTGGTTTAT 1733 447 AGGTGATGCTTCCGAGTCA 1836 448 GTACTCAATGAACGATGAA 2070 449 TACTCAATGAACGATGAAA 2071 450 GTGCTAGGCTTCTGCTTCT 2143 451 CATGGTAACAGGAGATCAT 2328 452 TGTGGTGCATGGTGCAGAA 2475 453 TGTTCATCATCCTCGGTAT 2861 454 GTTCATCATCCTCGGTATA 2862 455 GGCTTATGAGTCAGCTGAA 2952 456 GGACCTATGAGCAACGAAA 3203 457 CGGATCTCATCATCTCCAA 3281 458 TGGCTGCATTTCTGTCCTA 3377 459 GCTGCATTTCTGTCCTACA 3379 460 GTATTCTCATCTTCGTCTA 3470 461 TATTCTCATCTTCGTCTAT 3471 462 ACTAAACTCAGCAGATGAA 3554 463 GGCCAGAGATTATAAGTTT 3614 464 GCCAGAGATTATAAGTTTG 3615 465 CCAGAGATTATAAGTTTGA 3616 466 CAGAGATTATAAGTTTGAC 3617 467 ATAAGTTTGACACAACATC 3625 468 TAAGTTTGACACAACATCT 3626 469 TCTGAGACACTAGGATGAA 3642 470 AGACACTAGGATGAATTAT 3646 471 GACACTAGGATGAATTATC 3647 472 AGGATGAATTATCTTGGAT 3653 473 GATGAATTATCTTGGATGA 3655 474 CGTAGCCAGTCTAGACAGT 3797 475 GCCAGTCTAGACAGTAAAT 3801 476 CAGTCTAGACAGTAAATGT 3803 477 AGACAGTAAATGTCTGGAA 3809 478 GACAGTAAATGTCTGGAAA 3810 479 # of Starting Nucleotide with SEQ ATP1A4 variant 2 reference to ID Target Sequence SEQ ID NO:128 NO: GCTGGATTCTTTACCTACT 126 480 GTGGACCTATGAGCAACGA 251 481 TGGACCTATGAGCAACGAA 252 482 GGACCTATGAGCAACGAAA 253 483 CGGATCTCATCATCTCCAA 331 484 TGGCTGCATTTCTGTCCTA 427 485 GCTGCATTTCTGTCCTACA 429 486 GTATTCTCATCTTCGTCTA 520 487 TATTCTCATCTTCGTCTAT 521 488 CTTCGTCTATGATGAAATC 530 489 ACTACTAAACTCAGCAGAT 601 490 CTACTAAACTCAGCAGATG 602 491 TACTAAACTCAGCAGATGA 603 492 ACTAAACTCAGCAGATGAA 604 493 GGCCAGAGATTATAAGTTT 664 494 GCCAGAGATTATAAGTTTG 665 495 CCAGAGATTATAAGTTTGA 666 496 CAGAGATTATAAGTTTGAC 667 497 ATAAGTTTGACACAACATC 675 498 TAAGTTTGACACAACATCT 676 499 TCTGAGACACTAGGATGAA 692 500 AGACACTAGGATGAATTAT 696 501 GACACTAGGATGAATTATC 697 502 TAGGATGAATTATCTTGGA 702 503 AGGATGAATTATCTTGGAT 703 504 GATGAATTATCTTGGATGA 705 505 TGAATTATCTTGGATGAGA 707 506 CGTAGCCAGTCTAGACAGT 847 507 GCCAGTCTAGACAGTAAAT 851 508 CAGTCTAGACAGTAAATGT 853 509 AGACAGTAAATGTCTGGAA 859 510 GACAGTAAATGTCTGGAAA 860 511 # of Starting Nucleotide with SEQ ATP1B1 variant 1 reference to ID Target Sequence SEQ ID NO:129 NO: ACCTACTAGTCTTGAACAA 1096 512 TACTAGTCTTGAACAAACT 1099 513

GGACCTACACTTAATCTAT 1130 514 GACCTACACTTAATCTATA 1131 515 CTGCATTTAATAGGTTAGA 1167 516 CGTAACTGACTTGTAGTAA 1299 517 AGCAAGGTTTGCTGTCCAA 1441 518 TGCTGTCCAAGGTGTAAAT 1450 519 GCTGTCCAAGGTGTAAATA 1451 520 CTGTCCAAGGTGTAAATAT 1452 521 TTAACATACTCCATAGTCT 1564 522 GCCTTGTCCTCCGGTATGT 1746 523 TGTCCTCCGGTATGTTCTA 1750 524 GTCCTCCGGTATGTTCTAA 1751 525 TCCTCCGGTATGTTCTAAA 1752 526 CCATCACTTTGGCTAGTGA 1795 527 # of Starting ATP1B1 variant 1 and Nucleotide with SEQ variant 2 Common reference to ID Target Sequences SEQ ID NO:129 NO: ACCGGTGGCAGTTGGTTTA 203 528 CCGGTGGCAGTTGGTTTAA 204 529 TTGGTTTAAGATCCTTCTA 214 530 AGATCCTTCTATTCTACGT 222 531 ATCCTTCTATTCTACGTAA 224 532 TCCTTCTATTCTACGTAAT 225 533 CCTTCTATTCTACGTAATA 226 534 GAAATTTCCTTTCGTCCTA 380 535 AACGAGGAGACTTTAATCA 525 536 GAAATTGCTCTGGATTAAA 591 537 ATGAAACTTATGGCTACAA 612 538 TGAAACTTATGGCTACAAA 613 539 AAACTTATGGCTACAAAGA 615 540 GGCAAACCGTGCATTATTA 635 541 GCAAACCGTGCATTATTAT 636 542 ACCGAGTTCTAGGCTTCAA 663 543 CCGAGTTCTAGGCTTCAAA 664 544 TTCTAGGCTTCAAACCTAA 669 545 ATGAGTCCTTGGAGACTTA 699 546 GCAAGCGAGATGAAGATAA 765 547 AGTTGGAAATGTGGAGTAT 790 548 CTGCAGTATTATCCGTACT 839 549 TGCAGTATTATCCGTACTA 840 550 GCAGTATTATCCGTACTAT 841 551 CCGTACAGTTCACCAATCT 900 552 TCACCAATCTTACCATGGA 909 553 AAATTCGCATAGAGTGTAA 933 554 TGTAAGGCGTACGGTGAGA 947 555 # of Starting Nucleotide with SEQ ATP1B1 variant 2 reference to ID Target Sequence SEQ ID NO:130 NO: TGTGTTATGCTTGTATTGA 1063 556 GCCTTGTCCTCCGGTATGT 1102 557 TGTCCTCCGGTATGTTCTA 1106 558 GTCCTCCGGTATGTTCTAA 1107 559 TCCTCCGGTATGTTCTAAA 1108 560 CCTCCGGTATGTTCTAAAG 1109 561 TCCGGTATGTTCTAAAGCT 1111 562 CCATCACTTTGGCTAGTGA 1151 563 # of Starting Nucleotide with SEQ ATP1B2 reference to ID Target Sequence SEQ ID NO:131 NO: CCGAGGACGCACCAGTTTA 653 564 CGAGGACGCACCAGTTTAT 654 565 TGCAGACTGTCTCCGACCA 771 566 CAGACTGTCTCCGACCATA 773 567 CAAGACTGAGAACCTTGAT 841 568 AGAACCTTGATGTCATTGT 849 569 CCTTGATGTCATTGTCAAT 853 570 AAGTTCTTGGAGCCTTACA 917 571 AGTTCTTGGAGCCTTACAA 918 572 GAGCCTTACAACGACTCTA 926 573 AGCCTTACAACGACTCTAT 927 574 TTACAACGACTCTATCCAA 931 575 GCTATTACGAACAGCCAGA 981 576 TATTACGAACAGCCAGATA 983 577 ATTACGAACAGCCAGATAA 984 578 CAGATAATGGAGTCCTCAA 996 579 GATAATGGAGTCCTCAACT 998 580 AAACGTGCCTGCCAATTCA 1022 581 AACGTGCCTGCCAATTCAA 1023 582 AACCAGAGCATGAATGTTA 1160 583 CTCGGCAACTTCGTCATGT 1214 584 AATGTAGAATGTCGCATCA 1355 585 ATGTAGAATGTCGCATCAA 1356 586 CAACATCGCCACAGACGAT 1381 587 GACGATGAGCGAGACAAGT 1394 588 TGGCCTTCAAACTCCGCAT 1425 589 CCATCTCTCTCCTGTGGAT 1474 590 TTTGATAACAGAGCTATGA 1550 591 CCATTGCGGTTCCGTCACT 1620 592 AGGAGTTAGGAGCCTTTCT 1707 593 TGTGAGAGCTATCCACTCT 1740 594 CACTCTCCTGCCTGCATAT 1753 595 CGCCACACACACACACAAA 1825 596 TCTACACAGTCGCCATCTT 1956 597 TCGCCATCTTGGTGACTTT 1965 598 GGTTGACCTAGGCTGAATA 2598 599 GTTGACCTAGGCTGAATAT 2599 600 GGCTGAATATCCACTTTGT 2608 601 AGCAAGTTATCAACTAATC 2828 602 GCAAGTTATCAACTAATCA 2829 603 CCAAATCTAGCCTCTGAAT 2888 604 CTCCTGCTCTGAATATTCT 3012 605 TGTGTCAGATCTACTGTAA 3251 606 # of Starting Nucleotide with SEQ ATP1B3 reference to ID Target Sequence SEQ ID NO:132 NO: TTGCTCTTCTACCTAGTTT 292 607 CAGTGACCGCATTGGAATA 434 608 GACCGCATTGGAATATACA 438 609 TTCAGTAGGTCTGATCCAA 457 610 CAGTAGGTCTGATCCAACT 459 611 GGTACATTGAAGACCTTAA 488 612 TACATTGAAGACCTTAAGA 490 613 AGACCTTAAGAAGTTTCTA 498 614 GACCTTAAGAAGTTTCTAA 499 615 GTTTATGTTGCATGTCAGT 592 616 TGGTATGAATGATCCTGAT 639 617 TGAAGGAGTGCCAAGGATA 723 618 TGTAGCAGTTTATCCTCAT 774 619 GTAGCAGTTTATCCTCATA 775 620 CTCATAATGGAATGATAGA 788 621 AGCCATTGGTTGCTGTTCA 857 622 GCCATTGGTTGCTGTTCAG 858 623 GTAACAGTTGAGTGCAAGA 910 624 TAACAGTTGAGTGCAAGAT 911 625 TGATGGATCAGCCAACCTA 930 626 GATGGATCAGCCAACCTAA 931 627 ATGGATCAGCCAACCTAAA 932 628 GCATAGTATGAGTAGGATA 1009 629 CATAGTATGAGTAGGATAT 1010 630 GGATATCTCCACAGAGTAA 1023 631 GATATCTCCACAGAGTAAA 1024 632 AGAAAGGTGTGTGGTACAT 1111 633 ATAACGTGCTTCCAGATCA 1146 634 TAACGTGCTTCCAGATCAT 1147 635 AGTGTACAGTCGCCAGATA 1220 636 GTGAACACCTGATTCCAAA 1246 637 AGCTTAATATGCCGTGCTA 1321 638 TAATATGCCGTGCTATGTA 1325 639 AATATGCCGTGCTATGTAA 1326 640 ATATGCCGTGCTATGTAAA 1327 641 GCCGTGCTATGTAAATATT 1331 642 TGCAAGAAATGTGGTATGT 1437 643 ATGCTGAATTAGCCTCGAT 1548 644 TTGATTAAGAGCACAAACT 1571 645 AGCAGACTGTGGACTGTAA 1785 646 GCAGACTGTGGACTGTAAT 1786 647 CAGACTGTGGACTGTAATA 1787 648

[0141] Table 5 lists examples of siRNA target sequences within the SLC12A1 and SLC12A2 DNA sequences (SEQ ID NO:7 and SEQ ID NO:133, respectively) from which siRNAs of the present invention are designed in a manner as set forth above. As noted above, SLC12A1 and SLC12A2 encode the Na--K-2Cl cotransporter, NKCC2 and NKCC1, respectively. TABLE-US-00010 TABLE 5 SLC12A1 Target Sequences for siRNAs # of Starting Nucleotide with SEQ SLC12A1 reference to ID Target Sequence SEQ ID NO:7 NO: CCACCATAGTAACGACAAT 675 73 GGAATGGAATGGGAGGCAA 974 74 GGGATGAACTGCAATGGTT 1373 75 CCATGCCTCTTATGCCAAA 1780 76 CCTGCTCTCCTGGACATAA 2102 77 GCATCTGCTGTGAAGTCTT 2151 78 GCCTCAGGCTTAGGAAGAA 2315 79 GGAAGCGACTATCAAAGAT 2542 80 GCTGGCAAGTTGAACATTA 2609 81 GCAAGAAAGGGATCCATAT 3197 82 TAATACCAATCGCTTTCAA 67 649 ACCAATCGCTTTCAAGTTA 71 650 CAATCGCTTTCAAGTTAGT 73 651 ATAGAGTACTATCGTAACA 353 652 CCAGCCTGCTTGAGATTCA 405 653 CTGTAGTAGATCTACTTAA 864 654 ACCAATGACATCCGGATTA 911 655 CCAATGACATCCGGATTAT 912 656 CAATGACATCCGGATTATA 913 657 GGCTATGACTTCTCAAGAT 1409 658 GCCTCATATGCACTTATTA 1748 659 AGACCTGCGTATGGAATTT 1811 660 ACGTCTATGTGACTTGTAA 1935 661 GTCTATGTGACTTGTAAGA 1937 662 TTCCTACGTGAGTGCTTTA 1993 663 GACAATGCTCTGGAATTAA 2012 664 CTCTGGTGATTGGATATAA 2346 665 TGACAGAGATTGAGAACTA 2388 666 TGAGATTGGCGTGGTTATA 2437 667 GCATCCGAGGCTTGTTTAA 2586 668 ACCATATCGTCTCCATGAA 3007 669 CCATATCGTCTCCATGAAA 3008 670 TGAAAGCTGCAAAGATTTA 3022 671 TCGACTGAATGAACTCTTA 3130 672 CCATATCGGATTTGTTGTA 3210 673 GGTTGGAAATCCTCACAAA 3237 674 CTTACTAGTTAGAGGAAAT 3271 675 # of Starting Nucleotide with SEQ SLC12A2 reference to ID Target Sequence SEQ ID NO:133 NO: ACCACCAGCACTACTATTA 748 676 / CCACCAGCACTACTATTAT 749 677 CAGCACTACTATTATGATA 753 678 CTATCAGTCCTTGTAATAA 1119 679 ATTGTCTACTTCAGCAATA 1169 680 TATTGGTGATTTCGTCATA 1499 681 TTCGTCATAGGAACATTTA 1509 682 TAATGACACTATCGTAACA 1820 683 GATGTTTQCTAAAGGTTAT 2081 684 CTTCGTGGCTACATCTTAA 2118 685 TGCACTTGGATTCATCTTA 2147 686 GATGATCTGTGGCCATGTA 2615 687 CTCGAAGACAAGCCATGAA 2644 688 TGAAAGAGATGTCCATCGA 2659 689 AGAGATGTCCATCGATCAA 2663 690 CCATCGATCAAGCCAAATA 2671 691 CATCGATCAAGCCAAATAT 2672 692 GGTCGTATGAAGCCAAACA 2793 693 CACTTGTCCTTGGATTTAA 2812 694 TAGTGGTTATTCGCCTAAA 2914 695 ATCTCATCTTCAAGGACAA 2948 696 CGATTTAGATACTTCCAAA 3044 697 TCATTGGTGGAAAGATAAA 3334 698 TTAGCAAGTTCCGGATAGA 3391 699 GAAATCATTGAGCCATACA 3480 700 AGCAAGATATTGCAGATAA 3520 701 GATGAACCATGGCGAATAA 3549 702 CATTCAAGCACAGCTAATA 3639 703 TTCAGTGCCTAGTGTAGTA 3840 704 AGGAAAGTTGCTCCATTGA 3941 705 AAAGTTGCTCCATTGATAA 3944 706 CAATCTTAATGGTGATTCT 4001 707 TTGACATCATAGTCTAGTA 4995 708 GACATCATAGTCTAGTAAA 4997 709 GTGTGTGTGTGTGTATATA 5141 710 GTGTGTGTGTGTATATATA 5143 711 TAGGCAAACTTTGGTTTAA 5249 712 GGAGAATACTTCGCCTAAA 5375 713 TGAGTATGACCTAGGTATA 5834 714 AGAGATCTGATAACTTGAA 5852 715 GGTAAAGACAGTAGAAATA 5981 716 TTTAAGCTCTGGTGGATGA 6678 717

As cited in the examples above, one of skill in the art is able to use the target sequence information provided in Tables 1-5 to design interfering RNAs having a length shorter or longer than the sequences provided in Table 1-5 by referring to the sequence position in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, and adding or deleting nucleotides complementary or near complementary to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, respectively.

[0142] The target RNA cleavage reaction guided by siRNAs and other forms of interfering RNA is highly sequence specific. In general, siRNA containing a sense nucleotide strand identical in sequence to a portion of the target mRNA and an antisense nucleotide strand exactly complementary to a portion of the target mRNA are siRNA embodiments for inhibition of mRNAs cited herein. However, 100% sequence complementarity between the antisense siRNA strand and the target mRNA, or between the antisense siRNA strand and the sense siRNA strand, is not required to practice the present invention. Thus, for example, the invention allows for sequence variations that might be expected due to genetic mutation, strain polymorphism, or evolutionary divergence.

[0143] In one embodiment of the invention, the antisense strand of the siRNA has at least near-perfect contiguous complementarity of at least 19 nucleotides with the target mRNA. "Near-perfect," as used herein, means the antisense strand of the siRNA is "substantially complementary to," and the sense strand of the siRNA is "substantially identical" to at least a portion of the target mRNA. "Identity," as known by one of ordinary skill in the art, is the degree of sequence relatedness between nucleotide sequences as determined by matching the order and identity of nucleotides between the sequences. In one embodiment, the antisense strand of an siRNA having 80% and between 80% up to 100% complementarity, for example, 85%, 90% or 95% complementarity, to the target mRNA sequence are considered near-perfect complementarity and may be used in the present invention. "Perfect" contiguous complementarity is standard Watson-Crick base pairing of adjacent base pairs. "At least near-perfect" contiguous complementarity includes "perfect" complementarity as used herein. Computer methods for determining identity or complementarity are designed to identify the greatest degree of matching of nucleotide sequences, for example, BLASTN (Altschul, S. F., et al. (1990) J. Mol. Biol. 215:403-410).

[0144] The term "percent identity" describes the percentage of contiguous nucleotides in a first nucleic acid molecule that is the same as in a set of contiguous nucleotides of the same length in a second nucleic acid molecule. The term "percent complementarity" describes the percentage of contiguous nucleotides in a first nucleic acid molecule that can base pair in the Watson-Crick sense with a set of contiguous nucleotides in a second nucleic acid molecule.

[0145] The relationship between a target mRNA (sense strand) and one strand of an siRNA (the sense strand) is that of identity. The sense strand of an siRNA is also called a passenger strand, if present. The relationship between a target mRNA (sense strand) and the other strand of an siRNA (the antisense strand) is that of complementarity. The antisense strand of an siRNA is also called a guide strand.

[0146] The penultimate base in a nucleic acid sequence that is written in a 5' to 3' direction is the next to the last base, i.e., the base next to the 3' base. The penultimate 13 bases of a nucleic acid sequence written in a 5' to 3' direction are the last 13 bases of a sequence next to the 3' base and not including the 3' base. Similarly, the penultimate 14, 15, 16, 17, or 18 bases of a nucleic acid sequence written in a 5' to 3' direction are the last 14, 15, 16, 17, or 18 bases of a sequence, respectively, next to the 3' base and not including the 3' base.

[0147] The phrase "a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of (a sequence identifier)" allows a one nucleotide substitution. Two nucleotide substitutions (i.e., 11/13=85% identity/complementarity) are not included in such a phrase.

[0148] In one embodiment of the invention, the region of contiguous nucleotides is a region of at least 14 contiguous nucleotides having at least 85% sequence complementarity to, or at least 85% sequence identity with, the penultimate 14 nucleotides of the 3' end of the sequence identified by each sequence identifier. Two nucleotide substitutions (i.e., 12/14=86% identity/complementarity) are included in such a phrase.

[0149] In a further embodiment of the invention, the region of contiguous nucleotides is a region of at least 15, 16, 17, or 18 contiguous nucleotides having at least 80% sequence complementarity to, or at least 80% sequence identity with, the penultimate 14 nucleotides of the 3' end of the sequence of the sequence identifier. Three nucleotide substitutions are included in such a phrase.

[0150] The target sequence in the mRNAs corresponding to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, may be in the 5' or 3' untranslated regions of the mRNA as well as in the coding region of the mRNA.

[0151] One or both of the strands of double-stranded interfering RNA may have a 3' overhang of from 1 to 6 nucleotides, which may be ribonucleotides or deoxyribonucleotides or a mixture thereof. The nucleotides of the overhang are not base-paired. In one embodiment of the invention, the interfering RNA comprises a 3' overhang of TT or UU. In another embodiment of the invention, the interfering RNA comprises at least one blunt end. The termini usually have a 5' phosphate group or a 3' hydroxyl group. In other embodiments, the antisense strand has a 5' phosphate group, and the sense strand has a 5' hydroxyl group. In still other embodiments, the termini are further modified by covalent addition of other molecules or functional groups.

[0152] The sense and antisense strands of the double-stranded siRNA may be in a duplex formation of two single strands as described above or may be a single molecule where the regions of complementarity are base-paired and are covalently linked by a hairpin loop so as to form a single strand. It is believed that the hairpin is cleaved intracellularly by a protein termed dicer to form an interfering RNA of two individual base-paired RNA molecules.

[0153] Interfering RNAs may differ from naturally-occurring RNA by the addition, deletion, substitution or modification of one or more nucleotides. Non-nucleotide material may be bound to the interfering RNA, either at the 5' end, the 3' end, or internally. Such modifications are commonly designed to increase the nuclease resistance of the interfering RNAs, to improve cellular uptake, to enhance cellular targeting, to assist in tracing the interfering RNA, to further improve stability, or to reduce the potential for activation of the interferon pathway. For example, interfering RNAs may comprise a purine nucleotide at the ends of overhangs. Conjugation of cholesterol to the 3' end of the sense strand of an siRNA molecule by means of a pyrrolidine linker, for example, also provides stability to an siRNA.

[0154] Further modifications include a 3' terminal biotin molecule, a peptide known to have cell-penetrating properties, a nanoparticle, a peptidomimetic, a fluorescent dye, or a dendrimer, for example.

[0155] Nucleotides may be modified on their base portion, on their sugar portion, or on the phosphate portion of the molecule and function in embodiments of the present invention. Modifications include substitutions with alkyl, alkoxy, amino, deaza, halo, hydroxyl, thiol groups, or a combination thereof, for example. Nucleotides may be substituted with analogs with greater stability such as replacing a ribonucleotide with a deoxyribonucleotide, or having sugar modifications such as 2' OH groups replaced by 2' amino groups, 2' O-methyl groups, 2' methoxyethyl groups, or a 2'-O, 4'-C methylene bridge, for example. Examples of a purine or pyrimidine analog of nucleotides include a xanthine, a hypoxanthine, an azapurine, a methylthioadenine, 7-deaza-adenosine and O- and N-modified nucleotides. The phosphate group of the nucleotide may be modified by substituting one or more of the oxygens of the phosphate group with nitrogen or with sulfur (phosphorothioates). Modifications are useful, for example, to enhance function, to improve stability or permeability, or to direct localization or targeting.

[0156] There may be a region or regions of the antisense interfering RNA strand that is (are) not complementary to a portion of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134. Non-complementary regions may be at the 3', 5' or both ends of a complementary region or between two complementary regions.

[0157] Interfering RNAs may be generated exogenously by chemical synthesis, by in vitro transcription, or by cleavage of longer double-stranded RNA with dicer or another appropriate nuclease with similar activity. Chemically synthesized interfering RNAs, produced from protected ribonucleoside phosphoramidites using a conventional DNA/RNA synthesizer, may be obtained from commercial suppliers such as Ambion Inc. (Austin, Tex.), Invitrogen (Carlsbad, Calif.), or Dharmacon (Lafayette, Colo.). Interfering RNAs are purified by extraction with a solvent or resin, precipitation, electrophoresis, chromatography, or a combination thereof, for example. Alternatively, interfering RNA may be used with little if any purification to avoid losses due to sample processing.

[0158] Interfering RNAs can also be expressed endogenously from plasmid or viral expression vectors or from minimal expression cassettes, for example, PCR generated fragments comprising one or more promoters and an appropriate template or templates for the interfering RNA. Examples of commercially available plasmid-based expression vectors for shRNA include members of the pSilencer series (Ambion, Austin, Tex.) and pCpG-siRNA (InvivoGen, San Diego, Calif.). Viral vectors for expression of interfering RNA may be derived from a variety of viruses including adenovirus, adeno-associated virus, lentivirus (e.g., HIV, FIV, and EIAV), and herpes virus. Examples of commercially available viral vectors for shRNA expression include pSilencer adeno (Ambion, Austin, Tex.) and pLenti6/BLOCK-iT.TM.-DEST (Invitrogen, Carlsbad, Calif.). Selection of viral vectors, methods for expressing the interfering RNA from the vector and methods of delivering the viral vector are within the ordinary skill of one in the art. Examples of kits for production of PCR-generated shRNA expression cassettes include Silencer Express (Ambion, Austin, Tex.) and siXpress (Mirus, Madison, Wis.).

[0159] Interfering RNAs may be expressed from a variety of eukaryotic promoters known to those of ordinary skill in the art, including pol III promoters, such as the U6 or HI promoters, or pol II promoters, such as the cytomegalovirus promoter. Those of skill in the art will recognize that these promoters can also be adapted to allow inducible expression of the interfering RNA.

[0160] Hybridization under Physiological Conditions. In certain embodiments of the present invention, an antisense strand of an interfering RNA hybridizes with an mRNA in vivo as part of the RISC complex.

[0161] "Hybridization" refers to a process in which single-stranded nucleic acids with complementary or near-complementary base sequences interact to form hydrogen-bonded complexes called hybrids. Hybridization reactions are sensitive and selective. In vitro, the specificity of hybridization (i.e., stringency) is controlled by the concentrations of salt or formamide in prehybridization and hybridization solutions, for example, and by the hybridization temperature; such procedures are well known in the art. In particular, stringency is increased by reducing the concentration of salt, increasing the concentration of form amide, or raising the hybridization temperature.

[0162] For example, high stringency conditions could occur at about 50% formamide at 37.degree. C. to 42.degree. C. Reduced stringency conditions could occur at about 35% to 25% formamide at 30.degree. C. to 35.degree. C. Examples of stringency conditions for hybridization are provided in Sambrook, J., 1989, Molecular Cloning. A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Further examples of stringent hybridization conditions include 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50.degree. C. or 70.degree. C. for 12-16 hours followed by washing, or hybridization at 70.degree. C. in 1.times.SSC or 50.degree. C. in 1.times.SSC, 50% formamide followed by washing at 70.degree. C. in 0.3.times.SSC, or hybridization at 70.degree. C. in 4.times.SSC or 50.degree. C. in 4.times.SSC, 50% formamide followed by washing at 67.degree. C. in 1.times.SSC. The temperature for hybridization is about 5-10.degree. C. less than the melting temperature (T.sub.m) of the hybrid where T.sub.m is determined for hybrids between 19 and 49 base pairs in length using the following calculation: T.sub.m.degree. C.=81.5+16.6(log.sub.10[Na+])+0.41 (% G+C)-(600/N) where N is the number of bases in the hybrid, and [Na+] is the concentration of sodium ions in the hybridization buffer.

[0163] The above-described in vitro hybridization assay provides a method of predicting whether binding between a candidate siRNA and a target will have specificity. However, in the context of the RISC complex, specific cleavage of a target can also occur with an antisense strand that does not demonstrate high stringency for hybridization in vitro.

[0164] Single-stranded interfering RNA: As cited above, interfering RNAs ultimately function as single strands. Single-stranded (ss) interfering RNA has been found to effect mRNA silencing, albeit less efficiently than double-stranded RNA. Therefore, embodiments of the present invention also provide for administration of a ss interfering RNA that hybridizes under physiological conditions to a portion of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:101, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, or SEQ ID NO:134, respectively. The ss interfering RNA has a length of 19 to 49 nucleotides as for the ds interfering RNA cited above. The ss interfering RNA has a 5' phosphate or is phosphorylated in situ or in vivo at the 5' position. The term "5' phosphorylated" is used to describe, for example, polynucleotides or oligonucleotides having a phosphate group attached via ester linkage to the C5 hydroxyl of the sugar (e.g., ribose, deoxyribose, or an analog of same) at the 5' end of the polynucleotide or oligonucleotide.

[0165] SS interfering RNAs are synthesized chemically or by in vitro transcription or expressed endogenously from vectors or expression cassettes as for ds interfering RNAs. 5' Phosphate groups may be added via a kinase, or a 5' phosphate may be the result of nuclease cleavage of an RNA. Delivery is as for ds interfering RNAs. In one embodiment, ss interfering RNAs having protected ends and nuclease resistant modifications are administered for silencing. SS interfering RNAs may be dried for storage or dissolved in an aqueous solution. The solution may contain buffers or salts to inhibit annealing or for stabilization.

[0166] Hairpin interfering RNA: A hairpin interfering RNA is a single molecule (e.g., a single oligonucleotide chain) that comprises both the sense and antisense strands of an interfering RNA in a stem-loop or hairpin structure (e.g., a shRNA). For example, shRNAs can be expressed from DNA vectors in which the DNA oligonucleotides encoding a sense interfering RNA strand are linked to the DNA oligonucleotides encoding the reverse complementary antisense interfering RNA strand by a short spacer. If needed for the chosen expression vector, 3' terminal T's and nucleotides forming restriction sites may be added. The resulting RNA transcript folds back onto itself to form a stem-loop structure.

[0167] Mode of administration: Interfering RNA may be delivered directly to the eye by ocular tissue injection such as periocular, conjunctival, subtenon, intracameral, intravitreal, intraocular, subretinal, subconjunctival, retrobulbar, or intracanalicular injections; by direct application to the eye using a catheter or other placement device such as a retinal pellet, intraocular insert, suppository or an implant comprising a porous, non-porous, or gelatinous material; by topical ocular drops or ointments; or by a slow release device in the cul-de-sac or implanted adjacent to the sclera (transscleral) or within the eye. Intracameral injection may be through the cornea into the anterior chamber to allow the agent to reach the trabecular meshwork. Intracanalicular injection may be into the venous collector channels draining Schlemm's canal or into Schlemm's canal. Systemic or parenteral administration is contemplated including but not limited to intravenous, subcutaneous, and oral delivery.

[0168] Subject: A subject in need of treatment for ocular hypertension or at risk for developing ocular hypertension is a human or other mammal having ocular hypertension or at risk of having ocular hypertension associated with undesired or inappropriate expression or activity of targets as cited herein, i.e., carbonic anhydrase II, IV, or XII; .beta.1- or .beta.2-adrenergic receptors; acetylcholinesterase; Na.sup.+/K.sup.+-ATPase; or Na--K-2Cl cotransporter. Ocular structures associated with such disorders may include the eye, retina, choroid, lens, cornea, trabecular meshwork, iris, optic nerve, optic nerve head, sclera, aqueous chamber, vitreous chamber, or ciliary body, for example. A subject may also be an ocular cell, cell culture, organ or an ex vivo organ or tissue.

[0169] Formulations and Dosage: Pharmaceutical formulations comprise an interfering RNA, or salt thereof, of the invention up to 99% by weight mixed with a physiologically acceptable ophthalmic carrier medium such as water, buffer, saline, glycine, hyaluronic acid, mannitol, and the like.

[0170] Interfering RNAs of the present invention are administered as solutions, suspensions, or emulsions. The following are examples of possible formulations embodied by this invention. TABLE-US-00011 Amount in weight % Interfering RNA up to 99; 0.1-99; 0.1-50; 0.5-10.0 Hydroxypropylmethylcellulose 0.5 Sodium chloride 0.8 Benzalkonium Chloride 0.01 EDTA 0.01 NaOH/HCl qs pH 7.4 Purified water (RNase-free) qs 100 mL Phosphate Buffered Saline 1.0 Benzalkonium Chloride 0.01 Polysorbate 80 0.5 Purified water (RNase-free) q.s. to 100% Monobasic sodium phosphate 0.05 Dibasic sodium phosphate 0.15 (anhydrous) Sodium chloride 0.75 Disodium EDTA 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and/or NaOH pH 7.3-7.4 Purified water (RNase-free) q.s. to 100% Phosphate Buffered Saline 1.0 Hydroxypropyl-.beta.-cyclodextrin 4.0 Purified water (RNase-free) q.s. to 100%

[0171] Generally, an effective amount of the interfering RNA of embodiments of the invention results in an extracellular concentration at the surface of the target cell of from 100 pM to 100 nM, or from 1 nM to 50 nM, or from 5 nM to about 10 nM, or to about 25 nM. The dose required to achieve this local concentration will vary depending on a number of factors including the delivery method, the site of delivery, the number of cell layers between the delivery site and the target cell or tissue, whether delivery is local or systemic, etc. The concentration at the delivery site may be considerably higher than it is at the surface of the target cell or tissue. Topical compositions are delivered to the surface of the eye one to four times per day, or on an extended delivery schedule such as daily, weekly, bi-weekly, monthly, or longer, according to the routine discretion of a skilled clinician. The pH of the formulation is about pH 4-9, or pH 4.5 to pH 7.4.

[0172] Therapeutic treatment of patients with siRNAs directed against the ocular hypertension target mRNAs is expected to be beneficial over small molecule topical ocular drops by increasing the duration of action, thereby allowing less frequent dosing and greater patient compliance.

[0173] While the precise regimen is left to the discretion of the clinician, interfering RNA may be administered by placing one drop in each eye as directed by the clinician. An effective amount of a formulation may depend on factors such as the age, race, and sex of the subject, the severity of the ocular hypertension, the rate of target gene transcript/protein turnover, the interfering RNA potency, and the interfering RNA stability, for example. In one embodiment, the interfering RNA is delivered topically to the eye and reaches the trabecular meshwork, retina or optic nerve head at a therapeutic dose thereby ameliorating an ocular hypertension-associated disease process.

[0174] Acceptable carriers: An ophthalmically acceptable carrier refers to those carriers that cause at most, little to no ocular irritation, provide suitable preservation if needed, and deliver one or more interfering RNAs of the present invention in a homogenous dosage. An acceptable carrier for administration of interfering RNA of embodiments of the present invention include the cationic lipid-based transfection reagents TransIT.RTM.-TKO (Mirus Corporation, Madison, Wis.), LIPOFECTIN.RTM., Lipofectamine, OLIGOFECTAMINE.TM. (Invitrogen, Carlsbad, Calif.), or DHARMAFEC.TM. (Dharmacon, Lafayette, Colo.); polycations such as polyethyleneimine; cationic peptides such as Tat, polyarginine, or Penetratin (Antp peptide); or liposomes. Liposomes are formed from standard vesicle-forming lipids and a sterol, such as cholesterol, and may include a targeting molecule such as a monoclonal antibody having binding affinity for endothelial cell surface antigens, for example. Further, the liposomes may be PEGylated liposomes.

[0175] The interfering RNAs may be delivered in solution, in suspension, or in bioerodible or non-bioerodible delivery devices. The interfering RNAs can be delivered alone, as components of covalent conjugates, complexed with cationic lipids, cationic peptides, or cationic polymers, or encapsulated in targeted or non-targeted nanoparticles.

[0176] For ophthalmic delivery, an interfering RNA may be combined with ophthalmologically acceptable preservatives, co-solvents, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, or water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the interfering RNA in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the inhibitor. Viscosity building agents, such as hydroxymethyl cellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone, or the like may be added to the compositions of the present invention to improve the retention of the compound.

[0177] In order to prepare a sterile ophthalmic ointment formulation, the interfering RNA is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the interfering RNA in a hydrophilic base prepared from the combination of, for example, CARBOPOL.RTM.-940 (BF Goodrich, Charlotte, N.C.), or the like, according to methods known in the art for other ophthalmic formulations. VISCOAT.RTM. (Alcon Laboratories, Inc., Fort Worth, Tex.) may be used for intraocular injection, for example. Other compositions of the present invention may contain penetration enhancing agents such as cremephor and TWEEN.RTM. 80 (polyoxyethylene sorbitan monolaureate, Sigma Aldrich, St. Louis, Mo.), in the event the interfering RNA is less penetrating in the eye.

[0178] Kits: Embodiments of the present invention provide a kit that includes reagents for attenuating the expression of an mRNA as cited herein in a cell. The kit contains an siRNA or an shRNA expression vector. For siRNAs and non-viral shRNA expression vectors the kit also may contain a transfection reagent or other suitable delivery vehicle. For viral shRNA expression vectors, the kit may contain the viral vector and/or the necessary components for viral vector production (e.g., a packaging cell line as well as a vector comprising the viral vector template and additional helper vectors for packaging). The kit may also contain positive and negative control siRNAs or shRNA expression vectors (e.g., a non-targeting control siRNA or an siRNA that targets an unrelated mRNA). The kit also may contain reagents for assessing knockdown of the intended target gene (e.g., primers and probes for quantitative PCR to detect the target mRNA and/or antibodies against the corresponding protein for western blots). Alternatively, the kit may comprise an siRNA sequence or an shRNA sequence and the instructions and materials necessary to generate the siRNA by in vitro transcription or to construct an shRNA expression vector.

[0179] A pharmaceutical combination in kit form is further provided that includes, in packaged combination, a carrier means adapted to receive a container means in close confinement therewith and a first container means including an interfering RNA composition and an ophthalmically acceptable carrier. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

[0180] The ability of interfering RNA to knock-down the levels of endogenous target gene expression in, for example, human trabecular meshwork (TM) cells is evaluated in vitro as follows. Transformed human TM cells, for example, cell lines designated GTM-3 or HTM-3 (see Pang, I. H. et al., 1994. Curr. Eye Res. 13:51-63), are plated 24 h prior to transfection in standard growth medium (e.g., DMEM supplemented with 10% fetal bovine serum). Transfection is performed using Dharmafect 1 (Dharmacon, Lafayette, Colo.) according to the manufacturer's instructions at interfering RNA concentrations ranging from 0.1 nM-100 nM. Non-targeting control interfering RNA and lamin A/C interfering RNA (Dharmacon) are used as controls. Target mRNA levels are assessed by qPCR 24 h post-transfection using, for example, TAQMAN.RTM. forward and reverse primers and a probe set that encompasses the target site (Applied Biosystems, Foster City, Calif.). Target protein levels may be assessed approximately 72 h post-transfection (actual time dependent on protein turnover rate) by western blot, for example. Standard techniques for RNA and/or protein isolation from cultured cells are well-known to those skilled in the art. To reduce the chance of non-specific, off-target effects, the lowest possible concentration of interfering RNA should be used that will produce the desired level of knock-down in target gene expression.

[0181] The ability of interfering RNAs of the present invention to knock-down levels of CA2 protein expression is further exemplified in Example 1 as follows.

EXAMPLE 1

Interfering RNA for Specifically Silencing CA2 in HeLa Cells

[0182] The present study examines the ability of CA2-interfering RNA to knock down the levels of endogenous CA2 expression in cultured HeLa cells.

[0183] Transfection of HeLa cells was accomplished using standard in vitro concentrations (100 nM and 1 nM) of CA2 siRNAs, or a non-targeting control siRNA and DharmaFECT.TM. 1 transfection reagent (Dharmacon, Lafayette, Colo.). All siRNAs were dissolved in 1.times.siRNA buffer, an aqueous solution of 20 mM KCl, 6 mM HEPES (pH 7.5), 0.2 mM MgCl.sub.2. CA2 protein expression and actin protein expression (loading control) was evaluated by western blot analysis 72 hours post-transfection. The CA2 siRNAs are double-stranded interfering RNAs having specificity for the following target sequences: siCA2#1 targets SEQ ID NO:721; siCA2#3 targets SEQ ID NO:15; siCA2#4 targets SEQ ID NO:720; siCA2#5 targets SEQ ID NO:141. Each of the four CA2 siRNAs decreased CA2 expression significantly at both 100 nM and 1 nM relative to a non-targeting control siRNA as shown by the western blot data of FIG. 1. SiCA2#4 targeting SEQ ID NO:720 and siCA2#5 targeting SEQ ID NO:141 appeared to be particularly effective.

[0184] The references cited herein, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated by reference.

[0185] Those of skill in the art, in light of the present disclosure, will appreciate that obvious modifications of the embodiments disclosed herein can be made without departing from the spirit and scope of the invention. All of the embodiments disclosed herein can be made and executed without undue experimentation in light of the present disclosure. The full scope of the invention is set out in the disclosure and equivalent embodiments thereof. The specification should not be construed to unduly narrow the full scope of protection to which the present invention is entitled.

[0186] As used herein and unless otherwise indicated, the terms "a" and "an" are taken to mean "one", "at least one" or "one or more".

Sequence CWU 1

1

724 1 1551 DNA Homo sapiens 1 ggcgcccaag ccgccgccgc cagatcggtg ccgattcctg ccctgccccg accgccagcg 60 cgaccatgtc ccatcactgg gggtacggca aacacaacgg acctgagcac tggcataagg 120 acttccccat tgccaaggga gagcgccagt cccctgttga catcgacact catacagcca 180 agtatgaccc ttccctgaag cccctgtctg tttcctatga tcaagcaact tccctgagga 240 tcctcaacaa tggtcatgct ttcaacgtgg agtttgatga ctctcaggac aaagcagtgc 300 tcaagggagg acccctggat ggcacttaca gattgattca gtttcacttt cactggggtt 360 cacttgatgg acaaggttca gagcatactg tggataaaaa gaaatatgct gcagaacttc 420 acttggttca ctggaacacc aaatatgggg attttgggaa agctgtgcag caacctgatg 480 gactggccgt tctaggtatt tttttgaagg ttggcagcgc taaaccgggc cttcagaaag 540 ttgttgatgt gctggattcc attaaaacaa agggcaagag tgctgacttc actaacttcg 600 atcctcgtgg cctccttcct gaatccctgg attactggac ctacccaggc tcactgacca 660 cccctcctct tctggaatgt gtgacctgga ttgtgctcaa ggaacccatc agcgtcagca 720 gcgagcaggt gttgaaattc cgtaaactta acttcaatgg ggagggtgaa cccgaagaac 780 tgatggtgga caactggcgc ccagctcagc cactgaagaa caggcaaatc aaagcttcct 840 tcaaataaga tggtcccata gtctgtatcc aaataatgaa tcttcgggtg tttcccttta 900 gctaagcaca gatctacctt ggtgatttgg accctggttg ctttgtgtct agttttctag 960 acccttcatc tcttacttga tagacttact aataaaatgt gaagactaga ccaattgtca 1020 tgcttgacac aactgctgtg gctggttggt gctttgttta tggtagtagt ttttctgtaa 1080 cacagaatat aggataagaa ataagaataa agtaccttga ctttgttcac agcatgtagg 1140 gtgatgagca ctcacaattg ttgactaaaa tgctgctttt aaaacatagg aaagtagaat 1200 ggttgagtgc aaatccatag cacaagataa attgagctag ttaaggcaaa tcaggtaaaa 1260 tagtcatgat tctatgtaat gtaaaccaga aaaaataaat gttcatgatt tcaagatgtt 1320 atattaaaga aaaactttaa aaattattat atatttatag caaagttatc ttaaatatga 1380 attctgttgt aatttaatga cttttgaatt acagagatat aaatgaagta ttatctgtaa 1440 aaattgttat aattagagtt gtgatacaga gtatatttcc attcagacaa tatatcataa 1500 cttaataaat attgtatttt agatatattc tctaataaaa ttcagaattc t 1551 2 1104 DNA Homo sapiens 2 ctcggtgcgc gaccccggct cagaggactc tttgctgtcc cgcaagatgc ggatgctgct 60 ggcgctcctg gccctctccg cggcgcggcc atcggccagt gcagagtcac actggtgcta 120 cgaggttcaa gccgagtcct ccaactaccc ctgcttggtg ccagtcaagt ggggtggaaa 180 ctgccagaag gaccgccagt cccccatcaa catcgtcacc accaaggcaa aggtggacaa 240 aaaactggga cgcttcttct tctctggcta cgataagaag caaacgtgga ctgtccaaaa 300 taacgggcac tcagtgatga tgttgctgga gaacaaggcc agcatttctg gaggaggact 360 gcctgcccca taccaggcca aacagttgca cctgcactgg tccgacttgc catataaggg 420 ctcggagcac agcctcgatg gggagcactt tgccatggag atgcacatag tacatgagaa 480 agagaagggg acatcgagga atgtgaaaga ggcccaggac cctgaagacg aaattgcggt 540 gctggccttt ctggtggagg ctggaaccca ggtgaacgag ggcttccagc cactggtgga 600 ggcactgtct aatatcccca aacctgagat gagcactacg atggcagaga gcagcctgtt 660 ggacctgctc cccaaggagg agaaactgag gcactacttc cgctacctgg gctcactcac 720 cacaccgacc tgcgatgaga aggtcgtctg gactgtgttc cgggagccca ttcagcttca 780 cagagaacag atcctggcat tctctcagaa gctgtactac gacaaggaac agacagtgag 840 catgaaggac aatgtcaggc ccctgcagca gctggggcag cgcacggtga taaagtccgg 900 ggccccgggt cggccgctgc cctgggccct gcctgccctg ctgggcccca tgctggcctg 960 cctgctggcc ggcttcctgc gatgatggct cacttctgca cgcagcctct ctgttgcctc 1020 agctctccaa gttccaggct tccggtcctt agccttccca ggtgggactt taggcatgat 1080 taaaatatgg acatattttt ggag 1104 3 1723 DNA Homo sapiens 3 tgctacccgc gcccgggctt ctggggtgtt ccccaaccac ggcccagccc tgccacaccc 60 cccgcccccg gcctccgcag ctcggcatgg gcgcgggggt gctcgtcctg ggcgcctccg 120 agcccggtaa cctgtcgtcg gccgcaccgc tccccgacgg cgcggccacc gcggcgcggc 180 tgctggtgcc cgcgtcgccg cccgcctcgt tgctgcctcc cgccagcgaa agccccgagc 240 cgctgtctca gcagtggaca gcgggcatgg gtctgctgat ggcgctcatc gtgctgctca 300 tcgtggcggg caatgtgctg gtgatcgtgg ccatcgccaa gacgccgcgg ctgcagacgc 360 tcaccaacct cttcatcatg tccctggcca gcgccgacct ggtcatgggg ctgctggtgg 420 tgccgttcgg ggccaccatc gtggtgtggg gccgctggga gtacggctcc ttcttctgcg 480 agctgtggac ctcagtggac gtgctgtgcg tgacggccag catcgagacc ctgtgtgtca 540 ttgccctgga ccgctacctc gccatcacct cgcccttccg ctaccagagc ctgctgacgc 600 gcgcgcgggc gcggggcctc gtgtgcaccg tgtgggccat ctcggccctg gtgtccttcc 660 tgcccatcct catgcactgg tggcgggcgg agagcgacga ggcgcgccgc tgctacaacg 720 accccaagtg ctgcgacttc gtcaccaacc gggcctacgc catcgcctcg tccgtagtct 780 ccttctacgt gcccctgtgc atcatggcct tcgtgtacct gcgggtgttc cgcgaggccc 840 agaagcaggt gaagaagatc gacagctgcg agcgccgttt cctcggcggc ccagcgcggc 900 cgccctcgcc ctcgccctcg cccgtccccg cgcccgcgcc gccgcccgga cccccgcgcc 960 ccgccgccgc cgccgccacc gccccgctgg ccaacgggcg tgcgggtaag cggcggccct 1020 cgcgcctcgt ggccctacgc gagcagaagg cgctcaagac gctgggcatc atcatgggcg 1080 tcttcacgct ctgctggctg cccttcttcc tggccaacgt ggtgaaggcc ttccaccgcg 1140 agctggtgcc cgaccgcctc ttcgtcttct tcaactggct gggctacgcc aactcggcct 1200 tcaaccccat catctactgc cgcagccccg acttccgcaa ggccttccag ggactgctct 1260 gctgcgcgcg cagggctgcc cgccggcgcc acgcgaccca cggagaccgg ccgcgcgcct 1320 cgggctgtct ggcccggccc ggacccccgc catcgcccgg ggccgcctcg gacgacgacg 1380 acgacgatgt cgtcggggcc acgccgcccg cgcgcctgct ggagccctgg gccggctgca 1440 acggcggggc ggcggcggac agcgactcga gcctggacga gccgtgccgc cccggcttcg 1500 cctcggaatc caaggtgtag ggcccggcgc ggggcgcgga ctccgggcac ggcttcccag 1560 gggaacgagg agatctgtgt ttacttaaga ccgatagcag gtgaactcga agcccacaat 1620 cctcgtctga atcatccgag gcaaagagaa aagccacgga ccgttgcaca aaaaggaaag 1680 tttgggaagg gatgggagag tggcttgctg atgttccttg ttg 1723 4 2015 DNA Homo sapiens 4 actgcgaagc ggcttcttca gagcacgggc tggaactggc aggcaccgcg agcccctagc 60 acccgacaag ctgagtgtgc aggacgagtc cccaccacac ccacaccaca gccgctgaat 120 gaggcttcca ggcgtccgct cgcggcccgc agagccccgc cgtgggtccg cccgctgagg 180 cgcccccagc cagtgcgctt acctgccaga ctgcgcgcca tggggcaacc cgggaacggc 240 agcgccttct tgctggcacc caatagaagc catgcgccgg accacgacgt cacgcagcaa 300 agggacgagg tgtgggtggt gggcatgggc atcgtcatgt ctctcatcgt cctggccatc 360 gtgtttggca atgtgctggt catcacagcc attgccaagt tcgagcgtct gcagacggtc 420 accaactact tcatcacttc actggcctgt gctgatctgg tcatgggcct ggcagtggtg 480 ccctttgggg ccgcccatat tcttatgaaa atgtggactt ttggcaactt ctggtgcgag 540 ttttggactt ccattgatgt gctgtgcgtc acggccagca ttgagaccct gtgcgtgatc 600 gcagtggatc gctactttgc cattacttca cctttcaagt accagagcct gctgaccaag 660 aataaggccc gggtgatcat tctgatggtg tggattgtgt caggccttac ctccttcttg 720 cccattcaga tgcactggta ccgggccacc caccaggaag ccatcaactg ctatgccaat 780 gagacctgct gtgacttctt cacgaaccaa gcctatgcca ttgcctcttc catcgtgtcc 840 ttctacgttc ccctggtgat catggtcttc gtctactcca gggtctttca ggaggccaaa 900 aggcagctcc agaagattga caaatctgag ggccgcttcc atgtccagaa ccttagccag 960 gtggagcagg atgggcggac ggggcatgga ctccgcagat cttccaagtt ctgcttgaag 1020 gagcacaaag ccctcaagac gttaggcatc atcatgggca ctttcaccct ctgctggctg 1080 cccttcttca tcgttaacat tgtgcatgtg atccaggata acctcatccg taaggaagtt 1140 tacatcctcc taaattggat aggctatgtc aattctggtt tcaatcccct tatctactgc 1200 cggagcccag atttcaggat tgccttccag gagcttctgt gcctgcgcag gtcttctttg 1260 aaggcctatg ggaatggcta ctccagcaac ggcaacacag gggagcagag tggatatcac 1320 gtggaacagg agaaagaaaa taaactgctg tgtgaagacc tcccaggcac ggaagacttt 1380 gtgggccatc aaggtactgt gcctagcgat aacattgatt cacaagggag gaattgtagt 1440 acaaatgact cactgctgta aagcagtttt tctactttta aagacccccc cccccccaac 1500 agaacactaa acagactatt taacttgagg gtaataaact tagaataaaa ttgtaaaaat 1560 tgtatagaga tatgcagaag gaagggcatc cttctgcctt ttttattttt ttaagctgta 1620 aaaagagaga aaacttattt gagtgattat ttgttatttg tacagttcag ttcctctttg 1680 catggaattt gtaagtttat gtctaaagag ctttagtcct agaggacctg agtctgctat 1740 attttcatga cttttccatg tatctacctc actattcaag tattaggggt aatatattgc 1800 tgctggtaat ttgtatctga aggagatttt ccttcctaca cccttggact tgaggatttt 1860 gagtatctcg gacctttcag ctgtgaacat ggactcttcc cccactcctc ttatttgctc 1920 acacggggta ttttaggcag ggatttgagg agcagcttca gttgttttcc cgagcaaagg 1980 tctaaagttt acagtaaata aaatgtttga ccatg 2015 5 2909 DNA Homo sapiens 5 cagcctgcgc cggggaacat cggccgcctc cagctcccgg cgcggcccgg cccggcccgg 60 ctcggccgcc tcagacgccg cctgccctgc agccatgagg cccccgcagt gtctgctgca 120 cacgccttcc ctggcttccc cactccttct cctcctcctc tggctcctgg gtggaggagt 180 gggggctgag ggccgggagg atgcagagct gctggtgacg gtgcgtgggg gccggctgcg 240 gggcattcgc ctgaagaccc ccgggggccc tgtctctgct ttcctgggca tcccctttgc 300 ggagccaccc atgggacccc gtcgctttct gccaccggag cccaagcagc cttggtcagg 360 ggtggtagac gctacaacct tccagagtgt ctgctaccaa tatgtggaca ccctataccc 420 aggttttgag ggcaccgaga tgtggaaccc caaccgtgag ctgagcgagg actgcctgta 480 cctcaacgtg tggacaccat acccccggcc tacatccccc acccctgtcc tcgtctggat 540 ctatgggggt ggcttctaca gtggggcctc ctccttggac gtgtacgatg gccgcttctt 600 ggtacaggcc gagaggactg tgctggtgtc catgaactac cgggtgggag cctttggctt 660 cctggccctg ccggggagcc gagaggcccc gggcaatgtg ggtctcctgg atcagaggct 720 ggccctgcag tgggtgcagg agaacgtggc agccttcggg ggtgacccga catcagtgac 780 gctgtttggg gagagcgcgg gagccgcctc ggtgggcatg cacctgctgt ccccgcccag 840 ccggggcctg ttccacaggg ccgtgctgca gagcggtgcc cccaatggac cctgggccac 900 ggtgggcatg ggagaggccc gtcgcagggc cacgcagctg gcccaccttg tgggctgtcc 960 tccaggcggc actggtggga atgacacaga gctggtagcc tgccttcgga cacgaccagc 1020 gcaggtcctg gtgaaccacg aatggcacgt gctgcctcaa gaaagcgtct tccggttctc 1080 cttcgtgcct gtggtagatg gagacttcct cagtgacacc ccagaggccc tcatcaacgc 1140 gggagacttc cacggcctgc aggtgctggt gggtgtggtg aaggatgagg gctcgtattt 1200 tctggtttac ggggccccag gcttcagcaa agacaacgag tctctcatca gccgggccga 1260 gttcctggcc ggggtgcggg tcggggttcc ccaggtaagt gacctggcag ccgaggctgt 1320 ggtcctgcat tacacagact ggctgcatcc cgaggacccg gcacgcctga gggaggccct 1380 gagcgatgtg gtgggcgacc acaatgtcgt gtgccccgtg gcccagctgg ctgggcgact 1440 ggctgcccag ggtgcccggg tctacgccta cgtctttgaa caccgtgctt ccacgctctc 1500 ctggcccctg tggatggggg tgccccacgg ctacgagatc gagttcatct ttgggatccc 1560 cctggacccc tctcgaaact acacggcaga ggagaaaatc ttcgcccagc gactgatgcg 1620 atactgggcc aactttgccc gcacagggga tcccaatgag ccccgagacc ccaaggcccc 1680 acaatggccc ccgtacacgg cgggggctca gcagtacgtt agtctggacc tgcggccgct 1740 ggaggtgcgg cgggggctgc gcgcccaggc ctgcgccttc tggaaccgct tcctccccaa 1800 attgctcagc gccaccgcct cggaggctcc cagcacctgc ccaggcttca cccatgggga 1860 ggctgctccg aggcccggcc tccccctgcc cctcctcctc ctccaccagc ttctcctcct 1920 cttcctctcc cacctccggc ggctgtgaac acggcctctt cccctacggc cacaggggcc 1980 cctcctctaa tgagtggtcg gaccgtgggg aagggcccca ctcagggatc tcagacctag 2040 tgctcccttc ctcctcaaac cgagagactc acactggaca gggcaggagg agggggccgt 2100 gcctcccacc cttctcaggg acccccacgc ctttgttgtt tgaatggaaa tggaaaagcc 2160 agtattcttt tataaaatta tcttttggaa cctgagcctg acattggggg gaagtgggag 2220 gccccggacg gggtagcacc ccccattggg gctataacgg tcaaccattt ctgtctcttc 2280 tttttccccc aacctccccc tcctgtcccc tctgttcccg tcttccggtc attcttttct 2340 cctcctctct ccttcctgct gtccttctcc ggccccgcct ctgccctcat cctccctctc 2400 gtctttcgca cattctcctg atcctcttgc caccgtccca cgtggtcgcc tgcatttctc 2460 cgtgcgtcct ccctgcactg aaaccccccc ttcaacccgc ccaaatgtcc gatccccgac 2520 cttcctcgtg ccgtcctccc ctcccgcctc gctgggcgcc ctggccgcag acacgctcga 2580 cgaggcggag cgccagtgga aggccgagtt ccaccgctgg agctcctaca tggtgcactg 2640 gaagaaccag ttcgaccact acagcaagca ggatcgctgc tcagacctgt gaccccggcg 2700 ggacccccat gtcctccgct ccgcccggcc ccctagctgt atatactatt tatttcaggg 2760 ctgggctata acacagacga gccccagact ctgcccatcc ccaccccacc ccgacgtccc 2820 ccggggctcc cggtcctctg gcatgtcttc aggctgagct cctccccgcg tgccttcgcc 2880 ctctggctgc aaataaactg ttacaggcc 2909 6 5468 DNA Homo sapiens 6 tctctgtctg ccagggtctc cgactgtccc agacgggctg gtgtgggctt gggatcctcc 60 tggtgacctc tcccgctaag gtccctcagc cactctgccc caagatgggc cgtggggctg 120 gccgtgagta ctcacctgcc gccaccacgg cagagaatgg gggcggcaag aagaaacaga 180 aggagaagga actggatgag ctgaagaagg aggtggcaat ggatgaccac aagctgtcct 240 tggatgagct gggccgcaaa taccaagtgg acctgtccaa gggcctcacc aaccagcggg 300 ctcaggacgt tctggctcga gatgggccca acgccctcac accacctccc acaacccctg 360 agtgggtcaa gttctgccgt cagcttttcg gggggttctc catcctgctg tggattgggg 420 ctatcctctg cttcctggcc tacggcatcc aggctgccat ggaggatgaa ccatccaacg 480 acaatctata tctgggtgtg gtgctggcag ctgtggtcat tgtcactggc tgcttctcct 540 actaccagga ggccaagagc tccaagatca tggattcctt caagaacatg gtacctcagc 600 aagcccttgt gatccgggag ggagagaaga tgcagatcaa cgcagaggaa gtggtggtgg 660 gagacctggt ggaggtgaag ggtggagacc gcgtccctgc tgacctccgg atcatctctt 720 ctcatggctg taaggtggat aactcatcct taacaggaga gtcggagccc cagacccgct 780 cccccgagtt cacccatgag aaccccctgg agacccgcaa tatctgtttc ttctccacca 840 actgtgttga aggcactgcc aggggcattg tgattgccac aggagaccgg acggtgatgg 900 gccgcatagc tactctcgcc tcaggcctgg aggttgggcg gacacccata gcaatggaga 960 ttgaacactt catccagctg atcacagggg tcgctgtatt cctgggggtc tccttcttcg 1020 tgctctccct catcctgggc tacagctggc tggaggcagt catcttcctc atcggcatca 1080 tagtggccaa cgtgcctgag gggcttctgg ccactgtcac tgtgtgcctg accctgacag 1140 ccaagcgcat ggcacggaag aactgcctgg tgaagaacct ggaggcggtg gagacgctgg 1200 gctccacgtc caccatctgc tcggacaaga cgggcaccct cacccagaac cgcatgaccg 1260 tcgcccacat gtggttcgac aaccaaatcc atgaggctga caccaccgaa gatcagtctg 1320 gggccacttt tgacaaacga tcccctacgt ggacggccct gtctcgaatt gctggtctct 1380 gcaaccgcgc cgtcttcaag gcaggacagg agaacatctc cgtgtctaag cgggacacag 1440 ctggtgatgc ctctgagtca gctctgctca agtgcattga gctctcctgt ggctcagtga 1500 ggaaaatgag agacagaaac cccaaggtgg cagagattcc tttcaactct accaacaagt 1560 accagctgtc tatccacgag cgagaagaca gcccccagag ccacgtgctg gtgatgaagg 1620 gggccccaga gcgcattctg gaccggtgct ccaccatcct ggtgcagggc aaggagatcc 1680 cgctcgacaa ggagatgcaa gatgcctttc aaaatgccta catggagctg gggggacttg 1740 gggagcgtgt gctgggattc tgtcaactga atctgccatc tggaaagttt cctcggggct 1800 tcaaattcga cacggatgag ctgaactttc ccacggagaa gctttgcttt gtggggctca 1860 tgtctatgat tgaccctccc cgggctgctg tgccagatgc tgtgggcaag tgccgaagcg 1920 caggcatcaa ggtgatcatg gtaaccgggg atcaccctat cacagccaag gccattgcca 1980 aaggcgtggg catcatatca gagggtaacg agactgtgga ggacattgca gcccggctca 2040 acattcccat gagtcaagtc aaccccagag aagccaaggc atgcgtggtg cacggctctg 2100 acctgaagga catgacatcg gagcagctcg atgagatcct caagaaccac acagagatcg 2160 tctttgctcg aacgtctccc cagcagaagc tcatcattgt ggagggatgt cagaggcagg 2220 gagccattgt ggccgtgacg ggtgacgggg tgaacgactc ccctgcattg aagaaggctg 2280 acattggcat tgccatgggc atctctggct ctgacgtctc taagcaggca gccgacatga 2340 tcctgctgga tgacaacttt gcctccatcg tcacgggggt ggaggagggc cgcctgatct 2400 ttgacaactt gaagaaatcc atcgcctaca ccctgaccag caacatcccc gagatcaccc 2460 ccttcctgct gttcatcatt gccaacatcc ccctacctct gggcactgtg accatccttt 2520 gcattgacct gggcacagat atggtccctg ccatctcctt ggcctatgag gcagctgaga 2580 gtgatatcat gaagcggcag ccacgaaact cccagacgga caagctggtg aatgagaggc 2640 tcatcagcat ggcctacgga cagatcggga tgatccaggc actgggtggc ttcttcacct 2700 actttgtgat cctggcagag aacggtttcc tgccatcacg gctactggga atccgcctcg 2760 actgggatga ccggaccatg aatgatctgg aggacagcta tggacaggag tggacctatg 2820 agcagcggaa ggtggtggag ttcacgtgcc acacggcatt ctttgccagc atcgtggtgg 2880 tgcagtgggc tgacctcatc atctgcaaga cccgccgcaa ctcagtcttc cagcagggca 2940 tgaagaacaa gatcctgatt tttgggctcc tggaggagac ggcgttggct gcctttctct 3000 cttactgccc aggcatgggt gtagccctcc gcatgtaccc gctcaaagtc acctggtggt 3060 tctgcgcctt cccctacagc ctcctcatct tcatctatga tgaggtccga aagctcatcc 3120 tgcggcggta tcctggtggc tgggtggaga aggagacata ctactgaccc cattggaaga 3180 agaaccaggc atggaaagat ggggagctct ggaggtgttg tggggatggt gatggagagg 3240 gatggaaata acgggtggca ttgggtggca acatttgggg agagataatg aggcaactca 3300 gcaggctaag ttgcggggta tataaattgg ggtgatgacc ccatagacct aactgtgaac 3360 aatcagatta gacactatgt gttagagtcc ccccgaccag atccttttcc atcccactcc 3420 actatgttgt ctattttttc tgaggaatta agggttaccc caccctgccc actcccatcc 3480 cttcaacccc acttcctact gtaatagatc agcatccaaa agcaggaacc catctaaacc 3540 agaaggaagc cctctcagat caccccagcc tcactccatt tcccacttcc acccccgtta 3600 gcttcctgca ggactctatc cctggcttcc ccttcagacc ttgcaatcac aaaaggttct 3660 tctggtgagt gcaagagcct gagactggaa aaggtggact tgtctcccag tcgaggctgg 3720 taagggacct tcagggagag ctgggcagac aggtgggaga tggaggtagg gctggctgga 3780 ggaaggaaac aacaaaggaa gtgaggtagt gccaatgaca ggacatttga catgagtctc 3840 cagatagatg tcgtggactc cagctctacg tcccacattt tagaataccc caccagcaga 3900 acaaactcag atctcatcag ggtagcagca gaggcaggac cagaaggcaa tcaagagctt 3960 ccagaaatgc cacacttgtg tgccacagag ttccccgctg acccttggtt aggggtcctc 4020 ttagtccaca aggtccggat gtcactcatg tacttaataa cacttcacct tctgtaatac 4080 taagtcctca gagctccatg ctgttctgaa agggatggcc acaagttctt tcccagcctc 4140 ttccattccc tttcttttca tgcccatccc gatgaacctg catcattccc cgacactgcc 4200 aagccaaccc tggaaaagga gttcgctggc cattggctag aatcagggtg gagaagttcc 4260 ctgaaccttc ctgtctccca gggacatgta tgcttccagg gacaagctta ggtcatgaac 4320 atggtcagaa cctttggaca agaggaaaaa tactaagaga tttgcttttt ctgggtgcgg 4380 tggctcatgc ctgtaatccc agcactttgg gaggccgagg caggtggatc atgaggtcag 4440 gagttcgagg cgagcctggc caacatggtg aaaccctgtc tctactaaaa gtacaaaaaa 4500 ttagccagtc atggtggcac acgcctgtaa tctcagctac tcaggaggct gaggcaggag 4560 aattgcttga acctgtgagg aagaggttgc agtgagctga gatcgtgcca ttacactcca 4620 gcctgggcga aagggtgaga ctccatctca aaaaaaaaaa aaatgatttg cttttgacgt 4680 cttaggtggc agggctgttc cctccaggca aatgcccttc aaaccgacga tcattgtgcc 4740 cacttaccct gggctggaga gttggtttca ggttcctaca ggagatagct ttctttccct 4800 tactccctat ctaacacttt tgctctgcag gcagccttgc ccattctcta agcctggctt 4860 agaaggcact gggaatgtcc tgtagagaga gacctagata ggtcatgcaa gtgagaaaga 4920 catctgagga aaatggaaga cctaaggcag acaggaagga agcacaaaag acaagcattg 4980 ggtcagaccc ataaaccacc tcccaaaggc tgtcatttca ttgcactgga attttgcttt 5040 atcagaagca aggaagtaag ggagtcattg ccttgggcct gggaatctaa gtgggagaca 5100 atattaattt ggatccgatt aattggagat tactaactgt ggacaaaagt ttatctttgc 5160 acaatcaata aaaatggcat ttttttagta aattaagagc ataaacaata ttgctagagg 5220 tggcatgttt agtctaccaa aaacaatact tttcaggcac tttagaaata tccttttaga 5280 agcagcgagt gcatgggcta attatcatca atctttatgt atttgttaaa gaaacatcta 5340 caggatcttt attggtgacc ttttgtaaga cattagtttg aggtactacc tatgtacttg 5400 aaaataataa agtggcattt ctttatgaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 5460 aaaaaaaa

5468 7 3362 DNA Homo sapiens 7 aaaaaatcaa ttttggaaga tgtcactgaa caactcttcc aatgtatttc tggattcagt 60 gcccagtaat accaatcgct ttcaagttag tgtcataaat gagaaccatg agagcagtgc 120 agctgcagat gacaatactg acccaccaca ttatgaagaa acctcttttg gggatgaagc 180 tcagaaaaga ctcagaatca gctttaggcc tgggaatcag gagtgctatg acaatttcct 240 ccacagtgga gaaactgcta aaacagatgc cagttttcac gcttatgatt ctcacacaaa 300 cacatactat ctacaaactt ttggccacaa caccatggat gccgttccca agatagagta 360 ctatcgtaac accggcagca tcagtgggcc caaggtcaac cgacccagcc tgcttgagat 420 tcacgagcaa ctcgcaaaga atgtggcagt caccccaagt tcagctgaca gagttgctaa 480 cggtgatggg atacctggag atgaacaagc tgaaaataag gaagatgatc aagctggtgt 540 tgtgaagttt ggatgggtga aaggtgtgct ggtaagatgc atgctgaaca tctggggagt 600 catgctcttc attcgcctct cctggattgt tggagaagct ggaattggtc ttggagttat 660 catcattggc ctatccacca tagtaacgac aatcacaggt atgtccacgt ctgctattgc 720 cacgaacgga gttgttagag gaggtggggc ctactatctt atttccagaa gtttagggcc 780 cgagttcggt gggtcaatag gcctgatctt tgcttttgct aatgcagtgg ctgttgctat 840 gtatgtggtg ggattcgctg aaactgtagt agatctactt aaggagagtg attcgatgat 900 ggtggatcca accaatgaca tccggattat aggctccatc acagtggtga ttcttctagg 960 aatttcagta gctggaatgg aatgggaggc aaaggcccaa gtcattcttc tggtcattct 1020 tctaattgct attgcaaact tcttcattgg aactgtcatt ccatccaaca atgagaaaaa 1080 gtccagaggt ttctttaatt accaagcatc aatatttgca gaaaactttg ggccacgctt 1140 cacaaagggt gaaggcttct tctctgtctt tgccattttt ttcccagcag ctactgggat 1200 tcttgctggt gccaatatct caggagattt ggaggatccc caagatgcca tccccagagg 1260 aaccatgctg gccattttca tcaccactgt tgcctactta ggggttgcaa tttgtgtagg 1320 ggcctgtgtg gtccgagatg ccaccgggaa catgaatgac accatcattt ctgggatgaa 1380 ctgcaatggt tcagcagcat gtgggttggg ctatgacttc tcaagatgtc gacatgaacc 1440 atgtcagtac gggctgatga acaatttcca ggtcatgagc atggtatcag ggttcggccc 1500 cctcatcact gcgggaatct tttctgcaac actctcctcc gccctggcct cccttgtcag 1560 cgcacccaaa gtgttccagg ctctgtgcaa ggacaacatc tacaaagccc tgcagttttt 1620 tgcaaaggga tatgggaaaa acaatgaacc cctgagagga tatattctca cttttcttat 1680 agccatggca tttattctta ttgcggaact gaacaccatt gctcccatca tctccaactt 1740 tttcctggcc tcatatgcac ttattaattt ctcctgcttc catgcctctt atgccaaatc 1800 tccaggatgg agacctgcgt atggaattta caacatgtgg gtatctcttt ttggagctgt 1860 tttgtgctgt gcagtcatgt ttgtcatcaa ctggtgggca gctgtcatca cctatgtcat 1920 tgaattcttc ctttacgtct atgtgacttg taagaagcca gatgtgaact ggggctcctc 1980 cacacaggct ctttcctacg tgagtgcttt agacaatgct ctggaattaa ccacagtgga 2040 agaccacgta aaaaacttca ggccccagtg cattgtctta acagggggac ccatgacaag 2100 acctgctctc ctggacataa ctcacgcctt taccaagaac agtggccttt gcatctgctg 2160 tgaagtcttt gtgggaccgc gcaaactgtg tgttaaggag atgaacagtg gcatggcgaa 2220 aaaacaggcc tggcttataa agaacaaaat caaggctttt tatgctgcag tggcggcaga 2280 ctgtttcagg gatggtgtcc gaagtcttct tcaggcctca ggcttaggaa gaatgaaacc 2340 aaacactctg gtgattggat ataagaaaaa ctggaggaaa gctcccttga cagagattga 2400 gaactacgtg ggaatcatac atgatgcatt tgattttgag attggcgtgg ttatagtcag 2460 aatcagccaa ggatttgaca tctctcaggt tcttcaggtg caagaggaat tagagagatt 2520 agaacaggag agactagcat tggaagcgac tatcaaagat aatgagtgtg aagaggaaag 2580 tggaggcatc cgaggcttgt ttaaaaaagc tggcaagttg aacattacta agacaacgcc 2640 taaaaaagat ggcagcatta acacaagcca gtcgatgcat gtgggagagt tcaaccagaa 2700 actggtggaa gccagcactc aatttaaaaa gaaacaagaa aaaggcacaa ttgatgtttg 2760 gtggttgttt gatgatggag ggttaacact tcttatcccc tatatcttaa ctctcagaaa 2820 aaaatggaaa gactgtaaat taagaatcta tgtgggaggg aagatcaacc gcattgaaga 2880 agaaaaaatt gcaatggctt cccttctgag caaatttagg ataaaatttg cagacatcca 2940 tatcatcggt gacatcaaca ttaggccaaa caaagagagc tggaaagtct ttgaagagat 3000 gattgaacca tatcgtctcc atgaaagctg caaagattta acaactgctg agaaattaaa 3060 aagagaaact ccgtggaaaa ttacagatgc agaactggaa gcagtcaagg aaaagagtta 3120 ccgccaagtt cgactgaatg aactcttaca ggagcactcc agagctgcta atctcattgt 3180 cctgagcctt cccgtggcaa gaaagggatc catatcggat ttgttgtata tggcttggtt 3240 ggaaatcctc acaaagaacc tcccacctgt cttactagtt agaggaaatc acaaaaatgt 3300 cttgacattt tactcttaaa acatgaaaga ttggaataca ttttaactta atgtaatgca 3360 ta 3362 8 19 DNA Artificial Sequence TARGETING SEQUENCE 8 ccctgaggat cctcaacaa 19 9 21 DNA Artificial Sequence SENSE STRAND 9 cccugaggau ccucaacaan n 21 10 21 DNA Artificial Sequence ANTISENSE STRAND 10 uuguugagga uccucagggn n 21 11 21 RNA Artificial Sequence SENSE STRAND 11 cccugaggau ccucaacaau u 21 12 21 RNA Artificial Sequence ANTISENSE STRAND 12 uuguugagga uccucagggu u 21 13 48 DNA Artificial Sequence HAIRPIN DUPLEX WITH LOOP 13 cccugaggau ccucaacaan nnnnnnnuug uugaggaucc ucaggguu 48 14 19 DNA Artificial Sequence TARGETING SEQUENCE 14 gggccttcag aaagttgtt 19 15 19 DNA Artificial Sequence TARGETING SEQUENCE 15 gcgagcaggt gttgaaatt 19 16 19 DNA Artificial Sequence TARGETING SEQUENCE 16 ggtgttgaaa ttccgtaaa 19 17 19 DNA Artificial Sequence TARGETING SEQUENCE 17 gccactgaag aacaggcaa 19 18 19 DNA Artificial Sequence TARGETING SEQUENCE 18 ccactgaaga acaggcaaa 19 19 19 DNA Artificial Sequence TARGETING SEQUENCE 19 cccatagtct gtatccaaa 19 20 19 DNA Artificial Sequence TARGETING SEQUENCE 20 ccatagtctg tatccaaat 19 21 19 DNA Artificial Sequence TARGETING SEQUENCE 21 ggtgatttgg accctggtt 19 22 19 DNA Artificial Sequence TARGETING SEQUENCE 22 gggtgatgag cactcacaa 19 23 19 DNA Artificial Sequence TARGETING SEQUENCE 23 tcgtcaccac caaggcaaa 19 24 19 DNA Artificial Sequence TARGETING SEQUENCE 24 gcttcttctt ctctggcta 19 25 19 DNA Artificial Sequence TARGETING SEQUENCE 25 tcttctctgg ctacgataa 19 26 19 DNA Artificial Sequence TARGETING SEQUENCE 26 ggctacgata agaagcaaa 19 27 19 DNA Artificial Sequence TARGETING SEQUENCE 27 ggtccgactt gccatataa 19 28 19 DNA Artificial Sequence TARGETING SEQUENCE 28 ggagatgcac atagtacat 19 29 19 DNA Artificial Sequence TARGETING SEQUENCE 29 gcacatagta catgagaaa 19 30 19 DNA Artificial TARGETING SEQUENCE 30 gacatcgagg aatgtgaaa 19 31 19 DNA Artificial Sequence TARGETING SEQUENCE 31 ggtggaggca ctgtctaat 19 32 19 DNA Artificial Sequence TARGETING SEQUENCE 32 gggactttag gcatgatta 19 33 19 DNA Artificial Sequence TARGETING SEQUENCE 33 tccttcttct gcgagctgt 19 34 19 DNA Artificial Sequence TARGETING SEQUENCE 34 tcgagaccct gtgtgtcat 19 35 19 DNA Artificial TARGETING SEQUENCE 35 gcatcatggc cttcgtgta 19 36 19 DNA Artificial Sequence TARGETING SEQUENCE 36 gaacgaggag atctgtgtt 19 37 19 DNA Artificial Sequence TARGETING SEQUENCE 37 acgaggagat ctgtgttta 19 38 19 DNA Artificial Sequence TARGETING SEQUENCE 38 ggagatctgt gtttactta 19 39 19 DNA Artificial Sequence TARGETING SEQUENCE 39 gatagcaggt gaactcgaa 19 40 19 DNA Artificial Sequence TARGETING SEQUENCE 40 cccacaatcc tcgtctgaa 19 41 19 DNA Artificial Sequence TARGETING SEQUENCE 41 ccacaatcct cgtctgaat 19 42 19 DNA Artificial Sequence TARGETING SEQUENCE 42 tctgaatcat ccgaggcaa 19 43 19 DNA Artificial Sequence TARGETING SEQUENCE 43 gcatcgtcat gtctctcat 19 44 19 DNA Artificial Sequence TARGETING SEQUENCE 44 gctggtcatc acagccatt 19 45 19 DNA Artificial Sequence TARGETING SEQUENCE 45 ccctcaagac gttaggcat 19 46 19 DNA Artificial Sequence TARGETING SEQUENCE 46 gcatcatcat gggcacttt 19 47 19 DNA Artificial Sequence TARGETING SEQUENCE 47 cctaaattgg ataggctat 19 48 19 DNA Artificial Sequence TARGETING SEQUENCE 48 gctatgtcaa ttctggttt 19 49 19 DNA Artificial Sequence TARGETING SEQUENCE 49 ggaagacttt gtgggccat 19 50 19 DNA Artificial Sequence TARGETING SEQUENCE 50 gcctagcgat aacattgat 19 51 19 DNA Artificial Sequence TARGETING SEQUENCE 51 gggaggaatt gtagtacaa 19 52 19 DNA Artificial Sequence TARGETING SEQUENCE 52 gctgtgaaca tggactctt 19 53 19 DNA Artificial Sequence TARGETING SEQUENCE 53 ccagagtgtc tgctaccaa 19 54 19 DNA Artificial Sequence TARGETING SEQUENCE 54 gctaccaata tgtggacac 19 55 19 DNA Artificial Sequence TARGETING SEQUENCE 55 ccaatatgtg gacacccta 19 56 19 DNA Artificial Sequence TARGETING SEQUENCE 56 gctggtgtcc atgaactac 19 57 19 DNA Artificial Sequence TARGETING SEQUENCE 57 tcatcaacgc gggagactt 19 58 19 DNA Artificial TARGETING SEQUENCE 58 ggtctacgcc tacgtcttt 19 59 19 DNA Artificial Sequence TARGETING SEQUENCE 59 gctacgagat cgagttcat 19 60 19 DNA Artificial Sequence TARGETING SEQUENCE 60 gctataacgg tcaaccatt 19 61 19 DNA Artificial Sequence TARGETING SEQUENCE 61 ggctgcaaat aaactgtta 19 62 19 DNA Artificial Sequence TARGETING SEQUENCE 62 gctgcaaata aactgttac 19 63 19 DNA Artificial Sequence TARGETING SEQUENCE 63 ccatccaacg acaatctat 19 64 19 DNA Artificial Sequence TARGETING SEQUENCE 64 gcatcatatc agagggtaa 19 65 19 DNA Artificial Sequence TARGETING SEQUENCE 65 cctcctcatc ttcatctat 19 66 19 DNA Artificial Sequence TARGETING SEQUENCE 66 ggaagtgagg tagtgccaa 19 67 19 DNA Artificial Sequence TARGETING SEQUENCE 67 ggatgtcact catgtactt 19 68 19 DNA Artificial Sequence TARGETING SEQUENCE 68 gctccatgct gttctgaaa 19 69 19 DNA Artificial Sequence TARGETING SEQUENCE 69 gctggccatt ggctagaat 19 70 19 DNA Artificial Sequence TARGETING SEQUENCE 70 ggtcagaacc tttggacaa 19 71 19 DNA Artificial Sequence TARGETING SEQUENCE 71 gctagaggtg gcatgttta 19 72 19 DNA Artificial Sequence TARGETING SEQUENCE 72 gcgagtgcat gggctaatt 19 73 19 DNA Artificial Sequence TARGETING SEQUENCE 73 ccaccatagt aacgacaat 19 74 19 DNA Artificial Sequence TARGETING SEQUENCE 74 ggaatggaat gggaggcaa 19 75 19 DNA Artificial Sequence TARGETING SEQUENCE 75 gggatgaact gcaatggtt 19 76 19 DNA Artificial Sequence TARGETING SEQUENCE 76 ccatgcctct tatgccaaa 19 77 19 DNA Artificial Sequence TARGETING SEQUENCE 77 cctgctctcc tggacataa 19 78 19 DNA Artificial Sequence TARGETING SEQUENCE 78 gcatctgctg tgaagtctt 19 79 19 DNA Artificial Sequence TARGETING SEQUENCE 79 gcctcaggct taggaagaa 19 80 19 DNA Artificial Sequence TARGETING SEQUENCE 80 ggaagcgact atcaaagat 19 81 19 DNA Artificial Sequence TARGETING SEQUENCE 81 gctggcaagt tgaacatta 19 82 19 DNA Artificial Sequence TARGETING SEQUENCE 82 gcaagaaagg gatccatat 19 83 19 DNA Artificial Sequence TARGETING SEQUENCE 83 gaaggttggc agcgctaaa 19 84 19 DNA Artificial Sequence TARGETING SEQUENCE 84 atgtgctgga ttccattaa 19 85 19 DNA Artificial Sequence TARGETING SEQUENCE 85 tgtgctggat tccattaaa 19 86 19 DNA Artificial Sequence TARGETING SEQUENCE 86 ccgtaaactt aacttcaat 19 87 19 DNA Artificial Sequence TARGETING SEQUENCE 87 gatctacctt ggtgatttg 19 88 19 DNA Artificial Sequence TARGETING SEQUENCE 88 gaccaattgt catgcttga 19 89 19 DNA Artificial Sequence TARGETING SEQUENCE 89 ggtgatgagc actcacaat 19 90 19 DNA Artificial Sequence TARGETING SEQUENCE 90 cactcacaat tgttgacta 19 91 19 DNA Artificial Sequence TARGETING SEQUENCE 91 actcacaatt gttgactaa 19 92 19 DNA Artificial Sequence TARGETING SEQUENCE 92 ctcacaattg ttgactaaa 19 93 19 DNA Artificial Sequence TARGETING SEQUENCE 93 aggaaagtag aatggttga 19 94 19 DNA Artificial Sequence TARGETING SEQUENCE 94 gtagaatggt tgagtgcaa 19 95 19 DNA Artificial Sequence TARGETING SEQUENCE 95 tagaatggtt gagtgcaaa 19 96 19 DNA Artificial Sequence TARGETING SEQUENCE 96 caagataaat tgagctagt 19 97 19 DNA Artificial Sequence TARGETING SEQUENCE 97 agttaaggca aatcaggta 19 98 19 DNA Artificial Sequence TARGETING SEQUENCE 98 gagttgtgat acagagtat 19 99 19 DNA Artificial Sequence TARGETING SEQUENCE 99 agttgtgata cagagtata 19 100 19 DNA Artificial Sequence TARGETING SEQUENCE 100 gttgtgatac agagtatat 19 101 3992 DNA Homo sapiens 101 ataaaagctg cccggggaag ccaggagagc gaagggcgga cgtactcgcc acggcaccca 60 ggctgcgcgc acgcggtccc ggtgtgcagc tggagagcga gcggccaccg ggagcccccg 120 gcacagcccg cgcccgcccc gcaggagccc gcgaagatgc cccggcgcag cctgcacgcg 180 gcggccgtgc tcctgctggt gatcttaaag gaacagcctt ccagcccggc cccagtgaac 240 ggttccaagt ggacttattt tggtcctgat ggggagaata gctggtccaa gaagtacccg 300 tcgtgtgggg gcctgctgca gtcccccata gacctgcaca gtgacatcct ccagtatgac 360 gccagcctca cgcccctcga gttccaaggc tacaatctgt ctgccaacaa gcagtttctc 420 ctgaccaaca atggccattc agtgaagctg aacctgccct cggacatgca catccagggc 480 ctccagtctc gctacagtgc cacgcagctg cacctgcact gggggaaccc gaatgacccg 540 cacggctctg agcacaccgt cagcggacag cacttcgccg ccgagctgca cattgtccat 600 tataactcag acctttatcc tgacgccagc actgccagca acaagtcaga aggcctcgct 660 gtcctggctg ttctcattga gatgggctcc ttcaatccgt cctatgacaa gatcttcagt 720 caccttcaac atgtaaagta caaaggccag gaagcattcg tcccgggatt caacattgaa 780 gagctgcttc cggagaggac cgctgaatat taccgctacc gggggtccct gaccacaccc 840 ccttgcaacc ccactgtgct ctggacagtt ttccgaaacc ccgtgcaaat ttcccaggag 900 cagctgctgg ctttggagac agccctgtac tgcacacaca tggacgaccc ttcccccaga 960 gaaatgatca acaacttccg gcaggtccag aagttcgatg agaggctggt atacacctcc 1020 ttctcccaag tgcaagtctg tactgcggca ggactgagtc tgggcatcat cctctcactg 1080 gccctggctg gcattcttgg catctgtatt gtggtggtgg tgtccatttg gcttttcaga 1140 aggaagagta tcaaaaaagg tgataacaag ggagtcattt acaagccagc caccaagatg 1200 gagactgagg cccacgcttg aggtccccgg agctcccggg cacatccagg aaggaccttg 1260 ctttggaccc tacacacttc ggctctctgg acacttgcga cacctcaagg tgttctctgt 1320 agctcaatct gcaaacatgc caggcctcag ggatcctctg ctgggtgcct ccttgccttg 1380 ggaccatggc caccccagag ccatccgatc gatggatggg atgcactctc agaccaagca 1440 gcaggaattc aaagctgctt gctgtaactg tgtgagattg tgaagtggtc tgaattctgg 1500 aatcacaaac caagccatgc tggtgggcca ttaatggttg gaaaacactt tcatccgggg 1560 ctttgccaga gcgtgctttc aagtgtcctg gaaattctgc tgcttctcca agctttcaga 1620 caagaatgtg cactctctgc ttaggttttg cttgggaaac tcaacttctt tcctctggag 1680 acggggcatc tccctctgat ttccttctgc tatgacaaaa cctttaatct gcaccttaca 1740 actcggggac aaatggggac aggaaggatc aagttgtaga gagaaaaaga aaacaagaga 1800 tatacattgt

gatatattag ggacactttc acagtcctgt cctctggatc acagacactg 1860 cacagacctt agggaatggc aggttcaagt tccacttctt ggtggggatg agaagggaga 1920 gagagctaga gggacaaaga gaatgagaag acatggatga tctgggagag tctcactttg 1980 gaatcagaat tggaatcaca ttctgtttat caagccataa tgtaaggaca gaataataca 2040 atattaagtc caaatccaac ctcctgtcag tggagcagtt atgttttata ctctacagat 2100 tttacaaata atgaggctgt tccttgaaaa tgtgttgttg ctgtgtcctg gaggagacat 2160 gagttccgag atgacccaat ctgcctttga atctggagga aataggcaga aacaaaatga 2220 ctgtagaact tattctctgt aggccaaatt tcatttcagc cacttctgca ggatccctac 2280 tgccaacctg gaatggagac ttttatctac ttctctctct ctgaagatgt caaatcgtgg 2340 tttagatcaa atatatttca agctataaaa gcaggaggtt atctgtgcag ggggctggca 2400 tcatgtattt aggggcaagt aataatggaa tgctactaag atactccata ttcttccccg 2460 aatcacacag acagtttctg acaggcgcaa ctcctccatt ttcctcccgc aggtgagaac 2520 cctgtggaga tgagtcagtg ccatgactga gaaggaaccg acccctagtt gagagcacct 2580 tgcagttccc cgagaacttt ctgattcaca gtctcatttt gacagcatga aatgtcctct 2640 tgaagcatag ctttttaaat atctttttcc ttctactcct ccctctgact ctaagaattc 2700 tctcttctgg aatcgcttga acccaggagg cggaggttgc agtaagccaa ggtcatgcca 2760 ctgcactcta gcctgggtga cagagcgaga ctccatctca aaaaaaaaaa aaaaaaaatt 2820 attctgtacc atcacaactt ttcacaacga tggcaagcct tatgtcttgg gagcctgttt 2880 tgctaggcaa agttacaagt gacctaatgg gagctcaaat gtgtgtgtgt ctctctgtgt 2940 gtttgtgtgt gtgtgtgcac tcaagacctc taacagcctc gaagcctggg gtggcatccc 3000 ggccttgcca ttagcatgcc tcatgcatca tcagatgaca aggacaaccc tcatgacgaa 3060 gcaacatgaa ttagggggcc tcttggcctt ggtccaaaat tgtcaatcag aaatgaacat 3120 aaaggactcc agagcagtgg gactgtctgt caaaagactc tgtatatctt ttgtggatga 3180 gttttgtgag agaacagaga gaccattgta cctggcacaa gggctgttca tgaaaaggga 3240 gacttactgg gaggtgcaag acagtggcat ttctcctctc ctcttgctgc tcagcacagc 3300 cctggattgc agccccgagg ctgagaccag acaaagcccg ggaggcagaa agatgctcca 3360 agaaccaaca ctatcaatgt ctttgcaaat cctcacagga ttcctgtggg tccagctttg 3420 gaactgggaa acctttcttc ggatccgcac tcattccact gatgccagct gcccctgaag 3480 gatgccagta ctgtggtgtg tgagtctcag cagccgccca cacgctccta actctgctgc 3540 atggcagatg cctaggtgga aatagcaaaa acaaggccca ggctggggcc agggccagag 3600 gggaaggccc tggattctca ctcatgtgag atcttgaatc tctttctttg ttctgtttgt 3660 ttagttagta tcatctggta aaatagttaa aaaacaacaa aaaactctgt atctgtttct 3720 agcatgtgct gcattgactc tattaatcac atttcaaatt caccctacat tcctctcctc 3780 ttcactagcc tctctgaagg tgtcctggcc agccctggag aagcactggt gtctgcagca 3840 cccctcagtt cctgtgcctc agcccacagg ccactgtgat aatggtctgt ttagcacttc 3900 tgtatttatt gtaagaatga ttataatgaa gatacacact gtaactacaa gaaattataa 3960 atgtttttca catcaaaaaa aaaaaaaaaa aa 3992 102 19 DNA Artificial Sequence TARGETING SEQUENCE 102 tcctgctggt gatcttaaa 19 103 19 DNA Artificial Sequence TARGETING SEQUENCE 103 acggttccaa gtggactta 19 104 19 DNA Artificial Sequence TARGETING SEQUENCE 104 gagaatagct ggtccaaga 19 105 19 DNA Artificial Sequence TARGETING SEQUENCE 105 agaatagctg gtccaagaa 19 106 19 DNA Artificial Sequence TARGETING SEQUENCE 106 gtgacatcct ccagtatga 19 107 19 DNA Artificial Sequence TARGETING SEQUENCE 107 gctacaatct gtctgccaa 19 108 19 DNA Artificial Sequence TARGETING SEQUENCE 108 cagtttctcc tgaccaaca 19 109 19 DNA Artificial Sequence TARGETING SEQUENCE 109 agtttctcct gaccaacaa 19 110 19 DNA Artificial Sequence TARGETING SEQUENCE 110 gaccaacaat ggccattca 19 111 19 DNA Artificial Sequence TARGETING SEQUENCE 111 ctccttcaat ccgtcctat 19 112 19 DNA Artificial Sequence TARGETING SEQUENCE 112 ccttcaatcc gtcctatga 19 113 19 DNA Artificial Sequence TARGETING SEQUENCE 113 atccgtccta tgacaagat 19 114 19 DNA Artificial Sequence TARGETING SEQUENCE 114 agatcttcag tcaccttca 19 115 19 DNA Artificial Sequence TARGETING SEQUENCE 115 cggagaggac cgctgaata 19 116 19 DNA Artificial Sequence TARGETING SEQUENCE 116 ggagaggacc gctgaatat 19 117 19 DNA Artificial Sequence TARGETING SEQUENCE 117 agaggaccgc tgaatatta 19 118 19 DNA Artificial Sequence TARGETING SEQUENCE 118 aggtccagaa gttcgatga 19 119 19 DNA Artificial Sequence TARGETING SEQUENCE 119 gttcgatgag aggctggta 19 120 19 DNA Artificial Sequence TARGETING SEQUENCE 120 ttcgatgaga ggctggtat 19 121 19 DNA Artificial Sequence TARGETING SEQUENCE 121 tcgatgagag gctggtata 19 122 19 DNA Artificial Sequence TARGETING SEQUENCE 122 tgtactgcgg caggactga 19 123 2156 DNA Homo sapiens 123 cagcctgcgc cggggaacat cggccgcctc cagctcccgg cgcggcccgg cccggcccgg 60 ctcggccgcc tcagacgccg cctgccctgc agccatgagg cccccgcagt gtctgctgca 120 cacgccttcc ctggcttccc cactccttct cctcctcctc tggctcctgg gtggaggagt 180 gggggctgag ggccgggagg atgcagagct gctggtgacg gtgcgtgggg gccggctgcg 240 gggcattcgc ctgaagaccc ccgggggccc tgtctctgct ttcctgggca tcccctttgc 300 ggagccaccc atgggacccc gtcgctttct gccaccggag cccaagcagc cttggtcagg 360 ggtggtagac gctacaacct tccagagtgt ctgctaccaa tatgtggaca ccctataccc 420 aggttttgag ggcaccgaga tgtggaaccc caaccgtgag ctgagcgagg actgcctgta 480 cctcaacgtg tggacaccat acccccggcc tacatccccc acccctgtcc tcgtctggat 540 ctatgggggt ggcttctaca gtggggcctc ctccttggac gtgtacgatg gccgcttctt 600 ggtacaggcc gagaggactg tgctggtgtc catgaactac cgggtgggag cctttggctt 660 cctggccctg ccggggagcc gagaggcccc gggcaatgtg ggtctcctgg atcagaggct 720 ggccctgcag tgggtgcagg agaacgtggc agccttcggg ggtgacccga catcagtgac 780 gctgtttggg gagagcgcgg gagccgcctc ggtgggcatg cacctgctgt ccccgcccag 840 ccggggcctg ttccacaggg ccgtgctgca gagcggtgcc cccaatggac cctgggccac 900 ggtgggcatg ggagaggccc gtcgcagggc cacgcagctg gcccaccttg tgggctgtcc 960 tccaggcggc actggtggga atgacacaga gctggtagcc tgccttcgga cacgaccagc 1020 gcaggtcctg gtgaaccacg aatggcacgt gctgcctcaa gaaagcgtct tccggttctc 1080 cttcgtgcct gtggtagatg gagacttcct cagtgacacc ccagaggccc tcatcaacgc 1140 gggagacttc cacggcctgc aggtgctggt gggtgtggtg aaggatgagg gctcgtattt 1200 tctggtttac ggggccccag gcttcagcaa agacaacgag tctctcatca gccgggccga 1260 gttcctggcc ggggtgcggg tcggggttcc ccaggtaagt gacctggcag ccgaggctgt 1320 ggtcctgcat tacacagact ggctgcatcc cgaggacccg gcacgcctga gggaggccct 1380 gagcgatgtg gtgggcgacc acaatgtcgt gtgccccgtg gcccagctgg ctgggcgact 1440 ggctgcccag ggtgcccggg tctacgccta cgtctttgaa caccgtgctt ccacgctctc 1500 ctggcccctg tggatggggg tgccccacgg ctacgagatc gagttcatct ttgggatccc 1560 cctggacccc tctcgaaact acacggcaga ggagaaaatc ttcgcccagc gactgatgcg 1620 atactgggcc aactttgccc gcacagggga tcccaatgag ccccgagacc ccaaggcccc 1680 acaatggccc ccgtacacgg cgggggctca gcagtacgtt agtctggacc tgcggccgct 1740 ggaggtgcgg cgggggctgc gcgcccaggc ctgcgccttc tggaaccgct tcctccccaa 1800 attgctcagc gccaccgaca cgctcgacga ggcggagcgc cagtggaagg ccgagttcca 1860 ccgctggagc tcctacatgg tgcactggaa gaaccagttc gaccactaca gcaagcagga 1920 tcgctgctca gacctgtgac cccggcggga cccccatgtc ctccgctccg cccggccccc 1980 tagctgtata tactatttat ttcagggctg ggctataaca cagacgagcc ccagactctg 2040 cccatcccca ccccaccccg acgtcccccg gggctcccgg tcctctggca tgtcttcagg 2100 ctgagctcct ccccgcgtgc cttcgccctc tggctgcaaa taaactgtta caggcc 2156 124 3713 DNA Homo sapiens 124 attttaggaa gtgaggagga ggcgcgggct ggagctgcgg cggggtctgg ggcgcagagc 60 agcggcggga ggaggcggac acgtggcaac agcggtagca gcccgggcgg cggcagcaac 120 agcggcggcg gcatcggccc gagccgccgg ccgccctccc accctcccgc cccgcggcag 180 ccctagctcc ctccacttgg ctcccctggt cccgctcgct cggccgggag ctgctctgtg 240 cttttctctc tgattctcca gcgacaggac ccggcgccgg gcactgagca ccgccaccat 300 ggggaagggg gttggacgtg ataagtatga gcctgcagct gtttcagaac aaggtgataa 360 aaagggcaaa aagggcaaaa aagacaggga catggatgaa ctgaagaaag aagtttctat 420 ggatgatcat aaacttagcc ttgatgaact tcatcgtaaa tatggaacag acttgagccg 480 gggattaaca tctgctcgtg cagctgagat cctggcgcga gatggtccca acgccctcac 540 tccccctccc actactcctg aatggatcaa gttttgtcgg cagctctttg gggggttctc 600 aatgttactg tggattggag cgattctttg tttcttggct tatagcatcc aagctgctac 660 agaagaggaa cctcaaaacg ataatctgta cctgggtgtg gtgctatcag ccgttgtaat 720 cataactggt tgcttctcct actatcaaga agctaaaagt tcaaagatca tggaatcctt 780 caaaaacatg gtccctcagc aagcccttgt gattcgaaat ggtgagaaaa tgagcataaa 840 tgcggaggaa gttgtggttg gggatctggt ggaagtaaaa ggaggagacc gaattcctgc 900 tgacctcaga atcatatctg caaatggctg caaggtggat aactcctcgc tcactggtga 960 atcagaaccc cagactaggt ctccagattt cacaaatgaa aaccccctgg agacgaggaa 1020 cattgccttc ttttcaacca attgtgttga aggcaccgca cgtggtattg ttgtctacac 1080 tggggatcgc actgtgatgg gaagaattgc cacacttgct tctgggctgg aaggaggcca 1140 gacccccatt gctgcagaaa ttgaacattt tatccacatc atcacgggtg tggctgtgtt 1200 cctgggtgtg tctttcttca tcctttctct catccttgag tacacctggc ttgaggctgt 1260 catcttcctc atcggtatca tcgtagccaa tgtgccggaa ggtttgctgg ccactgtcac 1320 ggtctgtctg acacttactg ccaaacgcat ggcaaggaaa aactgcttag tgaagaactt 1380 agaagctgtg gagaccttgg ggtccacgtc caccatctgc tctgataaaa ctggaactct 1440 gactcagaac cggatgacag tggcccacat gtggtttgac aatcaaatcc atgaagctga 1500 tacgacagag aatcagagtg gtgtctcttt tgacaagact tcagctacct ggcttgctct 1560 gtccagaatt gcaggtcttt gtaacagggc agtgtttcag gctaaccagg aaaacctacc 1620 tattcttaag cgggcagttg caggagatgc ctctgagtca gcactcttaa agtgcataga 1680 gctgtgctgt ggttccgtga aggagatgag agaaagatac gccaaaatcg tcgagatacc 1740 cttcaactcc accaacaagt accagttgtc tattcataag aaccccaaca catcggagcc 1800 ccaacacctg ttggtgatga agggcgcccc agaaaggatc ctagaccgtt gcagctctat 1860 cctcctccac ggcaaggagc agcccctgga tgaggagctg aaagacgcct ttcagaacgc 1920 ctatttggag ctggggggcc tcggagaacg agtcctaggt ttctgccacc tctttctgcc 1980 agatgaacag tttcctgaag ggttccagtt tgacactgac gatgtgaatt tccctatcga 2040 taatctgtgc tttgttgggc tcatctccat gattgaccct ccacgggcgg ccgttcctga 2100 tgccgtgggc aaatgtcgaa gtgctggaat taaggtcatc atggtcacag gagaccatcc 2160 aatcacagct aaagctattg ccaaaggtgt gggcatcatc tcagaaggca atgagaccgt 2220 ggaagacatt gctgcccgcc tcaacatccc agtcagccag gtgaacccca gggatgccaa 2280 ggcctgcgta gtacacggca gtgatctaaa ggacatgacc tccgagcagc tggatgacat 2340 tttgaagtac cacactgaga tagtgtttgc caggacctcc cctcagcaga agctcatcat 2400 tgtggaaggc tgccaaagac agggtgctat cgtggctgtg actggtgacg gtgtgaatga 2460 ctctccagct ttgaagaaag cagacattgg ggttgctatg gggattgctg gctcagatgt 2520 gtccaagcaa gctgctgaca tgattcttct ggatgacaac tttgcctcaa ttgtgactgg 2580 agtagaggaa ggtcgtctga tctttgataa cttgaagaaa tccattgctt ataccttaac 2640 cagtaacatt cccgagatca ccccgttcct gatatttatt attgcaaaca ttccactacc 2700 actggggact gtcaccatcc tctgcattga cttgggcact gacatggttc ctgccatctc 2760 cctggcttat gagcaggctg agagtgacat catgaagaga cagcccagaa atcccaaaac 2820 agacaaactt gtgaatgagc ggctgatcag catggcctat gggcagattg gaatgatcca 2880 ggccctggga ggcttcttta cttactttgt gattctggct gagaacggct tcctcccaat 2940 tcacctgttg ggcctccgag tggactggga tgaccgctgg atcaacgatg tggaagacag 3000 ctacgggcag cagtggacct atgagcagag gaaaatcgtg gagttcacct gccacacagc 3060 cttcttcgtc agtatcgtgg tggtgcagtg ggccgacttg gtcatctgta agaccaggag 3120 gaattcggtc ttccagcagg ggatgaagaa caagatcttg atatttggcc tctttgaaga 3180 gacagccctg gctgctttcc tttcctactg ccctggaatg ggtgttgctc ttaggatgta 3240 tcccctcaaa cctacctggt ggttctgtgc cttcccctac tctcttctca tcttcgtata 3300 tgacgaagtc agaaaactca tcatcaggcg acgccctggc ggctgggtgg agaaggaaac 3360 ctactattag ccccccgtcc tgcacgccgt ggagcatcag gccacacact ctgcatccga 3420 cacccacccc ctctttgtgt acttcagtct tggagtttgg aactctaccc tggtaggaaa 3480 gcaccgcagc atgtggggaa gcaagacgtc ctggaatgaa gcatgtagct ctatgggggg 3540 aggggggagg gctgcctgaa aaccatccat ctgtggaaat gacagcgggg aaggttttta 3600 tgtgcctttt tgtttttgta aaaaaggaac acccggaaag actgaaagaa tacattttat 3660 atctggattt ttacaaataa agatggctat tataatggaa aaaaaaaaaa aaa 3713 125 2911 DNA Homo sapiens 125 attttaggaa gtgaggagga ggcgcgggct ggagctgcgg cggggtctgg ggcgcagagc 60 agcggcggga ggaggcggac acgtggcaac agcggtagca gcccgggcgg cggcagcaac 120 agcggcggcg gcatcggccc gagccgccgg ccgccctccc accctcccgc cccgcggcag 180 ccctagctcc ctccacttgg ctcccctggt cccgctcgct cggccgggag ctgctctgtg 240 cttttctctc tgattctcca gcgacaggac ccggcgccgg gcactgagca ccgccaccat 300 ggggaagggg gttggacgtg ataagtatga gcctgcagct gtttcagaac aaggtgataa 360 aaagggcaaa aagggcaaaa aagacaggga catggatgaa ctgaagaaag aagtttctat 420 ggatgatcat aaacttagcc ttgatgaact tcatcgtaaa tatggaacag acttgagccg 480 gggattaaca tctgctcgtg cagctgagat cctggcgcga gatggtccca acgccctcac 540 tccccctccc actactcctg aatggatcaa gttttgtcgg cagctctttg gggggttctc 600 aatgttactg tggattggag cgattctttg tttcttggct tatagcatcc aagctgctac 660 agaagaggaa cctcaaaacg ataatctgta cctgggtgtg gtgctatcag ccgttgtaat 720 cataactggt tgcttctcct actatcaaga agctaaaagt tcaaagatca tggaatcctt 780 caaaaacatg gtccctcagc aagcccttgt gattcgaaat ggtgagaaaa tgagcataaa 840 tgcggaggaa gttgtggttg gggatctggt ggaagtaaaa ggaggagacc gaattcctgc 900 tgacctcaga atcatatctg caaatggctg caaggtggat aactcctcgc tcactggtga 960 atcagaaccc cagactaggt ctccagattt cacaaatgaa aaccccctgg agacgaggaa 1020 cattgccttc ttttcaacca attgtgttga aggcaccgca cgtggtattg ttgtctacac 1080 tggggatcgc actgtgatgg gaagaattgc cacacttgct tctgggctgg aaggaggcca 1140 gacccccatt gctgcagaaa ttgaacattt tatccacatc atcacgggtg tggctgtgtt 1200 cctgggtgtg tctttcttca tcctttctct catccttgag tacacctggc ttgaggctgt 1260 catcttcctc atcggtatca tcgtagccaa tgtgccggaa ggtttgctgg ccactgtcac 1320 ggtctgtctg acacttactg ccaaacgcat ggcaaggaaa aactgcttag tgaagaactt 1380 agaagctgtg gagaccttgg ggtccacgtc caccatctgc tctgataaaa ctggaactct 1440 gactcagaac cggatgacag tggcccacat gtggtttgac aatcaaatcc atgaagctga 1500 tacgacagag aatcagagtg gtgtctcttt tgacaagact tcagctacct ggcttgctct 1560 gtccagaatt gcaggtcttt gtaacagggc agtgtttcag gctaaccagg aaaacctacc 1620 tattcttaag cgggcagttg caggagatgc ctctgagtca gcactcttaa agtgcataga 1680 gctgtgctgt ggttccgtga aggagatgag agaaagatac gccaaaatcg tcgagatacc 1740 cttcaactcc accaacaagt accagttgtc tattcataag aaccccaaca catcggagcc 1800 ccaacacctg ttggtgatga agggcgcccc agaaaggatc ctagaccgtt gcagctctat 1860 cctcctccac ggcaaggagc agcccctgga tgaggagctg aaagacgcct ttcagaacgc 1920 ctatttggag ctggggggcc tcggagaacg agtcctaggt ttctgccacc tctttctgcc 1980 agatgaacag tttcctgaag ggttccagtt tgacactgac gatgtgaatt tccctatcga 2040 taatctgtgc tttgttgggc tcatctccat gattgaccct ccacgggcgg ccgttcctga 2100 tgccgtgggc aaatgtcgaa gtgctggaat taaggtcatc atggtcacag gagaccatcc 2160 aatcacagct aaagctattg ccaaaggtgt gggcatcatc tcagaaggca atggacctat 2220 gagcagagga aaatcgtgga gttcacctgc cacacagcct tcttcgtcag tatcgtggtg 2280 gtgcagtggg ccgacttggt catctgtaag accaggagga attcggtctt ccagcagggg 2340 atgaagaaca agatcttgat atttggcctc tttgaagaga cagccctggc tgctttcctt 2400 tcctactgcc ctggaatggg tgttgctctt aggatgtatc ccctcaaacc tacctggtgg 2460 ttctgtgcct tcccctactc tcttctcatc ttcgtatatg acgaagtcag aaaactcatc 2520 atcaggcgac gccctggcgg ctgggtggag aaggaaacct actattagcc ccccgtcctg 2580 cacgccgtgg agcatcaggc cacacactct gcatccgaca cccaccccct ctttgtgtac 2640 ttcagtcttg gagtttggaa ctctaccctg gtaggaaagc accgcagcat gtggggaagc 2700 aagacgtcct ggaatgaagc atgtagctct atggggggag gggggagggc tgcctgaaaa 2760 ccatccatct gtggaaatga cagcggggaa ggtttttatg tgcctttttg tttttgtaaa 2820 aaaggaacac ccggaaagac tgaaagaata cattttatat ctggattttt acaaataaag 2880 atggctatta taatggaaaa aaaaaaaaaa a 2911 126 3587 DNA Homo sapiens 126 agcctctgtg cggtgggacc aacggacgga cggacggacg cgcgcaccta ccgaggcgcg 60 ggcgctgcag aggctcccag cccaagcctg agcctgagcc cgccccgagg tccccgcccc 120 gcccgcctgg ctctctcgcc gcggagccgc caagatgggg gacaagaaag atgacaagga 180 ctcacccaag aagaacaagg gcaaggagcg ccgggacctg gatgacctca agaaggaggt 240 ggctatgaca gagcacaaga tgtcagtgga agaggtctgc cggaaataca acacagactg 300 tgtgcagggt ttgacccaca gcaaagccca ggagatcctg gcccgggatg ggcctaacgc 360 actcacgcca ccgcctacca ccccagagtg ggtcaagttt tgccggcagc tcttcggggg 420 cttctccatc ctgctgtgga tcggggctat cctctgcttc ctggcctacg gtatccaggc 480 gggcaccgag gacgacccct ctggtgacaa cctgtacctg ggcatcgtgc tggcggccgt 540 ggtgatcatc actggctgct tctcctacta ccaggaggcc aagagctcca agatcatgga 600 gtccttcaag aacatggtgc cccagcaagc cctggtgatc cgggaaggtg agaagatgca 660 ggtgaacgct gaggaggtgg tggtcgggga cctggtggag atcaagggtg gagaccgagt 720 gccagctgac ctgcggatca tctcagccca cggctgcaag gtggacaact cctccctgac 780 tggcgaatcc gagccccaga ctcgctctcc cgactgcact cacgacaacc ccttggagac 840 tcggaacatc accttctttt ccaccaactg tgtggaaggc acggctcggg gcgtggtggt 900 ggccacgggc gaccgcactg tcatgggccg tatcgccacc ctggcatcag ggctggaggt 960 gggcaagacg cccatcgcca tcgagattga gcacttcatc cagctcatca ccggcgtggc 1020 tgtcttcctg ggtgtctcct tcttcatcct ctccctcatt ctcggataca cctggcttga 1080 ggctgtcatc ttcctcatcg gcatcatcgt ggccaatgtc ccagagggtc tgctggccac 1140 tgtcactgtg tgtctgacgc tgaccgccaa gcgcatggcc cggaagaact gcctggtgaa 1200 gaacctggag gctgtagaaa ccctgggctc cacgtccacc atctgctcag ataagacagg 1260 gaccctcact cagaaccgca tgacagtcgc ccacatgtgg tttgacaacc agatccacga 1320 ggctgacacc actgaggacc agtcagggac ctcatttgac aagagttcgc acacctgggt 1380 ggccctgtct cacatcgctg ggctctgcaa tcgcgctgtc ttcaagggtg gtcaggacaa 1440 catccctgtg ctcaagaggg atgtggctgg ggatgcgtct gagtctgccc tgctcaagtg 1500 catcgagctg tcctctggct ccgtgaagct gatgcgtgaa cgcaacaaga aagtggctga 1560 gattcccttc aattccacca acaaatacca gctctccatc catgagaccg aggaccccaa 1620 cgacaaccga tacctgctgg tgatgaaggg tgcccccgag cgcatcctgg accgctgctc 1680 caccatcctg ctacagggca aggagcagcc

tctggacgag gaaatgaagg aggccttcca 1740 gaatgcctac cttgagctcg gtggcctggg cgagcgcgtg cttggtttct gccattatta 1800 cctgcccgag gagcagttcc ccaagggctt tgccttcgac tgtgatgacg tgaacttcac 1860 cacggacaac ctctgctttg tgggcctcat gtccatgatc gacccacccc gggcagccgt 1920 ccctgacgcg gtgggcaagt gtcgcagcgc aggcatcaag gtcatcatgg tcaccggcga 1980 tcaccccatc acggccaagg ccattgccaa gggtgtgggc atcatctctg agggcaacga 2040 gactgtggag gacatcgccg cccggctcaa cattcccgtc agccaggtta acccccggga 2100 tgccaaggcc tgcgtgatcc acggcaccga cctcaaggac ttcacctccg agcaaatcga 2160 cgagatcctg cagaatcaca ccgagatcgt cttcgcccgc acatcccccc agcagaagct 2220 catcattgtg gagggctgtc agagacaggg tgcaattgtg gctgtgaccg gggatggtgt 2280 gaacgactcc cccgctctga agaaggccga cattggggtg gccatgggca tcgctggctc 2340 tgacgtctcc aagcaggcag ctgacatgat cctgctggac gacaactttg cctccatcgt 2400 cacaggggtg gaggagggcc gcctgatctt cgacaaccta aagaagtcca ttgcctacac 2460 cctgaccagc aatatcccgg agatcacgcc cttcctgctg ttcatcatgg ccaacatccc 2520 gctgcccctg ggcaccatca ccatcctctg catcgatctg ggcactgaca tggtccctgc 2580 catctcactg gcgtacgagg ctgccgaaag cgacatcatg aagagacagc ccaggaaccc 2640 gcggacggac aaattggtca atgagagact catcagcatg gcctacgggc agattggaat 2700 gatccaggct ctcggtggct tcttctctta ctttgtgatc ctggcagaaa atggcttctt 2760 gcccggcaac ctggtgggca tccggctgaa ctgggatgac cgcaccgtca atgacctgga 2820 agacagttac gggcagcagt ggacatacga gcagaggaag gtggtggagt tcacctgcca 2880 cacggccttc tttgtgagca tcgttgtcgt ccagtgggcc gatctgatca tctgcaagac 2940 ccggaggaac tcggtcttcc agcagggcat gaagaacaag atcctgatct tcgggctgtt 3000 tgaggagacg gccctggctg ccttcctgtc ctactgcccc ggcatggacg tggccctgcg 3060 catgtaccct ctcaagccca gctggtggtt ctgtgccttc ccctacagtt tcctcatctt 3120 cgtctacgac gaaatccgca aactcatcct gcgcaggaac ccagggggtt gggtggagaa 3180 ggaaacctac tactgacctc agccccacca catcgcccat ctcttccccg tcccccaggc 3240 ccaggaccgc ccctgtcagt ccccccaatt ttgtattctg gggggaggag ccctctcttc 3300 ctgtggcccc accttggccc ccaccccctc cactatctcc tgccgccccc actctggctg 3360 gcttctctcc cctgccccaa acctctctcc tctctctttt ctgtgtcagt ttctctccct 3420 ctcctcaccc ctctatccat tcctcccgcc ccagccacct ccctgggctc ttttttactc 3480 cccttcagcc ccccggctga tgccatctct ggttctggac aattatcaaa tatatcagtg 3540 gggagagaga aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 3587 127 3873 DNA Homo sapiens 127 aaccacaggg cctgggactg gggggttccc agatccttga agctcactcc gcctcctcac 60 tctcactgca tttcccacct tcctgtgggc cttgcggcat cttcatcact gaggcacctg 120 gttacgcttc acctcttgtt tcctgccctc actgcattcc ctcacctcta cctttttatc 180 cttccaccct aggcttctct cctccctctt ccctcactcc tgactcttcc tcttcccagc 240 ggacggctgg aggaccgctc agtctctcct ctctcacttc ccttcctctc tctcaccttc 300 accacccaac acctccctcc ctgcctcttt ctttctgctc cctcattctc tccccaccac 360 tctcttctcg tggccccctt gcccgcgcgc cctcttccct tccccttgcc tcactctctc 420 agctttcttc ccacagttga gctcgggcag ctctttctgg ggatagctat ggggctttgg 480 gggaagaaag ggacagtggc tccccatgac cagagtccaa gacgaagacc taaaaaaggg 540 cttatcaaga aaaaaatggt gaagagggaa aaacagaagc gcaatatgga ggaactgaag 600 aaggaagtgg tcatggatga tcacaaatta accttggaag agctgagcac caagtactcc 660 gtggacctga caaagggcca tagccaccaa agggcaaagg aaatcctgac tcgagatgga 720 cccaatactg ttaccccacc ccccaccact ccagaatggg tcaaattctg taagcaactg 780 ttcggaggct tctccctcct actatggact ggggccattc tctgctttgt ggcctacagc 840 atccagatat atttcaatga ggagcctacc aaagacaacc tctacctgag catcgtactg 900 tccgtcgtgg tcatcgtcac tggctgcttc tcctattatc aggaggccaa gagctccaag 960 atcatggagt cttttaagaa catggtgcct cagcaagctc tggtaattcg aggaggagag 1020 aagatgcaaa ttaatgtaca agaggtggtg ttgggagacc tggtggaaat caagggtgga 1080 gaccgagtcc ctgctgacct ccggcttatc tctgcacaag gatgtaaggt ggacaactca 1140 tccttgactg gggagtcaga accccagagc cgctcccctg acttcaccca tgagaaccct 1200 ctggagaccc gaaacatctg cttcttttcc accaactgtg tggaaggaac cgcccggggt 1260 attgtgattg ctacgggaga ctccacagtg atgggcagaa ttgcctccct gacgtcaggc 1320 ctggcggttg gccagacacc tatcgctgct gagatcgaac acttcatcca tctgatcact 1380 gtggtggccg tcttccttgg tgtcactttt tttgcgctct cacttctctt gggctatggt 1440 tggctggagg ctatcatttt tctcattggc atcattgtgg ccaatgtgcc tgaggggctg 1500 ttggccacag tcactgtgtg cctgaccctc acagccaagc gcatggcgcg gaagaactgc 1560 ctggtgaaga acctggaggc ggtggagacg ctgggctcca cgtccaccat ctgctcagac 1620 aagacgggca ccctcaccca gaaccgcatg accgtcgccc acatgtggtt tgatatgacc 1680 gtgtatgagg ccgacaccac tgaagaacag actggaaaaa catttaccaa gagctctgat 1740 acctggttta tgctggcccg aatcgctggc ctctgcaacc gggctgactt taaggctaat 1800 caggagatcc tgcccattgc taagagggcc acaacaggtg atgcttccga gtcagccctc 1860 ctcaagttca tcgagcagtc ttacagctct gtggcggaga tgagagagaa aaaccccaag 1920 gtggcagaga ttccctttaa ttctaccaac aagtaccaga tgtccatcca ccttcgggag 1980 gacagctccc agacccacgt actgatgatg aagggtgctc cggagaggat cttggagttt 2040 tgttctacct ttcttctgaa tgggcaggag tactcaatga acgatgaaat gaaggaagcc 2100 ttccaaaatg cctatttaga actgggaggt ctgggggaac gtgtgctagg cttctgcttc 2160 ttgaatctgc ctagcagctt ctccaaggga ttcccattta atacagatga aataaatttc 2220 cccatggaca acctttgttt tgtgggcctc atatccatga ttgaccctcc ccgagctgca 2280 gtgcctgatg ctgtgagcaa gtgtcgcagt gcaggaatta aggtgatcat ggtaacagga 2340 gatcatccca ttacagctaa ggccattgcc aagggtgtgg gcatcatctc agaaggcact 2400 gagacggcag aggaagtcgc tgcccggctt aagatcccta tcagcaaggt cgatgccagt 2460 gctgccaaag ccattgtggt gcatggtgca gaactgaagg acatacagtc caagcagctt 2520 gatcagatcc tccagaacca ccctgagatc gtgtttgctc ggacctcccc tcagcagaag 2580 ctcatcattg tcgagggatg tcagaggctg ggagccgttg tggccgtgac aggtgacggg 2640 gtgaacgact cccctgcgct gaagaaggct gacattggca ttgccatggg catctctggc 2700 tctgacgtct ctaagcaggc agccgacatg atcctgctgg atgacaactt tgcctccatc 2760 gtcacggggg tggaggaggg ccgcctgatc tttgacaacc tgaagaaatc catcatgtac 2820 accctgacca gcaacatccc cgagatcacg cccttcctga tgttcatcat cctcggtata 2880 cccctgcctc tgggaaccat aaccatcctc tgcattgatc tcggcactga catggtccct 2940 gccatctcct tggcttatga gtcagctgaa agcgacatca tgaagaggct tccaaggaac 3000 ccaaagacgg ataatctggt gaaccaccgt ctcattggca tggcctatgg acagattggg 3060 atgatccagg ctctggctgg attctttacc tactttgtaa tcctggctga gaatggtttt 3120 aggcctgttg atctgctggg catccgcctc cactgggaag ataaatactt gaatgacctg 3180 gaggacagct acggacagca gtggacctat gagcaacgaa aagttgtgga gttcacatgc 3240 caaacggcct tttttgtcac catcgtggtt gtgcagtggg cggatctcat catctccaag 3300 actcgccgca actcactttt ccagcagggc atgagaaaca aagtcttaat atttgggatc 3360 ctggaggaga cactcttggc tgcatttctg tcctacactc caggcatgga cgtggccctg 3420 cgaatgtacc cactcaagat aacctggtgg ctctgtgcca ttccctacag tattctcatc 3480 ttcgtctatg atgaaatcag aaaactcctc atccgtcagc acccggatgg ctgggtggaa 3540 agggagacgt actactaaac tcagcagatg aagagcttca tgtgacacag gggtgttgtg 3600 agagctggga tggggccaga gattataagt ttgacacaac atctgagaca ctaggatgaa 3660 ttatcttgga tgagaaagat gggcaatcct gggctggctt gagggaatca tgggcagagg 3720 atgaggtggg ctgaagggaa gcccagcctg catctagctg gagccccgca gggaggggca 3780 tggtcctgct gaatcccgta gccagtctag acagtaaatg tctggaaaag ccaaaaaaaa 3840 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 3873 128 951 DNA Homo sapiens 128 caccagccca gccagaagca agtcccagcc cccagccctc ccctggccta ccttttgggg 60 cccttctctg aaccaggctc ccctgtcctg caactctgtc attcacaggg atgatccagg 120 ctctggctgg attctttacc tactttgtaa tcctggctga gaatggtttt aggcctgttg 180 atctgctggg catccgcctc cactgggaag ataaatactt gaatgacctg gaggacagct 240 acggacagca gtggacctat gagcaacgaa aagttgtgga gttcacatgc caaacggcct 300 tttttgtcac catcgtggtt gtgcagtggg cggatctcat catctccaag actcgccgca 360 actcactttt ccagcagggc atgagaaaca aagtcttaat atttgggatc ctggaggaga 420 cactcttggc tgcatttctg tcctacactc caggcatgga cgtggccctg cgaatgtacc 480 cactcaagat aacctggtgg ctctgtgcca ttccctacag tattctcatc ttcgtctatg 540 atgaaatcag aaaactcctc atccgtcagc acccggatgg ctgggtggaa agggagacgt 600 actactaaac tcagcagatg aagagcttca tgtgacacag gggtgttgtg agagctggga 660 tggggccaga gattataagt ttgacacaac atctgagaca ctaggatgaa ttatcttgga 720 tgagaaagat gggcaatcct gggctggctt gagggaatca tgggcagagg atgaggtggg 780 ctgaagggaa gcccagcctg catctagctg gagccccgca gggaggggca tggtcctgct 840 gaatcccgta gccagtctag acagtaaatg tctggaaaag ccctcaaaaa aaaaaaaaaa 900 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 951 129 2212 DNA Homo sapiens 129 cagcggcgcg tcctgcctgc agagagccag gccggagaag ccgagcggcg cagaggacgc 60 cagggcgcgc gccgcagcca cccaccctcc ggaccgcggc agctgctgac ccgccatcgc 120 catggcccgc gggaaagcca aggaggaggg cagctggaag aaattcatct ggaactcaga 180 gaagaaggag tttctgggca ggaccggtgg cagttggttt aagatccttc tattctacgt 240 aatattttat ggctgcctgg ctggcatctt catcggaacc atccaagtga tgctgctcac 300 catcagtgaa tttaagccca catatcagga ccgagtggcc ccgccaggat taacacagat 360 tcctcagatc cagaagactg aaatttcctt tcgtcctaat gatcccaaga gctatgaggc 420 atatgtactg aacatagtta ggttcctgga aaagtacaaa gattcagccc agagggatga 480 catgattttt gaagattgtg gcgatgtgcc cagtgaaccg aaagaacgag gagactttaa 540 tcatgaacga ggagagcgaa aggtctgcag attcaagctt gaatggctgg gaaattgctc 600 tggattaaat gatgaaactt atggctacaa agagggcaaa ccgtgcatta ttataaagct 660 caaccgagtt ctaggcttca aacctaagcc tcccaagaat gagtccttgg agacttaccc 720 agtgatgaag tataacccaa atgtccttcc cgttcagtgc actggcaagc gagatgaaga 780 taaggataaa gttggaaatg tggagtattt tggactgggc aactcccctg gttttcctct 840 gcagtattat ccgtactatg gcaaactcct gcagcccaaa tacctgcagc ccctgctggc 900 cgtacagttc accaatctta ccatggacac tgaaattcgc atagagtgta aggcgtacgg 960 tgagaacatt gggtacagtg agaaagaccg ttttcaggga cgttttgatg taaaaattga 1020 agttaagagc tgatcacaag cacaaatctt tcccactagc catttaataa gttaaaaaaa 1080 gatacaaaaa caaaaaccta ctagtcttga acaaactgtc atacgtatgg gacctacact 1140 taatctatat gctttacact agctttctgc atttaatagg ttagaatgta aattaaagtg 1200 tagcaatagc aacaaaatat ttattctact gtaaatgaca aaagaaaaag aaaaattgag 1260 ccttgggacg tgcccatttt tactgtaaat tatgattccg taactgactt gtagtaagca 1320 gtgtttctgg cccctaagta ttgctgcctt gtgtatttta tttagtgtac agtactacag 1380 gtgcatactc tggtcatttt tcaagccatg ttttattgta tctgttttct actttatgtg 1440 agcaaggttt gctgtccaag gtgtaaatat tcaacgggaa taaaactggc atggtaattt 1500 tttttttttt tttttttttg ttttttggct ctttcaaagg taatggccca tcgatgagca 1560 tttttaacat actccatagt cttttcctgt ggtgttaggt ctttattttt atttttttcc 1620 tgggggctgg ggtgggggtt tgtcatgggg gaactgccct ttaaatttta agtgacacta 1680 cagaaaaaca caaaaaggtg atgggttgtg ttatgcttgt attgaatgct gtcttgacat 1740 ctcttgcctt gtcctccggt atgttctaaa gctgtgtctg agatctggat ctgcccatca 1800 ctttggctag tgacagggct aattaatttg ctttatacat tttcttttac tttccttttt 1860 tcctttctgg aggcatcaca tgctggtgct gtgtctttat gaatgtttta accattttca 1920 tggtggaaga attttatatt tatgcagttg tacaatttta tttttttctg caagaaaaag 1980 tgtaatgtat gaaataaacc aaagtcactt gtttgaaaat aaatctttat tttgaacttt 2040 ataaaaagca atgcagtacc ccatagactg gtgttaaatg ttgtctacag tgcaaaatcc 2100 atgttctaac atatgtaata attgccagga gtacagtgct cttgttgatc ttgtattcag 2160 tcaggttaaa acaacggaca ataaaagaat gaacacattc aaaaaaaaaa aa 2212 130 1568 DNA Homo sapiens 130 cagcggcgcg tcctgcctgc agagagccag gccggagaag ccgagcggcg cagaggacgc 60 cagggcgcgc gccgcagcca cccaccctcc ggaccgcggc agctgctgac ccgccatcgc 120 catggcccgc gggaaagcca aggaggaggg cagctggaag aaattcatct ggaactcaga 180 gaagaaggag tttctgggca ggaccggtgg cagttggttt aagatccttc tattctacgt 240 aatattttat ggctgcctgg ctggcatctt catcggaacc atccaagtga tgctgctcac 300 catcagtgaa tttaagccca catatcagga ccgagtggcc ccgccaggat taacacagat 360 tcctcagatc cagaagactg aaatttcctt tcgtcctaat gatcccaaga gctatgaggc 420 atatgtactg aacatagtta ggttcctgga aaagtacaaa gattcagccc agagggatga 480 catgattttt gaagattgtg gcgatgtgcc cagtgaaccg aaagaacgag gagactttaa 540 tcatgaacga ggagagcgaa aggtctgcag attcaagctt gaatggctgg gaaattgctc 600 tggattaaat gatgaaactt atggctacaa agagggcaaa ccgtgcatta ttataaagct 660 caaccgagtt ctaggcttca aacctaagcc tcccaagaat gagtccttgg agacttaccc 720 agtgatgaag tataacccaa atgtccttcc cgttcagtgc actggcaagc gagatgaaga 780 taaggataaa gttggaaatg tggagtattt tggactgggc aactcccctg gttttcctct 840 gcagtattat ccgtactatg gcaaactcct gcagcccaaa tacctgcagc ccctgctggc 900 cgtacagttc accaatctta ccatggacac tgaaattcgc atagagtgta aggcgtacgg 960 tgagaacatt gggtacagtg agaaagaccg ttttcaggga cgttttgatg taaaaattaa 1020 attttaagtg acactacaga aaaacacaaa aaggtgatgg gttgtgttat gcttgtattg 1080 aatgctgtct tgacatctct tgccttgtcc tccggtatgt tctaaagctg tgtctgagat 1140 ctggatctgc ccatcacttt ggctagtgac agggctaatt aatttgcttt atacattttc 1200 ttttactttc cttttttcct ttctggaggc atcacatgct ggtgctgtgt ctttatgaat 1260 gttttaacca ttttcatggt ggaagaattt tatatttatg cagttgtaca attttatttt 1320 tttctgcaag aaaaagtgta atgtatgaaa taaaccaaag tcacttgttt gaaaataaat 1380 ctttattttg aactttataa aaagcaatgc agtaccccat agactggtgt taaatgttgt 1440 ctacagtgca aaatccatgt tctaacatat gtaataattg ccaggagtac agtgctcttg 1500 ttgatcttgt attcagtcag gttaaaacaa cggacaataa aagaatgaac acattcaaaa 1560 aaaaaaaa 1568 131 3350 DNA Homo sapiens 131 ggagcggagc ctccgcctgg ggggcccccc atccctggct gtcccccagc tgcgcgtccc 60 cgccccaccc ccgcggctga gccaccaccg gtgcagtggt ctccgcttgg cggagcgagc 120 cttgagcttc gttccacagc ttctttgcat cttggatttc ggggcggccc cctcccccac 180 ctctctctgc ctttttgtac cccgcttttt ttctgcgttc tgctcggttt ttgtagccgt 240 ctgtttttgc accccatttc gttttgtttc tagacggttt ggtggggggt gaagctgcat 300 tcatacccct tcctcttgtt attctcccct gctctgacag cacccctttt catcgcagtt 360 ggggggccta ggatcggtgc atcttccgcc gcgctgccag caccccgcag cgcgtggtcg 420 tgcaccccgg aatctgcagc agctgcatat ctgagggggg tctcctttgc ccgcgccgcc 480 ttcgctcccc gtgcttttgg gtgtgtggag ggcttcagcg cgcggcgccc ccgcttctcc 540 gcaacccccc gccccgcgcc cggactcgcc ccgcgccacc aagatggtca tccagaaaga 600 gaagaagagc tgcgggcagg tggttgagga gtggaaggag ttcgtgtgga acccgaggac 660 gcaccagttt atgggccgca ccgggaccag ctgggccttt atcctcctct tctacctcgt 720 tttttatggg ttcctcaccg ccatgttcac cctcaccatg tgggtgatgc tgcagactgt 780 ctccgaccat acccccaagt accaggaccg actggccaca ccgggcttga tgattcgccc 840 caagactgag aaccttgatg tcattgtcaa tgtcagtgac actgaaagct gggaccagca 900 tgttcagaag ctcaacaagt tcttggagcc ttacaacgac tctatccaag cccaaaagaa 960 tgatgtctgc cgccctgggc gctattacga acagccagat aatggagtcc tcaactaccc 1020 caaacgtgcc tgccaattca accggaccca gctgggcaac tgctccggca ttggggactc 1080 cacccactat ggttacagca ctgggcagcc ctgtgtcttc atcaagatga accgggtcat 1140 caacttctat gcaggagcaa accagagcat gaatgttacc tgtgctggga agcgagatga 1200 agatgctgag aatctcggca acttcgtcat gttccccgcc aacggcaaca tcgacctcat 1260 gtacttcccc tactatggca aaaagttcca cgtgaactac acacagcccc tggtggctgt 1320 gaagttcctg aatgtgaccc ccaacgtgga ggtgaatgta gaatgtcgca tcaacgccgc 1380 caacatcgcc acagacgatg agcgagacaa gttcgccggc cgcgtggcct tcaaactccg 1440 catcaacaaa acctgaggcc ccttcctccc accccatctc tctcctgtgg atgctcctgg 1500 aatgtccctg accctgcctg atccctccct cacccacccc aaaggtattt ttgataacag 1560 agctatgact tgtctgagcc tcacatcctt ttccttgact tctcaaccca gcctgaagtc 1620 cattgcggtt ccgtcactcg cctttcccac caacttctcc caacctcaga tcagtcagac 1680 agggagctgg gctaagatgg ccacggagga gttaggagcc tttctagttc tggtttagct 1740 gtgagagcta tccactctcc tgcctgcata tcccctgaga gttataggaa gtgcccactg 1800 acccacccac ccacctacac cccccgccac acacacacac aaacgtgcac acgcgtctca 1860 tttgacccct ttgcttccag agatgaatgt ggcactccct ccttccattc ctaagctcta 1920 gccaccgtcc cttgatctct catactttct ccctgtctac acagtcgcca tcttggtgac 1980 tttgaattta tctggctcct gggcaggtct tctcctcctc tccatcccta ttccctcctc 2040 tgaaatgcac ccctttgtaa ttgaggacaa ggtggttctg tggccttttc cctctttgct 2100 ggcacgttct gcttctcacc ctctggtgac tctgtgagct gggaaatgag ggactggaag 2160 tgaggcctgt gttgaccctt cctgaaaatc ctctagcagc ccccgacttc agcagtttct 2220 ttctttgttt ttttgagatg gagtttcgct cttgttgccc aggctggagt gcaatggtgc 2280 aatctcagct cactgcaact tccgcatccc aggttcaagc gattctcccg cctcaggttc 2340 ccgagtagct gggactacag gcatgtgcca ccatgcccgg ctaatttctt tctttctttt 2400 tttttttttt tgcatttttt agtagagatg ggggtttctc cttgttggtc aggctggtct 2460 cgaactcccg acctcaggtg atccacctgc ctcggcctcc caaagtgttg ggattacagg 2520 cgtgagccac cgcgcccggc cttcagtttc ttcctaggcc gttctgtcac ccaaatagct 2580 gctacccaga ggggcggggt tgacctaggc tgaatatcca ctttgttttt atggatggct 2640 cccttccccc attcgccttc ccagaatatc cttcaagttc cacttcccag ggagctctgg 2700 gggaggggcg gccattctgg ctccgtcccc agtggccacc ttggaaacat cggctggctt 2760 tgggactatt ccacctcctt cccctgagcc cagatctgcc cccaccatcc tttctctggc 2820 ttcttttagc aagttatcaa ctaatcacta actccttcct tttcctctgc atgccagcct 2880 gaaaattcca aatctagcct ctgaatgtct tggctccatc tcttcagacc cctttgcctt 2940 taaaaaaaaa acaaaaacaa aaacaaaaaa acccataatg cccacagaat gtcaaatgag 3000 gggcctcctg cctcctgctc tgaatattct gtagctgtag aggcatttta accctttgtc 3060 ctccagcatc ccttcacttc ctcatcctct ctaacctcct ttttcttttt ttaatgctgc 3120 agcctccaca ctccacccac aggtggaccc ttcccttttt ctctagctgg atctgtgttt 3180 cttcccttcg ggcccccatg ttttcctgca cccgccctac catggtctct ctctgcagtt 3240 atttaatgcc tgtgtcagat ctactgtaaa aagaggatta agtaaaataa aatgagagca 3300 attatatata taaatatata tcatacacag agaaaaaaaa aaaaaaaaaa 3350 132 1853 DNA Homo sapiens 132 ggcgcggcgc ggcgcagtcg gctcgagtac tccccgtaac gaggaggtgt tctcggccgt 60 cccacccttc actgccgtct ccgggctgcg ccgccggagc cgggacgcgc ctccgcagcc 120 ctcgccgcct ccatccccgc ggccgcagct cctctcgccg tccgcgcgca caccatgacg 180 aagaacgaga agaagtccct caaccagagc ctggccgagt ggaagctctt catctacaac 240 ccgaccaccg gagaattcct ggggcgcacc gccaagagct ggggtttgat cttgctcttc 300 tacctagttt tttatgggtt cctggctgca ctcttctcat tcacgatgtg ggttatgctt 360 cagactctca acgatgaggt tccaaaatac cgtgaccaga ttcctagccc aggactcatg 420 gtttttccaa aaccagtgac cgcattggaa tatacattca gtaggtctga tccaacttcg 480 tatgcagggt acattgaaga ccttaagaag tttctaaaac catatacttt agaagaacag 540 aagaacctca cagtctgtcc tgatggagca ctttttgaac agaagggtcc agtttatgtt 600 gcatgtcagt ttcctatttc attacttcaa gcatgcagtg gtatgaatga tcctgatttt 660 ggctattctc aaggaaaccc ttgtattctt gtgaaaatga acagaataat tggattaaag 720 cctgaaggag tgccaaggat agattgtgtt tcaaagaatg aagatatacc aaatgtagca 780 gtttatcctc ataatggaat gatagactta aaatatttcc catattatgg gaaaaaactg 840 catgttgggt atctacagcc attggttgct gttcaggtca gctttgctcc taacaacact 900 gggaaagaag taacagttga gtgcaagatt gatggatcag

ccaacctaaa aagtcaggat 960 gatcgtgaca agtttttggg acgagttatg ttcaaaatca cagcacgtgc atagtatgag 1020 taggatatct ccacagagta aatgttgtgt tgtctgtctt cattttgtaa cagctggacc 1080 ttccattcta gaattatgag accaccttgg agaaaggtgt gtggtacatg acattgggtt 1140 acatcataac gtgcttccag atcatagtgt tcagtgtcct ctgaagtaac tgcctgttgc 1200 ctctgctgcc ctttgaacca gtgtacagtc gccagatagg gaccggtgaa cacctgattc 1260 caaacatgta ggatgggggt cttgtcctct ttttatgtgg tttaattgcc aagtgtctaa 1320 agcttaatat gccgtgctat gtaaatattt tatggatata acaactgtca tattttgatg 1380 tcaacagagt tttagggata aaatggtacc cggccaacat caagtgactt tatagctgca 1440 agaaatgtgg tatgtggaga agttctgtat gtgaggaagg aaaaaaagaa aataaaagtg 1500 tgtttgaaaa atattatctt gggttctttg taaaatttat tttttacatg ctgaattagc 1560 ctcgatcttt ttgattaaga gcacaaactt ttttttgtaa aacatgtaaa aaaaaaaact 1620 gggattaatt tttagtgttg gaactgcctc ttattttagg ctgtagataa aatagcattt 1680 ttaggttagc cagtgtgact atgcacctaa ttttttatga gattaaattc ataagactta 1740 atttgtacaa tagtttgtga aatatcttgt tactgctttt atttagcaga ctgtggactg 1800 taataaagta tataaattgt gaaatataaa aacttggaac ttattcaaag ctt 1853 133 6891 DNA Homo sapiens 133 ggtggcctct gtggccgtcc aggctagcgg cggcccgcag gcggcgggga gaaagactct 60 ctcacctggt cttgcggctg tggccaccgc cggccagggg tgtggagggc gtgctgccgg 120 agacgtccgc cgggctctgc agttccgccg ggggtcgggc agctatggag ccgcggccca 180 cggcgccctc ctccggcgcc ccgggactgg ccggggtcgg ggagacgccg tcagccgctg 240 cgctggccgc agccagggtg gaactgcccg gcacggctgt gccctcggtg ccggaggatg 300 ctgcgcccgc gagccgggac ggcggcgggg tccgcgatga gggccccgcg gcggccgggg 360 acgggctggg cagacccttg gggcccaccc cgagccagag ccgtttccag gtggacctgg 420 tttccgagaa cgccgggcgg gccgctgctg cggcggcggc ggcggcggcg gcagcggcgg 480 cggctggtgc tggggcgggg gccaagcaga cccccgcgga cggggaagcc agcggcgaga 540 gcgagccggc taaaggcagc gaggaagcca agggccgctt ccgcgtgaac ttcgtggacc 600 cagctgcctc ctcgtcggct gaagacagcc tgtcagatgc tgccggggtc ggagtcgacg 660 ggcccaacgt gagcttccag aacggcgggg acacggtgct gagcgagggc agcagcctgc 720 actccggcgg cggcggcggc agtgggcacc accagcacta ctattatgat acccacacca 780 acacctacta cctgcgcacc ttcggccaca acaccatgga cgctgtgccc aggatcgatc 840 actaccggca cacagccgcg cagctgggcg agaagctgct ccggcctagc ctggcggagc 900 tccacgacga gctggaaaag gaaccttttg aggatggctt tgcaaatggg gaagaaagta 960 ctccaaccag agatgctgtg gtcacgtata ctgcagaaag taaaggagtc gtgaagtttg 1020 gctggatcaa gggtgtatta gtacgttgta tgttaaacat ttggggtgtg atgcttttca 1080 ttagattgtc atggattgtg ggtcaagctg gaataggtct atcagtcctt gtaataatga 1140 tggccactgt tgtgacaact atcacaggat tgtctacttc agcaatagca actaatggat 1200 ttgtaagagg aggaggagca tattatttaa tatctagaag tctagggcca gaatttggtg 1260 gtgcaattgg tctaatcttc gcctttgcca acgctgttgc agttgctatg tatgtggttg 1320 gatttgcaga aaccgtggtg gagttgctta aggaacattc catacttatg atagatgaaa 1380 tcaatgatat ccgaattatt ggagccatta cagtcgtgat tcttttaggt atctcagtag 1440 ctggaatgga gtgggaagca aaagctcaga ttgttctttt ggtgatccta cttcttgcta 1500 ttggtgattt cgtcatagga acatttatcc cactggagag caagaagcca aaagggtttt 1560 ttggttataa atctgaaata tttaatgaga actttgggcc cgattttcga gaggaagaga 1620 ctttcttttc tgtatttgcc atcttttttc ctgctgcaac tggtattctg gctggagcaa 1680 atatctcagg tgatcttgca gatcctcagt cagccatacc caaaggaaca ctcctagcca 1740 ttttaattac tacattggtt tacgtaggaa ttgcagtatc tgtaggttct tgtgttgttc 1800 gagatgccac tggaaacgtt aatgacacta tcgtaacaga gctaacaaac tgtacttctg 1860 cagcctgcaa attaaacttt gatttttcat cttgtgaaag cagtccttgt tcctatggcc 1920 taatgaacaa cttccaggta atgagtatgg tgtcaggatt tacaccacta atttctgcag 1980 gtatattttc agccactctt tcttcagcat tagcatccct agtgagtgct cccaaaatat 2040 ttcaggctct atgtaaggac aacatctacc cagctttcca gatgtttgct aaaggttatg 2100 ggaaaaataa tgaacctctt cgtggctaca tcttaacatt cttaattgca cttggattca 2160 tcttaattgc tgaactgaat gttattgcac caattatctc aaacttcttc cttgcatcat 2220 atgcattgat caatttttca gtattccatg catcacttgc aaaatctcca ggatggcgtc 2280 ctgcattcaa atactacaac atgtggatat cacttcttgg agcaattctt tgttgcatag 2340 taatgttcgt cattaactgg tgggctgcat tgctaacata tgtgatagtc cttgggctgt 2400 atatttatgt tacctacaaa aaaccagatg tgaattgggg atcctctaca caagccctga 2460 cttacctgaa tgcactgcag cattcaattc gtctttctgg agtggaagac cacgtgaaaa 2520 actttaggcc acagtgtctt gttatgacag gtgctccaaa ctcacgtcca gctttacttc 2580 atcttgttca tgatttcaca aaaaatgttg gtttgatgat ctgtggccat gtacatatgg 2640 gtcctcgaag acaagccatg aaagagatgt ccatcgatca agccaaatat cagcgatggc 2700 ttattaagaa caaaatgaag gcattttatg ctccagtaca tgcagatgac ttgagagaag 2760 gtgcacagta tttgatgcag gctgctggtc ttggtcgtat gaagccaaac acacttgtcc 2820 ttggatttaa gaaagattgg ttgcaagcag atatgaggga tgtggatatg tatataaact 2880 tatttcatga tgcttttgac atacaatatg gagtagtggt tattcgccta aaagaaggtc 2940 tggatatatc tcatcttcaa ggacaagaag aattattgtc atcacaagag aaatctcctg 3000 gcaccaagga tgtggtagta agtgtggaat atagtaaaaa gtccgattta gatacttcca 3060 aaccactcag tgaaaaacca attacacaca aagttgagga agaggatggc aagactgcaa 3120 ctcaaccact gttgaaaaaa gaatccaaag gccctattgt gcctttaaat gtagctgacc 3180 aaaagcttct tgaagctagt acacagtttc agaaaaaaca aggaaagaat actattgatg 3240 tctggtggct ttttgatgat ggaggtttga ccttattgat accttacctt ctgacgacca 3300 agaaaaaatg gaaagactgt aagatcagag tattcattgg tggaaagata aacagaatag 3360 accatgaccg gagagcgatg gctactttgc ttagcaagtt ccggatagac ttttctgata 3420 tcatggttct aggagatatc aataccaaac caaagaaaga aaatattata gcttttgagg 3480 aaatcattga gccatacaga cttcatgaag atgataaaga gcaagatatt gcagataaaa 3540 tgaaagaaga tgaaccatgg cgaataacag ataatgagct tgaactttat aagaccaaga 3600 cataccggca gatcaggtta aatgagttat taaaggaaca ttcaagcaca gctaatatta 3660 ttgtcatgag tctcccagtt gcacgaaaag gtgctgtgtc tagtgctctc tacatggcat 3720 ggttagaagc tctatctaag gacctaccac caatcctcct agttcgtggg aatcatcaga 3780 gtgtccttac cttctattca taaatgttct atacagtgga cagccctcca gaatggtact 3840 tcagtgccta gtgtagtaac tgaaatcttc aatgacacat taacatcaca atggcgaatg 3900 gtgacttttc tttcacgatt tcattaattt gaaagcacac aggaaagttg ctccattgat 3960 aacgtgtatg gagacttcgg ttttagtcaa ttccatatct caatcttaat ggtgattctt 4020 ctctgttgaa ctgaagtttg tgagagtagt tttcctttgc tacttgaata gcaataaaag 4080 cgtgttaact ttttgattga tgaaagaagt acaaaaagcc tttagccttg aggtgccttc 4140 tgaaattaac caaatttcat ccatatatcc tcttttataa acttatagaa tgtcaaactt 4200 tgccttcaac tgtttttatt tctagtctct tccactttaa aacaaaatga acactgcttg 4260 tcttcttcca ttgaccattt agtgttgagt actgtatgtg ttttgttaat tctataaagg 4320 tatctgttag atattaaagg tgagaattag ggcaggttaa tcaaaaatgg ggaaggggaa 4380 atggtaacca aaaagtaacc ccatggtaag gtttatatga gtatatgtga atatagagct 4440 aggaaaaaaa gcccccccaa ataccttttt aacccctctg attggctatt attactatat 4500 ttattattat ttattgaaac cttagggaag attgaagatt catcccatac ttctatatac 4560 catgcttaaa aatcacgtca ttctttaaac aaaaatactc aagatcattt atatttattt 4620 ggagagaaaa ctgtcctaat ttagaatttc cctcaaatct gagggacttt taagaaatgc 4680 taacagattt ttctggagga aatttagaca aaacaatgtc atttagtaga atatttcagt 4740 atttaagtgg aatttcagta tactgtacta tcctttataa gtcattaaaa taatgtttca 4800 tcaaatggtt aaatggacca ctggtttctt agagaaatgt ttttaggctt aattcattca 4860 attgtcaagt acacttagtc ttaatacact caggtttgaa cagattattc tgaatattaa 4920 aatttaatcc attcttaata ttttaaaact tttgttaaga aaaactgcca gtttgtgctt 4980 ttgaaatgtc tgttttgaca tcatagtcta gtaaaatttt gacagtgcat atgtactgtt 5040 actaaaagct ttatatgaaa ttattaatgt gaagtttttc atttataatt caaggaagga 5100 tttcctgaaa acatttcaag ggatttatgt ctacatattt gtgtgtgtgt gtgtatatat 5160 atgtaatatg catacacaga tgcatatgtg tatatataat gaaatttatg ttgctggtat 5220 tttgcatttt aaagtgatca agattcatta ggcaaacttt ggtttaagta aacatatgtt 5280 caaaatcaga ttaacagata caggtttcat agagaacaaa ggtgatcatt tgaagggcat 5340 gctgtaattt cacacaattt tccagttcaa aaatggagaa tacttcgcct aaaatactgt 5400 taagtgggtt aattgataca agtttctgtg gtggaaaatt tatgcaggtt ttcacgaatc 5460 cttttttttt tttttttttt tttttgagac ggagtcttgc tctgttgcca cgctggaatg 5520 cagtaacgtg atcttggctc actgcgacct ccacctcccc agttcaagcg attctcctgc 5580 ctcagcctcc ctagtagctg ggactacggg tgcacgccac catgcccagc taatttttgt 5640 attttgagta gagacagggt ttcaccgtgt tggctaggat ggtgtctatc tcttgacctt 5700 gtgatccacc cgcctcagcc tcccagagtg ctgggattac aggtgcgagc cactgcgcct 5760 ggctggtttt catgaatctt gatagacatc tataacgtta ttattttcag tggtgtgcag 5820 catttttgct tcatgagtat gacctaggta tagagatctg ataacttgaa ttcagaatat 5880 taagaaaatg aagtaactga ttttctaaaa aaaaaaaaaa aaaaaatttc tacattataa 5940 ctcacagcat tgttccattg caggttttgc aatgtttggg ggtaaagaca gtagaaatat 6000 tattcagtaa acaataatgt gtgaactttt aagatggata atagggcatg gactgagtgc 6060 tgctatcttg aaatgtgcac aggtacactt accttttttt tttttttttt taagtttttc 6120 ccattcagga aaacaacatt gtgatctgta ctacaggaac caaatgtcat gcgtcataca 6180 tgtgggtata aagtacataa aatatatcta actattcata atgtggggtg ggtaatactg 6240 tctgtgaaat aatgtaagaa gcttttcact taaaaaaaat gcattacttt cacttaacac 6300 tagacaccag gtcgaaaatt ttcaaggtta tagtacttat ttcaacaatt cttagagatg 6360 ctagctagtg ttgaagctaa aaatagcttt atttatgctg aattgtgatt tttttatgcc 6420 aaattttttt tagttctaat cattgatgat agcttggaaa taaataatta tgccatggca 6480 tttgacagtt cattattcct ataagaatta aattgagttt agagagaatg gtggtgttga 6540 gctgattatt aacagttact gaaatcaaat atttatttgt tacattattc catttgtatt 6600 ttaggtttcc ttttacattc tttttatatg cattctgaca ttacatattt tttaagacta 6660 tggaaataat ttaaagattt aagctctggt ggatgattat ctgctaagta agtctgaaaa 6720 tgtaatattt tgataatact gtaatatacc tgtcacacaa atgcttttct aatgttttaa 6780 ccttgagtat tgcagttgct gctttgtaca gaggttactg caataaagga agtggattca 6840 ttaaacctat ttaatgtcca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 6891 134 3959 DNA Homo sapiens 134 ataaaagctg cccggggaag ccaggagagc gaagggcgga cgtactcgcc acggcaccca 60 ggctgcgcgc acgcggtccc ggtgtgcagc tggagagcga gcggccaccg ggagcccccg 120 gcacagcccg cgcccgcccc gcaggagccc gcgaagatgc cccggcgcag cctgcacgcg 180 gcggccgtgc tcctgctggt gatcttaaag gaacagcctt ccagcccggc cccagtgaac 240 ggttccaagt ggacttattt tggtcctgat ggggagaata gctggtccaa gaagtacccg 300 tcgtgtgggg gcctgctgca gtcccccata gacctgcaca gtgacatcct ccagtatgac 360 gccagcctca cgcccctcga gttccaaggc tacaatctgt ctgccaacaa gcagtttctc 420 ctgaccaaca atggccattc agtgaagctg aacctgccct cggacatgca catccagggc 480 ctccagtctc gctacagtgc cacgcagctg cacctgcact gggggaaccc gaatgacccg 540 cacggctctg agcacaccgt cagcggacag cacttcgccg ccgagctgca cattgtccat 600 tataactcag acctttatcc tgacgccagc actgccagca acaagtcaga aggcctcgct 660 gtcctggctg ttctcattga gatgggctcc ttcaatccgt cctatgacaa gatcttcagt 720 caccttcaac atgtaaagta caaaggccag gaagcattcg tcccgggatt caacattgaa 780 gagctgcttc cggagaggac cgctgaatat taccgctacc gggggtccct gaccacaccc 840 ccttgcaacc ccactgtgct ctggacagtt ttccgaaacc ccgtgcaaat ttcccaggag 900 cagctgctgg ctttggagac agccctgtac tgcacacaca tggacgaccc ttcccccaga 960 gaaatgatca acaacttccg gcaggtccag aagttcgatg agaggctggt atacacctcc 1020 ttctcccaag gcatcatcct ctcactggcc ctggctggca ttcttggcat ctgtattgtg 1080 gtggtggtgt ccatttggct tttcagaagg aagagtatca aaaaaggtga taacaaggga 1140 gtcatttaca agccagccac caagatggag actgaggccc acgcttgagg tccccggagc 1200 tcccgggcac atccaggaag gaccttgctt tggaccctac acacttcggc tctctggaca 1260 cttgcgacac ctcaaggtgt tctctgtagc tcaatctgca aacatgccag gcctcaggga 1320 tcctctgctg ggtgcctcct tgccttggga ccatggccac cccagagcca tccgatcgat 1380 ggatgggatg cactctcaga ccaagcagca ggaattcaaa gctgcttgct gtaactgtgt 1440 gagattgtga agtggtctga attctggaat cacaaaccaa gccatgctgg tgggccatta 1500 atggttggaa aacactttca tccggggctt tgccagagcg tgctttcaag tgtcctggaa 1560 attctgctgc ttctccaagc tttcagacaa gaatgtgcac tctctgctta ggttttgctt 1620 gggaaactca acttctttcc tctggagacg gggcatctcc ctctgatttc cttctgctat 1680 gacaaaacct ttaatctgca ccttacaact cggggacaaa tggggacagg aaggatcaag 1740 ttgtagagag aaaaagaaaa caagagatat acattgtgat atattaggga cactttcaca 1800 gtcctgtcct ctggatcaca gacactgcac agaccttagg gaatggcagg ttcaagttcc 1860 acttcttggt ggggatgaga agggagagag agctagaggg acaaagagaa tgagaagaca 1920 tggatgatct gggagagtct cactttggaa tcagaattgg aatcacattc tgtttatcaa 1980 gccataatgt aaggacagaa taatacaata ttaagtccaa atccaacctc ctgtcagtgg 2040 agcagttatg ttttatactc tacagatttt acaaataatg aggctgttcc ttgaaaatgt 2100 gttgttgctg tgtcctggag gagacatgag ttccgagatg acccaatctg cctttgaatc 2160 tggaggaaat aggcagaaac aaaatgactg tagaacttat tctctgtagg ccaaatttca 2220 tttcagccac ttctgcagga tccctactgc caacctggaa tggagacttt tatctacttc 2280 tctctctctg aagatgtcaa atcgtggttt agatcaaata tatttcaagc tataaaagca 2340 ggaggttatc tgtgcagggg gctggcatca tgtatttagg ggcaagtaat aatggaatgc 2400 tactaagata ctccatattc ttccccgaat cacacagaca gtttctgaca ggcgcaactc 2460 ctccattttc ctcccgcagg tgagaaccct gtggagatga gtcagtgcca tgactgagaa 2520 ggaaccgacc cctagttgag agcaccttgc agttccccga gaactttctg attcacagtc 2580 tcattttgac agcatgaaat gtcctcttga agcatagctt tttaaatatc tttttccttc 2640 tactcctccc tctgactcta agaattctct cttctggaat cgcttgaacc caggaggcgg 2700 aggttgcagt aagccaaggt catgccactg cactctagcc tgggtgacag agcgagactc 2760 catctcaaaa aaaaaaaaaa aaaaattatt ctgtaccatc acaacttttc acaacgatgg 2820 caagccttat gtcttgggag cctgttttgc taggcaaagt tacaagtgac ctaatgggag 2880 ctcaaatgtg tgtgtgtctc tctgtgtgtt tgtgtgtgtg tgtgcactca agacctctaa 2940 cagcctcgaa gcctggggtg gcatcccggc cttgccatta gcatgcctca tgcatcatca 3000 gatgacaagg acaaccctca tgacgaagca acatgaatta gggggcctct tggccttggt 3060 ccaaaattgt caatcagaaa tgaacataaa ggactccaga gcagtgggac tgtctgtcaa 3120 aagactctgt atatcttttg tggatgagtt ttgtgagaga acagagagac cattgtacct 3180 ggcacaaggg ctgttcatga aaagggagac ttactgggag gtgcaagaca gtggcatttc 3240 tcctctcctc ttgctgctca gcacagccct ggattgcagc cccgaggctg agaccagaca 3300 aagcccggga ggcagaaaga tgctccaaga accaacacta tcaatgtctt tgcaaatcct 3360 cacaggattc ctgtgggtcc agctttggaa ctgggaaacc tttcttcgga tccgcactca 3420 ttccactgat gccagctgcc cctgaaggat gccagtactg tggtgtgtga gtctcagcag 3480 ccgcccacac gctcctaact ctgctgcatg gcagatgcct aggtggaaat agcaaaaaca 3540 aggcccaggc tggggccagg gccagagggg aaggccctgg attctcactc atgtgagatc 3600 ttgaatctct ttctttgttc tgtttgttta gttagtatca tctggtaaaa tagttaaaaa 3660 acaacaaaaa actctgtatc tgtttctagc atgtgctgca ttgactctat taatcacatt 3720 tcaaattcac cctacattcc tctcctcttc actagcctct ctgaaggtgt cctggccagc 3780 cctggagaag cactggtgtc tgcagcaccc ctcagttcct gtgcctcagc ccacaggcca 3840 ctgtgataat ggtctgttta gcacttctgt atttattgta agaatgatta taatgaagat 3900 acacactgta actacaagaa attataaatg tttttcacat caaaaaaaaa aaaaaaaaa 3959 135 19 DNA Artificial Sequence TARGETING SEQUENCE 135 gacctgagca ctggcataa 19 136 19 DNA Artificial Sequence TARGETING SEQUENCE 136 tgacatcgac actcataca 19 137 19 DNA Artificial Sequence TARGETING SEQUENCE 137 acactcatac agccaagta 19 138 19 DNA Artificial Sequence TARGETING SEQUENCE 138 acaatggtca tgctttcaa 19 139 19 DNA Artificial Sequence TARGETING SEQUENCE 139 aggacaaagc agtgctcaa 19 140 19 DNA Artificial Sequence TARGETING SEQUENCE 140 gatggcactt acagattga 19 141 19 DNA Artificial Sequence TARGETING SEQUENCE 141 gcacttacag attgattca 19 142 19 DNA Artificial Sequence TARGETING SEQUENCE 142 acagattgat tcagtttca 19 143 19 DNA Artificial Sequence TARGETING SEQUENCE 143 acaaggttca gagcatact 19 144 19 DNA Artificial Sequence TARGETING SEQUENCE 144 cagaacttca cttggttca 19 145 19 DNA Artificial Sequence TARGETING SEQUENCE 145 actggccgtt ctaggtatt 19 146 19 DNA Artificial Sequence TARGETING SEQUENCE 146 ttgaaggttg gcagcgcta 19 147 19 DNA Artificial Sequence TARGETING SEQUENCE 147 tgaaggttgg cagcgctaa 19 148 19 DNA Artificial Sequence TARGETING SEQUENCE 148 ttgttgatgt gctggattc 19 149 19 DNA Artificial Sequence TARGETING SEQUENCE 149 gaaattccgt aaacttaac 19 150 19 DNA Artificial Sequence TARGETING SEQUENCE 150 ccgaagaact gatggtgga 19 151 19 DNA Artificial Sequence TARGETING SEQUENCE 151 gaactgatgg tggacaact 19 152 19 DNA Artificial Sequence TARGETING SEQUENCE 152 tgaagaacag gcaaatcaa 19 153 19 DNA Artificial Sequence TARGETING SEQUENCE 153 cttacttgat agacttact 19 154 19 DNA Artificial Sequence TARGETING SEQUENCE 154 tgtgaagact agaccaatt 19 155 19 DNA Artificial Sequence TARGETING SEQUENCE 155 ttgagctagt taaggcaaa 19 156 19 DNA Artificial Sequence TARGETING SEQUENCE 156 acactggtgc tacgaggtt 19 157 19 DNA Artificial Sequence TARGETING SEQUENCE 157 ctggtgctac gaggttcaa 19 158 19 DNA Artificial Sequence TARGETING SEQUENCE 158 gttcaagccg agtcctcca 19 159 19 DNA Artificial Sequence TARGETING SEQUENCE 159 ttcaagccga gtcctccaa 19 160 19 DNA Artificial Sequence TARGETING SEQUENCE 160 cctgcttggt gccagtcaa 19 161 19 DNA Artificial Sequence TARGETING SEQUENCE 161 tctctggcta cgataagaa 19 162 19 DNA Artificial Sequence TARGETING SEQUENCE 162 tggctacgat aagaagcaa 19 163 19 DNA Artificial Sequence TARGETING SEQUENCE 163 gcaaacgtgg actgtccaa 19 164 19 DNA Artificial Sequence TARGETING SEQUENCE 164 tggtccgact tgccatata 19 165 19 DNA Artificial Sequence TARGETING SEQUENCE 165 ccatggagat

gcacatagt 19 166 19 DNA Artificial Sequence TARGETING SEQUENCE 166 agatgcacat agtacatga 19 167 19 DNA Artificial Sequence TARGETING SEQUENCE 167 tgcacatagt acatgagaa 19 168 19 DNA Artificial Sequence TARGETING SEQUENCE 168 atagtacatg agaaagaga 19 169 19 DNA Artificial Sequence TARGETING SEQUENCE 169 catcgaggaa tgtgaaaga 19 170 19 DNA Artificial Sequence TARGETING SEQUENCE 170 ttgcggtgct ggcctttct 19 171 19 DNA Artificial Sequence TARGETING SEQUENCE 171 gaacagatcc tggcattct 19 172 19 DNA Artificial Sequence TARGETING SEQUENCE 172 tctctcagaa gctgtacta 19 173 19 DNA Artificial Sequence TARGETING SEQUENCE 173 aggaacagac agtgagcat 19 174 19 DNA Artificial Sequence TARGETING SEQUENCE 174 gaacagacag tgagcatga 19 175 19 DNA Artificial Sequence TARGETING SEQUENCE 175 ggcagcgcac ggtgataaa 19 176 19 DNA Artificial Sequence TARGETING SEQUENCE 176 cagcctctct gttgcctca 19 177 19 DNA Artificial Sequence TARGETING SEQUENCE 177 tgttgcctca gctctccaa 19 178 19 DNA Artificial Sequence TARGETING SEQUENCE 178 ttcaatccgt cctatgaca 19 179 19 DNA Artificial Sequence TARGETING SEQUENCE 179 agagcgtgct ttcaagtgt 19 180 19 DNA Artificial Sequence TARGETING SEQUENCE 180 gatgtcaaat cgtggttta 19 181 19 DNA Artificial Sequence TARGETING SEQUENCE 181 aaatcgtggt ttagatcaa 19 182 19 DNA Artificial Sequence TARGETING SEQUENCE 182 atggaatgct actaagata 19 183 19 DNA Artificial Sequence TARGETING SEQUENCE 183 ctactaagat actccatat 19 184 19 DNA Artificial Sequence TARGETING SEQUENCE 184 acaacgatgg caagcctta 19 185 19 DNA Artificial Sequence TARGETING SEQUENCE 185 caacgatggc aagccttat 19 186 19 DNA Artificial Sequence TARGETING SEQUENCE 186 ttgctaggca aagttacaa 19 187 19 DNA Artificial Sequence TARGETING SEQUENCE 187 taggcaaagt tacaagtga 19 188 19 DNA Artificial Sequence TARGETING SEQUENCE 188 agttacaagt gacctaatg 19 189 19 DNA Artificial Sequence TARGETING SEQUENCE 189 tgtgcactca agacctcta 19 190 19 DNA Artificial Sequence TARGETING SEQUENCE 190 gtgcactcaa gacctctaa 19 191 19 DNA Artificial Sequence TARGETING SEQUENCE 191 tgcactcaag acctctaac 19 192 19 DNA Artificial Sequence TARGETING SEQUENCE 192 gcactcaaga cctctaaca 19 193 19 DNA Artificial Sequence TARGETING SEQUENCE 193 agacctctaa cagcctcga 19 194 19 DNA Artificial Sequence TARGETING SEQUENCE 194 gacctctaac agcctcgaa 19 195 19 DNA Artificial Sequence TARGETING SEQUENCE 195 tgccattagc atgcctcat 19 196 19 DNA Artificial Sequence TARGETING SEQUENCE 196 gccattagca tgcctcatg 19 197 19 DNA Artificial Sequence TARGETING SEQUENCE 197 tagcatgcct catgcatca 19 198 19 DNA Artificial Sequence TARGETING SEQUENCE 198 catcatcaga tgacaagga 19 199 19 DNA Artificial Sequence TARGETING SEQUENCE 199 ctccttcaat ccgtcctat 19 200 19 DNA Artificial Sequence TARGETING SEQUENCE 200 agagcgtgct ttcaagtgt 19 201 19 DNA Artificial Sequence TARGETING SEQUENCE 201 gatgtcaaat cgtggttta 19 202 19 DNA Artificial Sequence TARGETING SEQUENCE 202 aaatcgtggt ttagatcaa 19 203 19 DNA Artificial Sequence TARGETING SEQUENCE 203 atggaatgct actaagata 19 204 19 DNA Artificial Sequence TARGETING SEQUENCE 204 ctactaagat actccatat 19 205 19 DNA Artificial Sequence TARGETING SEQUENCE 205 acaacgatgg caagcctta 19 206 19 DNA Artificial Sequence TARGETING SEQUENCE 206 caacgatggc aagccttat 19 207 19 DNA Artificial Sequence TARGETING SEQUENCE 207 ttgctaggca aagttacaa 19 208 19 DNA Artificial Sequence TARGETING SEQUENCE 208 taggcaaagt tacaagtga 19 209 19 DNA Artificial Sequence TARGETING SEQUENCE 209 agttacaagt gacctaatg 19 210 19 DNA Artificial Sequence TARGETING SEQUENCE 210 tgtgcactca agacctcta 19 211 19 DNA Artificial Sequence TARGETING SEQUENCE 211 gtgcactcaa gacctctaa 19 212 19 DNA Artificial Sequence TARGETING SEQUENCE 212 tgcactcaag acctctaac 19 213 19 DNA Artificial Sequence TARGETING SEQUENCE 213 gcactcaaga cctctaaca 19 214 19 DNA Artificial Sequence TARGETING SEQUENCE 214 agacctctaa cagcctcga 19 215 19 DNA Artificial Sequence TARGETING SEQUENCE 215 gacctctaac agcctcgaa 19 216 19 DNA Artificial Sequence TARGETING SEQUENCE 216 tgccattagc atgcctcat 19 217 19 DNA Artificial Sequence TARGETING SEQUENCE 217 gccattagca tgcctcatg 19 218 19 DNA Artificial Sequence TARGETING SEQUENCE 218 tagcatgcct catgcatca 19 219 19 DNA Artificial Sequence TARGETING SEQUENCE 219 catcatcaga tgacaagga 19 220 19 DNA Artificial Sequence TARGETING SEQUENCE 220 gcaatgtgct ggtgatcgt 19 221 19 DNA Artificial Sequence TARGETING SEQUENCE 221 tgatcgtggc catcgccaa 19 222 19 DNA Artificial Sequence TARGETING SEQUENCE 222 aagtgctgcg acttcgtca 19 223 19 DNA Artificial Sequence TARGETING SEQUENCE 223 cgtccgtagt ctccttcta 19 224 19 DNA Artificial Sequence TARGETING SEQUENCE 224 ccgtagtctc cttctacgt 19 225 19 DNA Artificial Sequence TARGETING SEQUENCE 225 atcatggcct tcgtgtacc 19 226 19 DNA Artificial Sequence TARGETING SEQUENCE 226 tcatggcctt cgtgtacct 19 227 19 DNA Artificial Sequence TARGETING SEQUENCE 227 cctcggaatc caaggtgta 19 228 19 DNA Artificial Sequence TARGETING SEQUENCE 228 tgtgtttact taagaccga 19 229 19 DNA Artificial Sequence TARGETING SEQUENCE 229 gtgtttactt aagaccgat 19 230 19 DNA Artificial Sequence TARGETING SEQUENCE 230 gtttacttaa gaccgatag 19 231 19 DNA Artificial Sequence TARGETING SEQUENCE 231 tttacttaag accgatagc 19 232 19 DNA Artificial Sequence TARGETING SEQUENCE 232 ttacttaaga ccgatagca 19 233 19 DNA Artificial Sequence TARGETING SEQUENCE 233 taagaccgat agcaggtga 19 234 19 DNA Artificial Sequence TARGETING SEQUENCE 234 accgatagca ggtgaactc 19 235 19 DNA Artificial Sequence TARGETING SEQUENCE 235 cgatagcagg tgaactcga 19 236 19 DNA Artificial Sequence TARGETING SEQUENCE 236 atagcaggtg aactcgaag 19 237 19 DNA Artificial Sequence TARGETING SEQUENCE 237 cacaatcctc gtctgaatc 19 238 19 DNA Artificial Sequence TARGETING SEQUENCE 238 acaatcctcg tctgaatca 19 239 19 DNA Artificial Sequence TARGETING SEQUENCE 239 tcatccgagg caaagagaa 19 240 19 DNA Artificial Sequence TARGETING SEQUENCE 240 catccgaggc aaagagaaa 19 241 19 DNA Artificial Sequence TARGETING SEQUENCE 241 ccacggaccg ttgcacaaa 19 242 19 DNA Artificial Sequence TARGETING SEQUENCE 242 cacgacgtca cgcagcaaa 19 243 19 DNA Artificial Sequence TARGETING SEQUENCE 243 gatcgctact ttgccatta 19 244 19 DNA Artificial Sequence TARGETING SEQUENCE 244 atcgctactt tgccattac 19 245 19 DNA Artificial Sequence TARGETING SEQUENCE 245 tcgctacttt gccattact 19 246 19 DNA Artificial Sequence TARGETING SEQUENCE 246 gccattactt cacctttca 19 247 19 DNA Artificial Sequence TARGETING SEQUENCE 247 ttacttcacc tttcaagta 19 248 19 DNA Artificial Sequence TARGETING SEQUENCE 248 ccattcagat gcactggta 19 249 19 DNA Artificial Sequence TARGETING SEQUENCE 249 tgatcatggt cttcgtcta 19 250 19 DNA Artificial Sequence TARGETING SEQUENCE 250 agacgttagg catcatcat 19 251 19 DNA Artificial Sequence TARGETING SEQUENCE 251 tcgttaacat tgtgcatgt 19 252 19 DNA Artificial Sequence TARGETING SEQUENCE 252 aggataacct catccgtaa 19 253 19 DNA Artificial Sequence TARGETING SEQUENCE 253 tcatccgtaa ggaagttta 19 254 19 DNA Artificial Sequence TARGETING SEQUENCE 254 aagtttacat cctcctaaa 19 255 19 DNA Artificial Sequence TARGETING SEQUENCE 255 agtttacatc ctcctaaat 19 256 19 DNA Artificial Sequence TARGETING SEQUENCE 256 taaattggat aggctatgt 19 257 19 DNA Artificial Sequence TARGETING SEQUENCE 257 ctatgtcaat tctggtttc 19 258 19 DNA Artificial Sequence TARGETING SEQUENCE 258 ggtactgtgc ctagcgata 19 259 19 DNA Artificial Sequence TARGETING SEQUENCE 259 gtactgtgcc tagcgataa 19 260 19 DNA Artificial Sequence TARGETING SEQUENCE 260 tactgtgcct agcgataac 19 261 19 DNA Artificial Sequence TARGETING SEQUENCE 261 gcgataacat tgattcaca 19 262 19 DNA Artificial Sequence TARGETING SEQUENCE 262 cgataacatt gattcacaa 19 263 19 DNA Artificial Sequence TARGETING SEQUENCE 263 ggaggaattg tagtacaaa 19 264 19 DNA Artificial Sequence TARGETING SEQUENCE 264 gaggaattgt agtacaaat 19 265 19 DNA Artificial Sequence TARGETING SEQUENCE 265 aggaattgta gtacaaatg 19 266 19 DNA Artificial Sequence TARGETING SEQUENCE 266 caaatgactc actgctgta 19 267 19 DNA Artificial Sequence TARGETING SEQUENCE 267 gacctgagtc tgctatatt 19 268 19 DNA Artificial Sequence TARGETING SEQUENCE 268 acctgagtct gctatattt 19 269 19 DNA Artificial Sequence TARGETING SEQUENCE 269 ccatgtatct acctcacta 19 270 19 DNA Artificial Sequence TARGETING SEQUENCE 270 catgtatcta cctcactat 19 271 19 DNA Artificial Sequence TARGETING SEQUENCE 271 atgtatctac ctcactatt 19 272 19 DNA Artificial Sequence TARGETING SEQUENCE 272 cctcactatt caagtatta 19 273 19 DNA Artificial Sequence TARGETING SEQUENCE 273 taatatattg ctgctggta 19 274 19 DNA Artificial Sequence TARGETING SEQUENCE 274 aatatattgc tgctggtaa 19 275 19 DNA Artificial Sequence TARGETING SEQUENCE 275 atatattgct gctggtaat 19 276 19 DNA Artificial Sequence TARGETING SEQUENCE 276 tatattgctg ctggtaatt 19 277 19 DNA Artificial Sequence TARGETING SEQUENCE 277 ctggtaattt gtatctgaa 19 278 19 DNA Artificial Sequence TARGETING SEQUENCE 278 gagtatctcg gacctttca 19 279 19 DNA Artificial Sequence TARGETING SEQUENCE 279 cggacctttc agctgtgaa 19 280 19 DNA Artificial Sequence TARGETING SEQUENCE 280 cgagcaaagg tctaaagtt 19 281 19 DNA Artificial Sequence TARGETING SEQUENCE 281 gagcaaaggt ctaaagttt 19 282 19 DNA Artificial Sequence TARGETING SEQUENCE 282 ggtctaaagt ttacagtaa 19 283 19 DNA Artificial Sequence TARGETING SEQUENCE 283 agtgtctgct accaatatg 19 284 19 DNA Artificial Sequence TARGETING SEQUENCE 284 agacaacgag tctctcatc 19 285 19 DNA Artificial Sequence TARGETING SEQUENCE 285 ggctgtggtc ctgcattac 19 286 19 DNA Artificial Sequence TARGETING SEQUENCE 286 cttcctcctc aaaccgaga 19 287 19 DNA Artificial Sequence TARGETING SEQUENCE 287 tcctcctcaa accgagaga 19 288 19 DNA Artificial Sequence TARGETING SEQUENCE 288 cctcaaaccg agagactca 19 289 19 DNA Artificial Sequence TARGETING SEQUENCE 289 tcaaaccgag agactcaca 19 290 19 DNA Artificial Sequence TARGETING SEQUENCE 290 aaaccgagag actcacact 19 291 19 DNA Artificial Sequence TARGETING SEQUENCE 291 ccacgccttt gttgtttga 19 292 19 DNA Artificial Sequence TARGETING SEQUENCE 292 cacgcctttg ttgtttgaa 19 293 19 DNA Artificial Sequence TARGETING SEQUENCE 293 acgcctttgt tgtttgaat 19 294 19 DNA Artificial Sequence TARGETING SEQUENCE 294 ggctataacg gtcaaccat 19 295 19 DNA Artificial Sequence TARGETING SEQUENCE 295 tataacggtc aaccatttc 19 296 19 DNA Artificial Sequence TARGETING SEQUENCE 296 cggtcaacca tttctgtct 19 297 19 DNA Artificial Sequence TARGETING SEQUENCE 297 gtcaaccatt tctgtctct 19 298 19 DNA Artificial Sequence TARGETING SEQUENCE 298 ccgtcttccg gtcattctt 19 299 19 DNA Artificial Sequence TARGETING SEQUENCE 299 cctctcgtct ttcgcacat 19 300 19 DNA Artificial Sequence TARGETING SEQUENCE 300 tctcgtcttt cgcacattc 19 301 19 DNA Artificial Sequence TARGETING SEQUENCE 301 tttcgcacat tctcctgat 19 302 19 DNA Artificial Sequence TARGETING SEQUENCE 302 ttcgcacatt ctcctgatc 19 303 19 DNA Artificial Sequence TARGETING SEQUENCE 303 agaaccagtt cgaccacta 19 304 19 DNA Artificial Sequence TARGETING SEQUENCE 304 aaccagttcg accactaca 19 305 19 DNA Artificial Sequence TARGETING SEQUENCE 305 ctgcaaataa actgttaca 19 306 19 DNA Artificial Sequence TARGETING SEQUENCE 306 tagacgctac aaccttcca 19 307 19 DNA Artificial Sequence TARGETING SEQUENCE 307 cgctacaacc ttccagagt 19 308 19 DNA Artificial Sequence TARGETING SEQUENCE 308 agagtgtctg ctaccaata

19 309 19 DNA Artificial Sequence TARGETING SEQUENCE 309 gagtgtctgc taccaatat 19 310 19 DNA Artificial Sequence TARGETING SEQUENCE 310 ctgtcctcgt ctggatcta 19 311 19 DNA Artificial Sequence TARGETING SEQUENCE 311 atggccgctt cttggtaca 19 312 19 DNA Artificial Sequence TARGETING SEQUENCE 312 cgacatcagt gacgctgtt 19 313 19 DNA Artificial Sequence TARGETING SEQUENCE 313 gcacgtgctg cctcaagaa 19 314 19 DNA Artificial Sequence TARGETING SEQUENCE 314 cacgtgctgc ctcaagaaa 19 315 19 DNA Artificial Sequence TARGETING SEQUENCE 315 gaaagcgtct tccggttct 19 316 19 DNA Artificial Sequence TARGETING SEQUENCE 316 tgtggtagat ggagacttc 19 317 19 DNA Artificial Sequence TARGETING SEQUENCE 317 gacaacgagt ctctcatca 19 318 19 DNA Artificial Sequence TARGETING SEQUENCE 318 aggctgtggt cctgcatta 19 319 19 DNA Artificial Sequence TARGETING SEQUENCE 319 gctgtggtcc tgcattaca 19 320 19 DNA Artificial Sequence TARGETING SEQUENCE 320 gtctacgcct acgtctttg 19 321 19 DNA Artificial Sequence TARGETING SEQUENCE 321 tctacgccta cgtctttga 19 322 19 DNA Artificial Sequence TARGETING SEQUENCE 322 ctacgcctac gtctttgaa 19 323 19 DNA Artificial Sequence TARGETING SEQUENCE 323 cggctacgag atcgagttc 19 324 19 DNA Artificial Sequence TARGETING SEQUENCE 324 cagcgactga tgcgatact 19 325 19 DNA Artificial Sequence TARGETING SEQUENCE 325 ggctcagcag tacgttagt 19 326 19 DNA Artificial Sequence TARGETING SEQUENCE 326 agtacgttag tctggacct 19 327 19 DNA Artificial Sequence TARGETING SEQUENCE 327 acatggtgca ctggaagaa 19 328 19 DNA Artificial Sequence TARGETING SEQUENCE 328 agaaccagtt cgaccacta 19 329 19 DNA Artificial Sequence TARGETING SEQUENCE 329 gaaccagttc gaccactac 19 330 19 DNA Artificial Sequence TARGETING SEQUENCE 330 ggctataaca cagacgagc 19 331 19 DNA Artificial Sequence TARGETING SEQUENCE 331 gctataacac agacgagcc 19 332 19 DNA Artificial Sequence TARGETING SEQUENCE 332 gctgcaaata aactgttac 19 333 19 DNA Artificial Sequence TARGETING SEQUENCE 333 ctgcaaataa actgttaca 19 334 19 DNA Artificial Sequence TARGETING SEQUENCE 334 gcaatgagac cgtggaaga 19 335 19 DNA Artificial Sequence TARGETING SEQUENCE 335 tgccaaggcc tgcgtagta 19 336 19 DNA Artificial Sequence TARGETING SEQUENCE 336 taaaggacat gacctccga 19 337 19 DNA Artificial Sequence TARGETING SEQUENCE 337 agcaagctgc tgacatgat 19 338 19 DNA Artificial Sequence TARGETING SEQUENCE 338 acatgattct tctggatga 19 339 19 DNA Artificial Sequence TARGETING SEQUENCE 339 gtcgtctgat ctttgataa 19 340 19 DNA Artificial Sequence TARGETING SEQUENCE 340 cttatacctt aaccagtaa 19 341 19 DNA Artificial Sequence TARGETING SEQUENCE 341 ggatcaacga tgtggaaga 19 342 19 DNA Artificial Sequence TARGETING SEQUENCE 342 acgatgtgga agacagcta 19 343 19 DNA Artificial Sequence TARGETING SEQUENCE 343 ccgacttggt catctgtaa 19 344 19 DNA Artificial Sequence TARGETING SEQUENCE 344 taggaaagca ccgcagcat 19 345 19 DNA Artificial Sequence TARGETING SEQUENCE 345 agacgtcctg gaatgaagc 19 346 19 DNA Artificial Sequence TARGETING SEQUENCE 346 gacgtcctgg aatgaagca 19 347 19 DNA Artificial Sequence TARGETING SEQUENCE 347 acgtcctgga atgaagcat 19 348 19 DNA Artificial Sequence TARGETING SEQUENCE 348 gaagcatgta gctctatgg 19 349 19 DNA Artificial Sequence TARGETING SEQUENCE 349 ttcagaacaa ggtgataaa 19 350 19 DNA Artificial Sequence TARGETING SEQUENCE 350 tgatgaactt catcgtaaa 19 351 19 DNA Artificial Sequence TARGETING SEQUENCE 351 ggtgctatca gccgttgta 19 352 19 DNA Artificial Sequence TARGETING SEQUENCE 352 tcagccgttg taatcataa 19 353 19 DNA Artificial Sequence TARGETING SEQUENCE 353 gattcgaaat ggtgagaaa 19 354 19 DNA Artificial Sequence TARGETING SEQUENCE 354 cagaatcata tctgcaaat 19 355 19 DNA Artificial Sequence TARGETING SEQUENCE 355 cacgtggtat tgttgtcta 19 356 19 DNA Artificial Sequence TARGETING SEQUENCE 356 ctgcttagtg aagaactta 19 357 19 DNA Artificial Sequence TARGETING SEQUENCE 357 gtttcaggct aaccaggaa 19 358 19 DNA Artificial Sequence TARGETING SEQUENCE 358 cactcttaaa gtgcataga 19 359 19 DNA Artificial Sequence TARGETING SEQUENCE 359 agtaccagtt gtctattca 19 360 19 DNA Artificial Sequence TARGETING SEQUENCE 360 taccagttgt ctattcata 19 361 19 DNA Artificial Sequence TARGETING SEQUENCE 361 agctgaaaga cgcctttca 19 362 19 DNA Artificial Sequence TARGETING SEQUENCE 362 tcgataatct gtgctttgt 19 363 19 DNA Artificial Sequence TARGETING SEQUENCE 363 acaggagacc atccaatca 19 364 19 DNA Artificial Sequence TARGETING SEQUENCE 364 tagccttgat gaacttcat 19 365 19 DNA Artificial Sequence TARGETING SEQUENCE 365 ttgatgaact tcatcgtaa 19 366 19 DNA Artificial Sequence TARGETING SEQUENCE 366 gatgaacttc atcgtaaat 19 367 19 DNA Artificial Sequence TARGETING SEQUENCE 367 ctactcctga atggatcaa 19 368 19 DNA Artificial Sequence TARGETING SEQUENCE 368 ggagcgattc tttgtttct 19 369 19 DNA Artificial Sequence TARGETING SEQUENCE 369 gtgctatcag ccgttgtaa 19 370 19 DNA Artificial Sequence TARGETING SEQUENCE 370 tgctatcagc cgttgtaat 19 371 19 DNA Artificial Sequence TARGETING SEQUENCE 371 gagcataaat gcggaggaa 19 372 19 DNA Artificial Sequence TARGETING SEQUENCE 372 gaaggcaatg gacctatga 19 373 19 DNA Artificial Sequence TARGETING SEQUENCE 373 ccgacttggt catctgtaa 19 374 19 DNA Artificial Sequence TARGETING SEQUENCE 374 tatatgacga agtcagaaa 19 375 19 DNA Artificial Sequence TARGETING SEQUENCE 375 tggcaatgga tgaccacaa 19 376 19 DNA Artificial Sequence TARGETING SEQUENCE 376 tgaaccatcc aacgacaat 19 377 19 DNA Artificial Sequence TARGETING SEQUENCE 377 accatccaac gacaatcta 19 378 19 DNA Artificial Sequence TARGETING SEQUENCE 378 catccaacga caatctata 19 379 19 DNA Artificial Sequence TARGETING SEQUENCE 379 atccaacgac aatctatat 19 380 19 DNA Artificial Sequence TARGETING SEQUENCE 380 gcagatcaac gcagaggaa 19 381 19 DNA Artificial Sequence TARGETING SEQUENCE 381 tgtttcttct ccaccaact 19 382 19 DNA Artificial Sequence TARGETING SEQUENCE 382 ccatagcaat ggagattga 19 383 19 DNA Artificial Sequence TARGETING SEQUENCE 383 agatgcaaga tgcctttca 19 384 19 DNA Artificial Sequence TARGETING SEQUENCE 384 ctgaatctgc catctggaa 19 385 19 DNA Artificial Sequence TARGETING SEQUENCE 385 tgaatctgcc atctggaaa 19 386 19 DNA Artificial Sequence TARGETING SEQUENCE 386 atcgtctttg ctcgaacgt 19 387 19 DNA Artificial Sequence TARGETING SEQUENCE 387 ctgcattgaa gaaggctga 19 388 19 DNA Artificial Sequence TARGETING SEQUENCE 388 atgaagcggc agccacgaa 19 389 19 DNA Artificial Sequence TARGETING SEQUENCE 389 tgaagcggca gccacgaaa 19 390 19 DNA Artificial Sequence TARGETING SEQUENCE 390 ggatgaccgg accatgaat 19 391 19 DNA Artificial Sequence TARGETING SEQUENCE 391 gctgcctttc tctcttact 19 392 19 DNA Artificial Sequence TARGETING SEQUENCE 392 tctatgatga ggtccgaaa 19 393 19 DNA Artificial Sequence TARGETING SEQUENCE 393 gtggagaagg agacatact 19 394 19 DNA Artificial Sequence TARGETING SEQUENCE 394 tggagaagga gacatacta 19 395 19 DNA Artificial Sequence TARGETING SEQUENCE 395 tagacctaac tgtgaacaa 19 396 19 DNA Artificial Sequence TARGETING SEQUENCE 396 agacctaact gtgaacaat 19 397 19 DNA Artificial Sequence TARGETING SEQUENCE 397 tccactatgt tgtctattt 19 398 19 DNA Artificial Sequence TARGETING SEQUENCE 398 tgagtgcaag agcctgaga 19 399 19 DNA Artificial Sequence TARGETING SEQUENCE 399 tgacatgagt ctccagata 19 400 19 DNA Artificial Sequence TARGETING SEQUENCE 400 gtcgtggact ccagctcta 19 401 19 DNA Artificial Sequence TARGETING SEQUENCE 401 tgtcactcat gtacttaat 19 402 19 DNA Artificial Sequence TARGETING SEQUENCE 402 gtcactcatg tacttaata 19 403 19 DNA Artificial Sequence TARGETING SEQUENCE 403 cacttcacct tctgtaata 19 404 19 DNA Artificial Sequence TARGETING SEQUENCE 404 gtagagagag acctagata 19 405 19 DNA Artificial Sequence TARGETING SEQUENCE 405 ctagataggt catgcaagt 19 406 19 DNA Artificial Sequence TARGETING SEQUENCE 406 aggtcatgca agtgagaaa 19 407 19 DNA Artificial Sequence TARGETING SEQUENCE 407 tatcagaagc aaggaagta 19 408 19 DNA Artificial Sequence TARGETING SEQUENCE 408 tccgattaat tggagatta 19 409 19 DNA Artificial Sequence TARGETING SEQUENCE 409 ccgattaatt ggagattac 19 410 19 DNA Artificial Sequence TARGETING SEQUENCE 410 gattactaac tgtggacaa 19 411 19 DNA Artificial Sequence TARGETING SEQUENCE 411 attactaact gtggacaaa 19 412 19 DNA Artificial Sequence TARGETING SEQUENCE 412 tcaggcactt tagaaatat 19 413 19 DNA Artificial Sequence TARGETING SEQUENCE 413 ggctaattat catcaatct 19 414 19 DNA Artificial Sequence TARGETING SEQUENCE 414 agtttgaggt actacctat 19 415 19 DNA Artificial Sequence TARGETING SEQUENCE 415 tactacctat gtacttgaa 19 416 19 DNA Artificial Sequence TARGETING SEQUENCE 416 actacctatg tacttgaaa 19 417 19 DNA Artificial Sequence TARGETING SEQUENCE 417 tggctatgac agagcacaa 19 418 19 DNA Artificial Sequence TARGETING SEQUENCE 418 gaggtctgcc ggaaataca 19 419 19 DNA Artificial Sequence TARGETING SEQUENCE 419 ctcacgccac cgcctacca 19 420 19 DNA Artificial Sequence TARGETING SEQUENCE 420 tcgactgtga tgacgtgaa 19 421 19 DNA Artificial Sequence TARGETING SEQUENCE 421 tgaacttcac cacggacaa 19 422 19 DNA Artificial Sequence TARGETING SEQUENCE 422 ccaaggcctg cgtgatcca 19 423 19 DNA Artificial Sequence TARGETING SEQUENCE 423 ggacttcacc tccgagcaa 19 424 19 DNA Artificial Sequence TARGETING SEQUENCE 424 gacttcacct ccgagcaaa 19 425 19 DNA Artificial Sequence TARGETING SEQUENCE 425 acttcacctc cgagcaaat 19 426 19 DNA Artificial Sequence TARGETING SEQUENCE 426 tcgacgagat cctgcagaa 19 427 19 DNA Artificial Sequence TARGETING SEQUENCE 427 cgacgagatc ctgcagaat 19 428 19 DNA Artificial Sequence TARGETING SEQUENCE 428 acgagatcct gcagaatca 19 429 19 DNA Artificial Sequence TARGETING SEQUENCE 429 gatcttcgac aacctaaag 19 430 19 DNA Artificial Sequence TARGETING SEQUENCE 430 ccatctcact ggcgtacga 19 431 19 DNA Artificial Sequence TARGETING SEQUENCE 431 ctgccgaaag cgacatcat 19 432 19 DNA Artificial Sequence TARGETING SEQUENCE 432 cggacaaatt ggtcaatga 19 433 19 DNA Artificial Sequence TARGETING SEQUENCE 433 caaattggtc aatgagaga 19 434 19 DNA Artificial Sequence TARGETING SEQUENCE 434 ggatgaccgc accgtcaat 19 435 19 DNA Artificial Sequence TARGETING SEQUENCE 435 caccgtcaat gacctggaa 19 436 19 DNA Artificial Sequence TARGETING SEQUENCE 436 atcttcgtct acgacgaaa 19 437 19 DNA Artificial Sequence TARGETING SEQUENCE 437 ctacgacgaa atccgcaaa 19 438 19 DNA Artificial Sequence TARGETING SEQUENCE 438 acgacgaaat ccgcaaact 19 439 19 DNA Artificial Sequence TARGETING SEQUENCE 439 acgaaatccg caaactcat 19 440 19 DNA Artificial Sequence TARGETING SEQUENCE 440 ccaaacctct ctcctctct 19 441 19 DNA Artificial Sequence TARGETING SEQUENCE 441 ggcacctggt tacgcttca 19 442 19 DNA Artificial Sequence TARGETING SEQUENCE 442 catggatgat cacaaatta 19 443 19 DNA Artificial Sequence TARGETING SEQUENCE 443 aatcctgact cgagatgga 19 444 19 DNA Artificial Sequence TARGETING SEQUENCE 444 cctacagcat ccagatata 19 445 19 DNA Artificial Sequence TARGETING SEQUENCE 445 ccggcttatc tctgcacaa 19 446 19 DNA Artificial Sequence TARGETING SEQUENCE 446 agctctgata cctggttta 19 447 19 DNA Artificial Sequence TARGETING SEQUENCE 447 gctctgatac ctggtttat 19 448 19 DNA Artificial Sequence TARGETING SEQUENCE 448 aggtgatgct tccgagtca 19 449 19 DNA Artificial Sequence TARGETING SEQUENCE 449 gtactcaatg aacgatgaa 19 450 19 DNA Artificial Sequence TARGETING SEQUENCE 450 tactcaatga acgatgaaa 19 451 19 DNA Artificial Sequence TARGETING SEQUENCE 451 gtgctaggct tctgcttct 19 452 19 DNA Artificial Sequence TARGETING SEQUENCE

452 catggtaaca ggagatcat 19 453 19 DNA Artificial Sequence TARGETING SEQUENCE 453 tgtggtgcat ggtgcagaa 19 454 19 DNA Artificial Sequence TARGETING SEQUENCE 454 tgttcatcat cctcggtat 19 455 19 DNA Artificial Sequence TARGETING SEQUENCE 455 gttcatcatc ctcggtata 19 456 19 DNA Artificial Sequence TARGETING SEQUENCE 456 ggcttatgag tcagctgaa 19 457 19 DNA Artificial Sequence TARGETING SEQUENCE 457 ggacctatga gcaacgaaa 19 458 19 DNA Artificial Sequence TARGETING SEQUENCE 458 cggatctcat catctccaa 19 459 19 DNA Artificial Sequence TARGETING SEQUENCE 459 tggctgcatt tctgtccta 19 460 19 DNA Artificial Sequence TARGETING SEQUENCE 460 gctgcatttc tgtcctaca 19 461 19 DNA Artificial Sequence TARGETING SEQUENCE 461 gtattctcat cttcgtcta 19 462 19 DNA Artificial Sequence TARGETING SEQUENCE 462 tattctcatc ttcgtctat 19 463 19 DNA Artificial Sequence TARGETING SEQUENCE 463 actaaactca gcagatgaa 19 464 19 DNA Artificial Sequence TARGETING SEQUENCE 464 ggccagagat tataagttt 19 465 19 DNA Artificial Sequence TARGETING SEQUENCE 465 gccagagatt ataagtttg 19 466 19 DNA Artificial Sequence TARGETING SEQUENCE 466 ccagagatta taagtttga 19 467 19 DNA Artificial Sequence TARGETING SEQUENCE 467 cagagattat aagtttgac 19 468 19 DNA Artificial Sequence TARGETING SEQUENCE 468 ataagtttga cacaacatc 19 469 19 DNA Artificial Sequence TARGETING SEQUENCE 469 taagtttgac acaacatct 19 470 19 DNA Artificial Sequence TARGETING SEQUENCE 470 tctgagacac taggatgaa 19 471 19 DNA Artificial Sequence TARGETING SEQUENCE 471 agacactagg atgaattat 19 472 19 DNA Artificial Sequence TARGETING SEQUENCE 472 gacactagga tgaattatc 19 473 19 DNA Artificial Sequence TARGETING SEQUENCE 473 aggatgaatt atcttggat 19 474 19 DNA Artificial Sequence TARGETING SEQUENCE 474 gatgaattat cttggatga 19 475 19 DNA Artificial Sequence TARGETING SEQUENCE 475 cgtagccagt ctagacagt 19 476 19 DNA Artificial Sequence TARGETING SEQUENCE 476 gccagtctag acagtaaat 19 477 19 DNA Artificial Sequence TARGETING SEQUENCE 477 cagtctagac agtaaatgt 19 478 19 DNA Artificial Sequence TARGETING SEQUENCE 478 agacagtaaa tgtctggaa 19 479 19 DNA Artificial Sequence TARGETING SEQUENCE 479 gacagtaaat gtctggaaa 19 480 19 DNA Artificial Sequence TARGETING SEQUENCE 480 gctggattct ttacctact 19 481 19 DNA Artificial Sequence TARGETING SEQUENCE 481 gtggacctat gagcaacga 19 482 19 DNA Artificial Sequence TARGETING SEQUENCE 482 tggacctatg agcaacgaa 19 483 19 DNA Artificial Sequence TARGETING SEQUENCE 483 ggacctatga gcaacgaaa 19 484 19 DNA Artificial Sequence TARGETING SEQUENCE 484 cggatctcat catctccaa 19 485 19 DNA Artificial Sequence TARGETING SEQUENCE 485 tggctgcatt tctgtccta 19 486 19 DNA Artificial Sequence TARGETING SEQUENCE 486 gctgcatttc tgtcctaca 19 487 19 DNA Artificial Sequence TARGETING SEQUENCE 487 gtattctcat cttcgtcta 19 488 19 DNA Artificial Sequence TARGETING SEQUENCE 488 tattctcatc ttcgtctat 19 489 19 DNA Artificial Sequence TARGETING SEQUENCE 489 cttcgtctat gatgaaatc 19 490 19 DNA Artificial Sequence TARGETING SEQUENCE 490 actactaaac tcagcagat 19 491 19 DNA Artificial Sequence TARGETING SEQUENCE 491 ctactaaact cagcagatg 19 492 19 DNA Artificial Sequence TARGETING SEQUENCE 492 tactaaactc agcagatga 19 493 19 DNA Artificial Sequence TARGETING SEQUENCE 493 actaaactca gcagatgaa 19 494 19 DNA Artificial Sequence TARGETING SEQUENCE 494 ggccagagat tataagttt 19 495 19 DNA Artificial Sequence TARGETING SEQUENCE 495 gccagagatt ataagtttg 19 496 19 DNA Artificial Sequence TARGETING SEQUENCE 496 ccagagatta taagtttga 19 497 19 DNA Artificial Sequence TARGETING SEQUENCE 497 cagagattat aagtttgac 19 498 19 DNA Artificial Sequence TARGETING SEQUENCE 498 ataagtttga cacaacatc 19 499 19 DNA Artificial Sequence TARGETING SEQUENCE 499 taagtttgac acaacatct 19 500 19 DNA Artificial Sequence TARGETING SEQUENCE 500 tctgagacac taggatgaa 19 501 19 DNA Artificial Sequence TARGETING SEQUENCE 501 agacactagg atgaattat 19 502 19 DNA Artificial Sequence TARGETING SEQUENCE 502 gacactagga tgaattatc 19 503 19 DNA Artificial Sequence TARGETING SEQUENCE 503 taggatgaat tatcttgga 19 504 19 DNA Artificial Sequence TARGETING SEQUENCE 504 aggatgaatt atcttggat 19 505 19 DNA Artificial Sequence TARGETING SEQUENCE 505 gatgaattat cttggatga 19 506 19 DNA Artificial Sequence TARGETING SEQUENCE 506 tgaattatct tggatgaga 19 507 19 DNA Artificial Sequence TARGETING SEQUENCE 507 cgtagccagt ctagacagt 19 508 19 DNA Artificial Sequence TARGETING SEQUENCE 508 gccagtctag acagtaaat 19 509 19 DNA Artificial Sequence TARGETING SEQUENCE 509 cagtctagac agtaaatgt 19 510 19 DNA Artificial Sequence TARGETING SEQUENCE 510 agacagtaaa tgtctggaa 19 511 19 DNA Artificial Sequence TARGETING SEQUENCE 511 gacagtaaat gtctggaaa 19 512 19 DNA Artificial Sequence TARGETING SEQUENCE 512 acctactagt cttgaacaa 19 513 19 DNA Artificial Sequence TARGETING SEQUENCE 513 tactagtctt gaacaaact 19 514 19 DNA Artificial Sequence TARGETING SEQUENCE 514 ggacctacac ttaatctat 19 515 19 DNA Artificial Sequence TARGETING SEQUENCE 515 gacctacact taatctata 19 516 19 DNA Artificial Sequence TARGETING SEQUENCE 516 ctgcatttaa taggttaga 19 517 19 DNA Artificial Sequence TARGETING SEQUENCE 517 cgtaactgac ttgtagtaa 19 518 19 DNA Artificial Sequence TARGETING SEQUENCE 518 agcaaggttt gctgtccaa 19 519 19 DNA Artificial Sequence TARGETING SEQUENCE 519 tgctgtccaa ggtgtaaat 19 520 19 DNA Artificial Sequence TARGETING SEQUENCE 520 gctgtccaag gtgtaaata 19 521 19 DNA Artificial Sequence TARGETING SEQUENCE 521 ctgtccaagg tgtaaatat 19 522 19 DNA Artificial Sequence TARGETING SEQUENCE 522 ttaacatact ccatagtct 19 523 19 DNA Artificial Sequence TARGETING SEQUENCE 523 gccttgtcct ccggtatgt 19 524 19 DNA Artificial Sequence TARGETING SEQUENCE 524 tgtcctccgg tatgttcta 19 525 19 DNA Artificial Sequence TARGETING SEQUENCE 525 gtcctccggt atgttctaa 19 526 19 DNA Artificial Sequence TARGETING SEQUENCE 526 tcctccggta tgttctaaa 19 527 19 DNA Artificial Sequence TARGETING SEQUENCE 527 ccatcacttt ggctagtga 19 528 19 DNA Artificial Sequence TARGETING SEQUENCE 528 accggtggca gttggttta 19 529 19 DNA Artificial Sequence TARGETING SEQUENCE 529 ccggtggcag ttggtttaa 19 530 19 DNA Artificial Sequence TARGETING SEQUENCE 530 ttggtttaag atccttcta 19 531 19 DNA Artificial Sequence TARGETING SEQUENCE 531 agatccttct attctacgt 19 532 19 DNA Artificial Sequence TARGETING SEQUENCE 532 atccttctat tctacgtaa 19 533 19 DNA Artificial Sequence TARGETING SEQUENCE 533 tccttctatt ctacgtaat 19 534 19 DNA Artificial Sequence TARGETING SEQUENCE 534 ccttctattc tacgtaata 19 535 19 DNA Artificial Sequence TARGETING SEQUENCE 535 gaaatttcct ttcgtccta 19 536 19 DNA Artificial Sequence TARGETING SEQUENCE 536 aacgaggaga ctttaatca 19 537 19 DNA Artificial Sequence TARGETING SEQUENCE 537 gaaattgctc tggattaaa 19 538 19 DNA Artificial Sequence TARGETING SEQUENCE 538 atgaaactta tggctacaa 19 539 19 DNA Artificial Sequence TARGETING SEQUENCE 539 tgaaacttat ggctacaaa 19 540 19 DNA Artificial Sequence TARGETING SEQUENCE 540 aaacttatgg ctacaaaga 19 541 19 DNA Artificial Sequence TARGETING SEQUENCE 541 ggcaaaccgt gcattatta 19 542 19 DNA Artificial Sequence TARGETING SEQUENCE 542 gcaaaccgtg cattattat 19 543 19 DNA Artificial Sequence TARGETING SEQUENCE 543 accgagttct aggcttcaa 19 544 19 DNA Artificial Sequence TARGETING SEQUENCE 544 ccgagttcta ggcttcaaa 19 545 19 DNA Artificial Sequence TARGETING SEQUENCE 545 ttctaggctt caaacctaa 19 546 19 DNA Artificial Sequence TARGETING SEQUENCE 546 atgagtcctt ggagactta 19 547 19 DNA Artificial Sequence TARGETING SEQUENCE 547 gcaagcgaga tgaagataa 19 548 19 DNA Artificial Sequence TARGETING SEQUENCE 548 agttggaaat gtggagtat 19 549 19 DNA Artificial Sequence TARGETING SEQUENCE 549 ctgcagtatt atccgtact 19 550 19 DNA Artificial Sequence TARGETING SEQUENCE 550 tgcagtatta tccgtacta 19 551 19 DNA Artificial Sequence TARGETING SEQUENCE 551 gcagtattat ccgtactat 19 552 19 DNA Artificial Sequence TARGETING SEQUENCE 552 ccgtacagtt caccaatct 19 553 19 DNA Artificial Sequence TARGETING SEQUENCE 553 tcaccaatct taccatgga 19 554 19 DNA Artificial Sequence TARGETING SEQUENCE 554 aaattcgcat agagtgtaa 19 555 19 DNA Artificial Sequence TARGETING SEQUENCE 555 tgtaaggcgt acggtgaga 19 556 19 DNA Artificial Sequence TARGETING SEQUENCE 556 tgtgttatgc ttgtattga 19 557 19 DNA Artificial Sequence TARGETING SEQUENCE 557 gccttgtcct ccggtatgt 19 558 19 DNA Artificial Sequence TARGETING SEQUENCE 558 tgtcctccgg tatgttcta 19 559 19 DNA Artificial Sequence TARGETING SEQUENCE 559 gtcctccggt atgttctaa 19 560 19 DNA Artificial Sequence TARGETING SEQUENCE 560 tcctccggta tgttctaaa 19 561 19 DNA Artificial Sequence TARGETING SEQUENCE 561 cctccggtat gttctaaag 19 562 19 DNA Artificial Sequence TARGETING SEQUENCE 562 tccggtatgt tctaaagct 19 563 19 DNA Artificial Sequence TARGETING SEQUENCE 563 ccatcacttt ggctagtga 19 564 19 DNA Artificial Sequence TARGETING SEQUENCE 564 ccgaggacgc accagttta 19 565 19 DNA Artificial Sequence TARGETING SEQUENCE 565 cgaggacgca ccagtttat 19 566 19 DNA Artificial Sequence TARGETING SEQUENCE 566 tgcagactgt ctccgacca 19 567 19 DNA Artificial Sequence TARGETING SEQUENCE 567 cagactgtct ccgaccata 19 568 19 DNA Artificial Sequence TARGETING SEQUENCE 568 caagactgag aaccttgat 19 569 19 DNA Artificial Sequence TARGETING SEQUENCE 569 agaaccttga tgtcattgt 19 570 19 DNA Artificial Sequence TARGETING SEQUENCE 570 ccttgatgtc attgtcaat 19 571 19 DNA Artificial Sequence TARGETING SEQUENCE 571 aagttcttgg agccttaca 19 572 19 DNA Artificial Sequence TARGETING SEQUENCE 572 agttcttgga gccttacaa 19 573 19 DNA Artificial Sequence TARGETING SEQUENCE 573 gagccttaca acgactcta 19 574 19 DNA Artificial Sequence TARGETING SEQUENCE 574 agccttacaa cgactctat 19 575 19 DNA Artificial Sequence TARGETING SEQUENCE 575 ttacaacgac tctatccaa 19 576 19 DNA Artificial Sequence TARGETING SEQUENCE 576 gctattacga acagccaga 19 577 19 DNA Artificial Sequence TARGETING SEQUENCE 577 tattacgaac agccagata 19 578 19 DNA Artificial Sequence TARGETING SEQUENCE 578 attacgaaca gccagataa 19 579 19 DNA Artificial Sequence TARGETING SEQUENCE 579 cagataatgg agtcctcaa 19 580 19 DNA Artificial Sequence TARGETING SEQUENCE 580 gataatggag tcctcaact 19 581 19 DNA Artificial Sequence TARGETING SEQUENCE 581 aaacgtgcct gccaattca 19 582 19 DNA Artificial Sequence TARGETING SEQUENCE 582 aacgtgcctg ccaattcaa 19 583 19 DNA Artificial Sequence TARGETING SEQUENCE 583 aaccagagca tgaatgtta 19 584 19 DNA Artificial Sequence TARGETING SEQUENCE 584 ctcggcaact tcgtcatgt 19 585 19 DNA Artificial Sequence TARGETING SEQUENCE 585 aatgtagaat gtcgcatca 19 586 19 DNA Artificial Sequence TARGETING SEQUENCE 586 atgtagaatg tcgcatcaa 19 587 19 DNA Artificial Sequence TARGETING SEQUENCE 587 caacatcgcc acagacgat 19 588 19 DNA Artificial Sequence TARGETING SEQUENCE 588 gacgatgagc gagacaagt 19 589 19 DNA Artificial Sequence TARGETING SEQUENCE 589 tggccttcaa actccgcat 19 590 19 DNA Artificial Sequence TARGETING SEQUENCE 590 ccatctctct cctgtggat 19 591 19 DNA Artificial Sequence TARGETING SEQUENCE 591 tttgataaca gagctatga 19 592 19 DNA Artificial Sequence TARGETING SEQUENCE 592 ccattgcggt tccgtcact 19 593 19 DNA Artificial Sequence TARGETING SEQUENCE 593 aggagttagg agcctttct 19 594 19 DNA Artificial Sequence TARGETING SEQUENCE 594 tgtgagagct atccactct 19 595 19 DNA Artificial Sequence TARGETING SEQUENCE 595 cactctcctg cctgcatat

19 596 19 DNA Artificial Sequence TARGETING SEQUENCE 596 cgccacacac acacacaaa 19 597 19 DNA Artificial Sequence TARGETING SEQUENCE 597 tctacacagt cgccatctt 19 598 19 DNA Artificial Sequence TARGETING SEQUENCE 598 tcgccatctt ggtgacttt 19 599 19 DNA Artificial Sequence TARGETING SEQUENCE 599 ggttgaccta ggctgaata 19 600 19 DNA Artificial Sequence TARGETING SEQUENCE 600 gttgacctag gctgaatat 19 601 19 DNA Artificial Sequence TARGETING SEQUENCE 601 ggctgaatat ccactttgt 19 602 19 DNA Artificial Sequence TARGETING SEQUENCE 602 agcaagttat caactaatc 19 603 19 DNA Artificial Sequence TARGETING SEQUENCE 603 gcaagttatc aactaatca 19 604 19 DNA Artificial Sequence TARGETING SEQUENCE 604 ccaaatctag cctctgaat 19 605 19 DNA Artificial Sequence TARGETING SEQUENCE 605 ctcctgctct gaatattct 19 606 19 DNA Artificial Sequence TARGETING SEQUENCE 606 tgtgtcagat ctactgtaa 19 607 19 DNA Artificial Sequence TARGETING SEQUENCE 607 ttgctcttct acctagttt 19 608 19 DNA Artificial Sequence TARGETING SEQUENCE 608 cagtgaccgc attggaata 19 609 19 DNA Artificial Sequence TARGETING SEQUENCE 609 gaccgcattg gaatataca 19 610 19 DNA Artificial Sequence TARGETING SEQUENCE 610 ttcagtaggt ctgatccaa 19 611 19 DNA Artificial Sequence TARGETING SEQUENCE 611 cagtaggtct gatccaact 19 612 19 DNA Artificial Sequence TARGETING SEQUENCE 612 ggtacattga agaccttaa 19 613 19 DNA Artificial Sequence TARGETING SEQUENCE 613 tacattgaag accttaaga 19 614 19 DNA Artificial Sequence TARGETING SEQUENCE 614 agaccttaag aagtttcta 19 615 19 DNA Artificial Sequence TARGETING SEQUENCE 615 gaccttaaga agtttctaa 19 616 19 DNA Artificial Sequence TARGETING SEQUENCE 616 gtttatgttg catgtcagt 19 617 19 DNA Artificial Sequence TARGETING SEQUENCE 617 tggtatgaat gatcctgat 19 618 19 DNA Artificial Sequence TARGETING SEQUENCE 618 tgaaggagtg ccaaggata 19 619 19 DNA Artificial Sequence TARGETING SEQUENCE 619 tgtagcagtt tatcctcat 19 620 19 DNA Artificial Sequence TARGETING SEQUENCE 620 gtagcagttt atcctcata 19 621 19 DNA Artificial Sequence TARGETING SEQUENCE 621 ctcataatgg aatgataga 19 622 19 DNA Artificial Sequence TARGETING SEQUENCE 622 agccattggt tgctgttca 19 623 19 DNA Artificial Sequence TARGETING SEQUENCE 623 gccattggtt gctgttcag 19 624 19 DNA Artificial Sequence TARGETING SEQUENCE 624 gtaacagttg agtgcaaga 19 625 19 DNA Artificial Sequence TARGETING SEQUENCE 625 taacagttga gtgcaagat 19 626 19 DNA Artificial Sequence TARGETING SEQUENCE 626 tgatggatca gccaaccta 19 627 19 DNA Artificial Sequence TARGETING SEQUENCE 627 gatggatcag ccaacctaa 19 628 19 DNA Artificial Sequence TARGETING SEQUENCE 628 atggatcagc caacctaaa 19 629 19 DNA Artificial Sequence TARGETING SEQUENCE 629 gcatagtatg agtaggata 19 630 19 DNA Artificial Sequence TARGETING SEQUENCE 630 catagtatga gtaggatat 19 631 19 DNA Artificial Sequence TARGETING SEQUENCE 631 ggatatctcc acagagtaa 19 632 19 DNA Artificial Sequence TARGETING SEQUENCE 632 gatatctcca cagagtaaa 19 633 19 DNA Artificial Sequence TARGETING SEQUENCE 633 agaaaggtgt gtggtacat 19 634 19 DNA Artificial Sequence TARGETING SEQUENCE 634 ataacgtgct tccagatca 19 635 19 DNA Artificial Sequence TARGETING SEQUENCE 635 taacgtgctt ccagatcat 19 636 19 DNA Artificial Sequence TARGETING SEQUENCE 636 agtgtacagt cgccagata 19 637 19 DNA Artificial Sequence TARGETING SEQUENCE 637 gtgaacacct gattccaaa 19 638 19 DNA Artificial Sequence TARGETING SEQUENCE 638 agcttaatat gccgtgcta 19 639 19 DNA Artificial Sequence TARGETING SEQUENCE 639 taatatgccg tgctatgta 19 640 19 DNA Artificial Sequence TARGETING SEQUENCE 640 aatatgccgt gctatgtaa 19 641 19 DNA Artificial Sequence TARGETING SEQUENCE 641 atatgccgtg ctatgtaaa 19 642 19 DNA Artificial Sequence TARGETING SEQUENCE 642 gccgtgctat gtaaatatt 19 643 19 DNA Artificial Sequence TARGETING SEQUENCE 643 tgcaagaaat gtggtatgt 19 644 19 DNA Artificial Sequence TARGETING SEQUENCE 644 atgctgaatt agcctcgat 19 645 19 DNA Artificial Sequence TARGETING SEQUENCE 645 ttgattaaga gcacaaact 19 646 19 DNA Artificial Sequence TARGETING SEQUENCE 646 agcagactgt ggactgtaa 19 647 19 DNA Artificial Sequence TARGETING SEQUENCE 647 gcagactgtg gactgtaat 19 648 19 DNA Artificial Sequence TARGETING SEQUENCE 648 cagactgtgg actgtaata 19 649 19 DNA Artificial Sequence TARGETING SEQUENCE 649 taataccaat cgctttcaa 19 650 19 DNA Artificial Sequence TARGETING SEQUENCE 650 accaatcgct ttcaagtta 19 651 19 DNA Artificial Sequence TARGETING SEQUENCE 651 caatcgcttt caagttagt 19 652 19 DNA Artificial Sequence TARGETING SEQUENCE 652 atagagtact atcgtaaca 19 653 19 DNA Artificial Sequence TARGETING SEQUENCE 653 ccagcctgct tgagattca 19 654 19 DNA Artificial Sequence TARGETING SEQUENCE 654 ctgtagtaga tctacttaa 19 655 19 DNA Artificial Sequence TARGETING SEQUENCE 655 accaatgaca tccggatta 19 656 19 DNA Artificial Sequence TARGETING SEQUENCE 656 ccaatgacat ccggattat 19 657 19 DNA Artificial Sequence TARGETING SEQUENCE 657 caatgacatc cggattata 19 658 19 DNA Artificial Sequence TARGETING SEQUENCE 658 ggctatgact tctcaagat 19 659 19 DNA Artificial Sequence TARGETING SEQUENCE 659 gcctcatatg cacttatta 19 660 19 DNA Artificial Sequence TARGETING SEQUENCE 660 agacctgcgt atggaattt 19 661 19 DNA Artificial Sequence TARGETING SEQUENCE 661 acgtctatgt gacttgtaa 19 662 19 DNA Artificial Sequence TARGETING SEQUENCE 662 gtctatgtga cttgtaaga 19 663 19 DNA Artificial Sequence TARGETING SEQUENCE 663 ttcctacgtg agtgcttta 19 664 19 DNA Artificial Sequence TARGETING SEQUENCE 664 gacaatgctc tggaattaa 19 665 19 DNA Artificial Sequence TARGETING SEQUENCE 665 ctctggtgat tggatataa 19 666 19 DNA Artificial Sequence TARGETING SEQUENCE 666 tgacagagat tgagaacta 19 667 19 DNA Artificial Sequence TARGETING SEQUENCE 667 tgagattggc gtggttata 19 668 19 DNA Artificial Sequence TARGETING SEQUENCE 668 gcatccgagg cttgtttaa 19 669 19 DNA Artificial Sequence TARGETING SEQUENCE 669 accatatcgt ctccatgaa 19 670 19 DNA Artificial Sequence TARGETING SEQUENCE 670 ccatatcgtc tccatgaaa 19 671 19 DNA Artificial Sequence TARGETING SEQUENCE 671 tgaaagctgc aaagattta 19 672 19 DNA Artificial Sequence TARGETING SEQUENCE 672 tcgactgaat gaactctta 19 673 19 DNA Artificial Sequence TARGETING SEQUENCE 673 ccatatcgga tttgttgta 19 674 19 DNA Artificial Sequence TARGETING SEQUENCE 674 ggttggaaat cctcacaaa 19 675 19 DNA Artificial Sequence TARGETING SEQUENCE 675 cttactagtt agaggaaat 19 676 19 DNA Artificial Sequence TARGETING SEQUENCE 676 accaccagca ctactatta 19 677 19 DNA Artificial Sequence TARGETING SEQUENCE 677 ccaccagcac tactattat 19 678 19 DNA Artificial Sequence TARGETING SEQUENCE 678 cagcactact attatgata 19 679 19 DNA Artificial Sequence TARGETING SEQUENCE 679 ctatcagtcc ttgtaataa 19 680 19 DNA Artificial Sequence TARGETING SEQUENCE 680 attgtctact tcagcaata 19 681 19 DNA Artificial Sequence TARGETING SEQUENCE 681 tattggtgat ttcgtcata 19 682 19 DNA Artificial Sequence TARGETING SEQUENCE 682 ttcgtcatag gaacattta 19 683 19 DNA Artificial Sequence TARGETING SEQUENCE 683 taatgacact atcgtaaca 19 684 19 DNA Artificial Sequence TARGETING SEQUENCE 684 gatgtttgct aaaggttat 19 685 19 DNA Artificial Sequence TARGETING SEQUENCE 685 cttcgtggct acatcttaa 19 686 19 DNA Artificial Sequence TARGETING SEQUENCE 686 tgcacttgga ttcatctta 19 687 19 DNA Artificial Sequence TARGETING SEQUENCE 687 gatgatctgt ggccatgta 19 688 19 DNA Artificial Sequence TARGETING SEQUENCE 688 ctcgaagaca agccatgaa 19 689 19 DNA Artificial Sequence TARGETING SEQUENCE 689 tgaaagagat gtccatcga 19 690 19 DNA Artificial Sequence TARGETING SEQUENCE 690 agagatgtcc atcgatcaa 19 691 19 DNA Artificial Sequence TARGETING SEQUENCE 691 ccatcgatca agccaaata 19 692 19 DNA Artificial Sequence TARGETING SEQUENCE 692 catcgatcaa gccaaatat 19 693 19 DNA Artificial Sequence TARGETING SEQUENCE 693 ggtcgtatga agccaaaca 19 694 19 DNA Artificial Sequence TARGETING SEQUENCE 694 cacttgtcct tggatttaa 19 695 19 DNA Artificial Sequence TARGETING SEQUENCE 695 tagtggttat tcgcctaaa 19 696 19 DNA Artificial Sequence TARGETING SEQUENCE 696 atctcatctt caaggacaa 19 697 19 DNA Artificial Sequence TARGETING SEQUENCE 697 cgatttagat acttccaaa 19 698 19 DNA Artificial Sequence TARGETING SEQUENCE 698 tcattggtgg aaagataaa 19 699 19 DNA Artificial Sequence TARGETING SEQUENCE 699 ttagcaagtt ccggataga 19 700 19 DNA Artificial Sequence TARGETING SEQUENCE 700 gaaatcattg agccataca 19 701 19 DNA Artificial Sequence TARGETING SEQUENCE 701 agcaagatat tgcagataa 19 702 19 DNA Artificial Sequence TARGETING SEQUENCE 702 gatgaaccat ggcgaataa 19 703 19 DNA Artificial Sequence TARGETING SEQUENCE 703 cattcaagca cagctaata 19 704 19 DNA Artificial Sequence TARGETING SEQUENCE 704 ttcagtgcct agtgtagta 19 705 19 DNA Artificial Sequence TARGETING SEQUENCE 705 aggaaagttg ctccattga 19 706 19 DNA Artificial Sequence TARGETING SEQUENCE 706 aaagttgctc cattgataa 19 707 19 DNA Artificial Sequence TARGETING SEQUENCE 707 caatcttaat ggtgattct 19 708 19 DNA Artificial Sequence TARGETING SEQUENCE 708 ttgacatcat agtctagta 19 709 19 DNA Artificial Sequence TARGETING SEQUENCE 709 gacatcatag tctagtaaa 19 710 19 DNA Artificial Sequence TARGETING SEQUENCE 710 gtgtgtgtgt gtgtatata 19 711 19 DNA Artificial Sequence TARGETING SEQUENCE 711 gtgtgtgtgt gtatatata 19 712 19 DNA Artificial Sequence TARGETING SEQUENCE 712 taggcaaact ttggtttaa 19 713 19 DNA Artificial Sequence TARGETING SEQUENCE 713 ggagaatact tcgcctaaa 19 714 19 DNA Artificial Sequence TARGETING SEQUENCE 714 tgagtatgac ctaggtata 19 715 19 DNA Artificial Sequence TARGETING SEQUENCE 715 agagatctga taacttgaa 19 716 19 DNA Artificial Sequence TARGETING SEQUENCE 716 ggtaaagaca gtagaaata 19 717 19 DNA Artificial Sequence TARGETING SEQUENCE 717 tttaagctct ggtggatga 19 718 25 RNA Artificial Sequence SENSE STRAND 718 cccugaggau ccucaacaau gguca 25 719 27 RNA Artificial Sequence ANTISENSE STRAND 719 ugaccauugu ugaggauccu caggguu 27 720 19 DNA Artificial Sequence TARGETING SEQUENCE 720 ggatggcact tacagattg 19 721 19 DNA Artificial Sequence TARGETING SEQUENCE 721 gaaatatgct gcagaactt 19 722 19 RNA Artificial Sequence SENSE STRAND 722 cccugaggau ccucaacaa 19 723 19 RNA Artificial Sequence ANTISENSE STRAND 723 uuguugagga uccucaggg 19 724 25 DNA Artificial Sequence TARGETING SEQUENCE 724 ccctgaggat cctcaacaat ggtca 25

Claims

1. A method of attenuating expression of an ocular hypertension target mRNA in a subject, the method comprising: administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:33-SEQ ID NO:82, and SEQ ID NO:220-SEQ ID NO:717.

2. The method of claim 1 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

3. The method of claim 1 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

4. The method of claim 1 wherein the interfering RNA is an shRNA.

5. The method of claim 1 wherein the ocular hypertension target mRNA encodes a .beta.-adrenergic receptor, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:33-SEQ ID NO:52, and SEQ ID NO:220-SEQ ID NO:282.

6. The method of claim 1 wherein the ocular hypertension target mRNA encodes acetylcholinesterase, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:53-SEQ ID NO:62 and SEQ ID NO:283-333.

7. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1A1, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:334-SEQ ID NO:374.

8. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1A2, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:63-SEQ ID NO:72 and SEQ ID NO:375-SEQ ID NO:416.

9. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1A3, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:417-SEQ ID NO:440.

10. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1A4, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:441-SEQ ID NO:511.

11. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1B1, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:512-SEQ ID NO:563.

12. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1B2, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:564-SEQ ID NO:606.

13. The method of claim 1 wherein the ocular hypertension target mRNA encodes ATP1B3, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:607-SEQ ID NO:648.

14. The method of claim 1 wherein the ocular hypertension target mRNA encodes SLC12A1, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:73-SEQ ID NO:82 and SEQ ID NO:649-SEQ ID NO:675.

15. The method of claim 1 wherein the ocular hypertension target mRNA encodes SLC12A2, and the interfering RNA comprises: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:676-SEQ ID NO:717.

16. The method of claim 1 wherein the region of contiguous nucleotides is a region of at least 14 contiguous nucleotides having at least 85% sequence complementarity to, or at least 85% sequence identity with, the penultimate 14 nucleotides of the 3' end of the sequence of the sequence identifier.

17. The method of claim 1 wherein the region of contiguous nucleotides is a region of at least 15, 16, 17, or 18 contiguous nucleotides having at least 80% sequence complementarity to, or at least 80% sequence identity with, the penultimate 15, 16, 17, or 18 nucleotides, respectively, of the 3' end of the sequence of the sequence identifier.

18. The method of claim 1 wherein the interfering RNA is an mRNA.

19. The method of claim 1 wherein the interfering RNA is an siRNA.

20. A method of treating ocular hypertension in a subject in need thereof, the method comprising: administering to an eye of the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:33-SEQ ID NO:82, and SEQ ID NO:220-SEQ ID NO:717, wherein the ocular hypertension is treated thereby.

21. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:33-SEQ ID NO:42, and SEQ ID NO:220-SEQ ID NO:241.

22. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:43-SEQ ID NO:52, and SEQ ID NO:242-SEQ ID NO:282.

23. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:53-SEQ ID NO:62 and SEQ ID NO:283-333.

24. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:334-SEQ ID NO:374.

25. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:63-SEQ ID NO:72 and SEQ ID NO:375-SEQ ID NO:416.

26. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:417-SEQ ID NO:440.

27. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:441-SEQ ID NO:511.

28. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:512-SEQ ID NO:563.

29. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:564-SEQ ID NO:606.

30. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:607-SEQ ID NO:648.

31. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:73-SEQ ID NO:82 and SEQ ID NO:649-SEQ ID NO:675.

32. The method of claim 20 wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of any one of SEQ ID NO:676-SEQ ID NO:717.

33. The method of claim 20 wherein the interfering RNA is an shRNA.

34. The method of claim 20 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

35. The method of claim 20 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

36. The method of claim 20 wherein the interfering RNA is an mRNA.

37. The method of claim 20 wherein the interfering RNA is an siRNA.

38. A method of attenuating expression of an ocular hypertension target mRNA first variant without attenuating expression of an ocular hypertension target mRNA second variant in a subject, comprising: administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of the first variant, wherein the expression of the first variant mRNA is attenuated without attenuating expression of the second variant mRNA, and wherein the first variant target mRNA is SEQ ID NO:5, SEQ ID NO:124, SEQ ID NO:127, or SEQ ID NO:129, and the second variant target mRNA is SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:128, or SEQ ID NO:130, respectively.

39. A method of attenuating expression of an ocular hypertension target mRNA first variant without attenuating expression of an ocular hypertension target mRNA second variant in a subject, comprising: administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3' end of the first variant, wherein the expression of the first variant mRNA is attenuated without attenuating expression of the second variant mRNA, and wherein the first variant target mRNA is SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:128, or SEQ ID NO:130, and the second variant target mRNA is SEQ ID NO:5, SEQ ID NO:124, SEQ ID NO:127, or SEQ ID NO:129, respectively.

40. A method of attenuating expression of an ocular hypertension target mRNA of a subject, comprising: administering to the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides; wherein the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively, wherein the expression of an ocular hypertension target mRNA is attenuated.

41. The method of claim 40 wherein the subject is a human and the human has ocular hypertension.

42. The method of claim 40 wherein the subject is a human and the human is at risk of developing ocular hypertension.

43. The method of claim 40 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

44. The method of claim 40 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

45. The method of claim 40 wherein the ocular hypertension target mRNA encodes a .beta.1- or .beta.2-adrenergic receptor, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively.

46. The method of claim 40 wherein the ocular hypertension target mRNA encodes an acetylcholinesterase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123, respectively.

47. The method of claim 40 wherein the ocular hypertension target mRNA encodes a subunit of Na.sup.+/K.sup.+-ATPase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132, respectively.

48. The method of claim 40 wherein the ocular hypertension target mRNA encodes a Na--K-2Cl cotransporter, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133, respectively.

49. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:3 comprising nucleotide 468, 523, 799, 1563, 1565, 1569, 1593, 1613, 1614, 1626, 310, 322, 726, 769, 772, 801, 802, 1501, 1576, 1577, 1579, 1580, 1581, 1586, 1590, 1592, 1594, 1615, 1616, 1632, 1633, or 1654.

50. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:4 comprising nucleotide 329, 375, 1031, 1046, 1149, 1163, 1371, 1401, 1426, 1880, 283, 607, 608, 609, 619, 623, 722, 857, 1037, 1091, 1115, 1124, 1136, 1137, 1151, 1164, 1393, 1394, 1395, 1406, 1407, 1427, 1428, 1429, 1442, 1725, 1726, 1756, 1757, 1758, 1767, 1790, 1791, 1792, 1793, 1803, 1861, 1869, 1971, 1972, or 1979.

51. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:123 comprising nucleotide 1875, 1890, 1891, 2011, 2012, 2133, or 2134.

52. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:5 comprising nucleotide 366, 370, 384, 385, 525, 588, 768, 1045, 1046, 1061, 1090, 1232, 1314, 1316, 1460, 1461, 1462, 1528, 1607, 1705, 1713, 382, 393, 397, 622, 1131, 1459, 1530, 2251, 2885, 2886, 386, 1231, 1315, 2047, 2049, 2053, 2055, 2057, 2125, 2126, 2127, 2250, 2253, 2258, 2260, 2318, 2395, 2397, 2404, 2405, 2643, 2645, or 2887.

53. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:124 comprising nucleotide 2208, 2275, 2307, 2526, 2538, 2592, 2628, 2979, 2985, 3093, 3474, 3504, 3505, 3506, 3518, 343, 442, 700, 707, 811, 907, 1059, 1363, 1594, 1662, 1758, 1760, 1896, 2037, or 2147.

54. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:125 comprising nucleotide 436, 441, 443, 552, 617, 701, 702, 832, 2204, 2291, or 2495.

55. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:6 comprising nucleotide 471, 1990, 3080, 3797, 4037, 4093, 4225, 4323, 5213, 5285, 214, 467, 470, 472, 473, 632, 825, 946, 1693, 1767, 1768, 2157, 2263, 2589, 2590, 2765, 2988, 3094, 3144, 3145, 3344, 3345, 3418, 3666, 3828, 3850, 4040, 4041, 4061, 4882, 4894, 4900, 5040, 5114, 5115, 5128, 5129, 5253, 5296, 5375, 5384, or 5385.

56. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:126 comprising nucleotide 240, 272, 362, 1836, 1851, 2103, 2137, 2138, 2139, 2157, 2158, 2160, 2425, 2580, 2601, 2646, 2650, 2794, 2803, 3116, 3124, 3126, 3129, or 3377.

57. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:127 comprising nucleotide 113, 612, 702, 833, 1101, 1732, 1733, 1836, 2070, 2071, 2143, 2328, 2475, 2861, 2862, 2952, 3203, 3281, 3377, 3379, 3470, 3471, 3554, 3614, 3615, 3616, 3617, 3625, 3626, 3642, 3646, 3647, 3653, 3655, 3797, 3801, 3803, 3809 or 3810.

58. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:128 comprising nucleotide 126, 251, 252, 253, 331, 427, 429, 520, 521, 530, 601, 602, 603, 604, 664, 665, 666, 667, 675, 676, 692, 696, 697, 702, 703, 705, 707, 847, 851, 853, 859, or 860.

59. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:129 comprising nucleotide 1096, 1099, 1130, 1131, 1167, 1299, 1441, 1450, 1451, 1452, 1564, 1746, 1750, 1751, 1752, 1795, 203, 204, 214, 222, 224, 225, 226, 380, 525, 591, 612, 613, 615, 635, 636, 663, 664, 669, 699, 765, 790, 839, 840, 841, 900, 909, 933, or 947.

60. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:130 comprising nucleotide 1063, 1102, 1106, 1107, 1108, 1109, 1111, or 1151.

61. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:131 comprising nucleotide 653, 654, 771, 773, 841, 849, 853, 917, 918, 926, 927, 931, 981, 983, 984, 996, 998, 1022, 1023, 1160, 1214, 1355, 1356, 1381, 1394, 1425, 1474, 1550, 1620, 1707, 1740, 1753, 1825, 1956, 1965, 2598, 2599, 2608, 2828, 2829, 2888, 3012, or 3251.

62. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:132 comprising nucleotide 292, 434, 438, 457, 459, 488, 490, 498, 499, 592, 639, 723, 774, 775, 788, 857, 858, 910, 911, 930, 931, 932, 1009, 1010, 1023, 1024, 1111, 1146, 1147, 1220, 1246, 1321, 1325, 1326, 1327, 1331, 1437, 1548, 1571, 1785, 1786, or 1787.

63. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:7 comprising nucleotide 675, 974, 1373, 1780, 2102, 2151, 2315, 2542, 2609, 3197, 67, 71, 73, 353, 405, 864, 911, 912, 913, 1409, 1748, 1811, 1935, 1937, 1993, 2012, 2346, 2388, 2437, 2586, 3007, 3008, 3022, 3130, 3210, 3237, or 3271.

64. The method of claim 40 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:133 comprising nucleotide 748, 749, 753, 1119, 1169, 1499, 1509, 1820, 2081, 2118, 2147, 2615, 2644, 2659, 2663, 2671, 2672, 2793, 2812, 2914, 2948, 3044, 3334, 3391, 3480, 3520, 3549, 3639, 3840, 3941, 3944, 4001, 4995, 4997, 5141, 5143, 5249, 5375, 5834, 5852, 5981, or 6678.

65. The method of claim 40 further comprising administering to the subject a second interfering RNA having a length of 19 to 49 nucleotides, and comprising a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides; wherein the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively.

66. A method of treating ocular hypertension in a subject in need thereof, comprising: administering to an eye of the subject a composition comprising an effective amount of interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, the interfering RNA comprising: a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides; wherein the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively, wherein the ocular hypertension is treated thereby.

67. The method of claim 66 wherein the subject is a human.

68. The method of claim 66 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

69. The method of claim 66 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

70. The method of claim 67 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

71. The method of claim 67 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

72. The method of claim 66 wherein the ocular hypertension target mRNA encodes a .beta.1- or .beta.2-adrenergic receptor, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3 or SEQ ID NO:4, respectively.

73. The method of claim 66 wherein the ocular hypertension target mRNA encodes an acetylcholinesterase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:5 or SEQ ID NO:123, respectively.

74. The method of claim 66 wherein the ocular hypertension target mRNA encodes a subunit of Na.sup.+/K.sup.+-ATPase, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:6, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, or SEQ ID NO:132, respectively.

75. The method of claim 66 wherein the ocular hypertension target mRNA encodes a Na--K-2Cl cotransporter, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO: 7 or SEQ ID NO:133 and has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:7 or SEQ ID NO:133, respectively.

76. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:3 comprising nucleotide 468, 523, 799, 1563, 1565, 1569, 1593, 1613, 1614, 1626, 310, 322, 726, 769, 772, 801, 802, 1501, 1576, 1577, 1579, 1580, 1581, 1586, 1590, 1592, 1594, 1615, 1616, 1632, 1633, or 1654.

77. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:4 comprising nucleotide 329, 375, 1031, 1046, 1149, 1163, 1371, 1401, 1426, 1880, 283, 607, 608, 609, 619, 623, 722, 857, 1037, 1091, 1115, 1124, 1136, 1137, 1151, 1164, 1393, 1394, 1395, 1406, 1407, 1427, 1428, 1429, 1442, 1725, 1726, 1756, 1757, 1758, 1767, 1790, 1791, 1792, 1793, 1803, 1861, 1869, 1971, 1972, or 1979.

78. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:123 comprising nucleotide 1875, 1890, 1891, 2011, 2012, 2133, or 2134.

79. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:5 comprising nucleotide 366, 370, 384, 385, 525, 588, 768, 1045, 1046, 1061, 1090, 1232, 1314, 1316, 1460, 1461, 1462, 1528, 1607, 1705, 1713, 382, 393, 397, 622, 1131, 1459, 1530, 2251, 2885, 2886, 386, 1231, 1315, 2047, 2049, 2053, 2055, 2057, 2125, 2126, 2127, 2250, 2253, 2258, 2260, 2318, 2395, 2397, 2404, 2405, 2643, 2645, or 2887.

80. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:124 comprising nucleotide 2208, 2275, 2307, 2526, 2538, 2592, 2628, 2979, 2985, 3093, 3474, 3504, 3505, 3506, 3518, 343, 442, 700, 707, 811, 907, 1059, 1363, 1594, 1662, 1758, 1760, 1896, 2037, or 2147.

81. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:125 comprising nucleotide 436, 441, 443, 552, 617, 701, 702, 832, 2204, 2291, or 2495.

82. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:6 comprising nucleotide 471, 1990, 3080, 3797, 4037, 4093, 4225, 4323, 5213, 5285, 214, 467, 470, 472, 473, 632, 825, 946, 1693, 1767, 1768, 2157, 2263, 2589, 2590, 2765, 2988, 3094, 3144, 3145, 3344, 3345, 3418, 3666, 3828, 3850, 4040, 4041, 4061, 4882, 4894, 4900, 5040, 5114, 5115, 5128, 5129, 5253, 5296, 5375, 5384, or 5385.

83. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:126 comprising nucleotide 240, 272, 362, 1836, 1851, 2103, 2137, 2138, 2139, 2157, 2158, 2160, 2425, 2580, 2601, 2646, 2650, 2794, 2803, 3116, 3124, 3126, 3129, or 3377.

84. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:127 comprising nucleotide 113, 612, 702, 833, 1101, 1732, 1733, 1836, 2070, 2071, 2143, 2328, 2475, 2861, 2862, 2952, 3203, 3281, 3377, 3379, 3470, 3471, 3554, 3614, 3615, 3616, 3617, 3625, 3626, 3642, 3646, 3647, 3653, 3655, 3797, 3801, 3803, 3809 or 3810.

85. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:128 comprising nucleotide 126, 251, 252, 253, 331, 427, 429, 520, 521, 530, 601, 602, 603, 604, 664, 665, 666, 667, 675, 676, 692, 696, 697, 702, 703, 705, 707, 847, 851, 853, 859, or 860.

86. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:129 comprising nucleotide 1096, 1099, 1130, 1131, 1167, 1299, 1441, 1450, 1451, 1452, 1564, 1746, 1750, 1751, 1752, 1795, 203, 204, 214, 222, 224, 225, 226, 380, 525, 591, 612, 613, 615, 635, 636, 663, 664, 669, 699, 765, 790, 839, 840, 841, 900, 909, 933, or 947.

87. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:130 comprising nucleotide 1063, 1102, 1106, 1107, 1108, 1109, 1111, or 1151.

88. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:131 comprising nucleotide 653, 654, 771, 773, 841, 849, 853, 917, 918, 926, 927, 931, 981, 983, 984, 996, 998, 1022, 1023, 1160, 1214, 1355, 1356, 1381, 1394, 1425, 1474, 1550, 1620, 1707, 1740, 1753, 1825, 1956, 1965, 2598, 2599, 2608, 2828, 2829, 2888, 3012, or 3251.

89. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:132 comprising nucleotide 292, 434, 438, 457, 459, 488, 490, 498, 499, 592, 639, 723, 774, 775, 788, 857, 858, 910, 911, 930, 931, 932, 1009, 1010, 1023, 1024, 1111, 1146, 1147, 1220, 1246, 1321, 1325, 1326, 1327, 1331, 1437, 1548, 1571, 1785, 1786, or 1787.

90. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:7 comprising nucleotide 675, 974, 1373, 1780, 2102, 2151, 2315, 2542, 2609, 3197, 67, 71, 73, 353, 405, 864, 911, 912, 913, 1409, 1748, 1811, 1935, 1937, 1993, 2012, 2346, 2388, 2437, 2586, 3007, 3008, 3022, 3130, 3210, 3237, or 3271.

91. The method of claim 66 wherein the antisense strand is designed to target an mRNA corresponding to SEQ ID NO:133 comprising nucleotide 748, 749, 753, 1119, 1169, 1499, 1509, 1820, 2081, 2118, 2147, 2615, 2644, 2659, 2663, 2671, 2672, 2793, 2812, 2914, 2948, 3044, 3334, 3391, 3480, 3520, 3549, 3639, 3840, 3941, 3944, 4001, 4995, 4997, 5141, 5143, 5249, 5375, 5834, 5852, 5981, or 6678.

92. The method of claim 66 further comprising administering to the subject a second interfering RNA having a length of 19 to 49 nucleotides, and comprising a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides; wherein the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, or SEQ ID NO:133, respectively.

93. The method of claim 66 wherein the sense nucleotide strand and the antisense nucleotide strand are connected by a loop nucleotide sequence.

94. A method of attenuating expression of an ocular hypertension target mRNA of a subject, comprising: administering to the subject a composition comprising an effective amount of single-stranded interfering RNA having a length of 19 to 49 nucleotides and a pharmaceutically acceptable carrier, wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:3 comprising nucleotide 468, 523, 799, 1563, 1565, 1569, 1593, 1613, 1614, 1626, 310, 322, 726, 769, 772, 801, 802, 1501, 1576, 1577, 1579, 1580, 1581, 1586, 1590, 1592, 1594, 1615, 1616, 1632, 1633, or 1654, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:3; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:4 comprising nucleotide 329, 375, 1031, 1046, 1149, 1163, 1371, 1401, 1426, 1880, 283, 607, 608, 609, 619, 623, 722, 857, 1037, 1091, 1115, 1124, 1136, 1137, 1151, 1164, 1393, 1394, 1395, 1406, 1407, 1427, 1428, 1429, 1442, 1725, 1726, 1756, 1757, 1758, 1767, 1790, 1791, 1792, 1793, 1803, 1861, 1869, 1971, 1972, or 1979, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:4; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:123 comprising nucleotide 1875, 1890, 1891, 2011, 2012, 2133, or 2134, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:123; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:5 comprising nucleotide 366, 370, 384, 385, 525, 588, 768, 1045, 1046, 1061, 1090, 1232, 1314, 1316, 1460, 1461, 1462, 1528, 1607, 1705, 1713, 382, 393, 397, 622, 1131, 1459, 1530, 2251, 2885, 2886, 386, 1231, 1315, 2047, 2049, 2053, 2055, 2057, 2125, 2126, 2127, 2250, 2253, 2258, 2260, 2318, 2395, 2397, 2404, 2405, 2643, 2645, or 2887, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:5; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:124 comprising nucleotide 2208, 2275, 2307, 2526, 2538, 2592, 2628, 2979, 2985, 3093, 3474, 3504, 3505, 3506, 3518, 343, 442, 700, 707, 811, 907, 1059, 1363, 1594, 1662, 1758, 1760, 1896, 2037, or 2147, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:124; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:125 comprising nucleotide 436, 441, 443, 552, 617, 701, 702, 832, 2204, 2291, or 2495, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:125; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:6 comprising nucleotide 471, 1990, 3080, 3797, 4037, 4093, 4225, 4323, 5213, 5285, 214, 467, 470, 472, 473, 632, 825, 946, 1693, 1767, 1768, 2157, 2263, 2589, 2590, 2765, 2988, 3094, 3144, 3145, 3344, 3345, 3418, 3666, 3828, 3850, 4040, 4041, 4061, 4882, 4894, 4900, 5040, 5114, 5115, 5128, 5129, 5253, 5296, 5375, 5384, or 5385, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:6; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:126 comprising nucleotide 240, 272, 362, 1836, 1851, 2103, 2137, 2138, 2139, 2157, 2158, 2160, 2425, 2580, 2601, 2646, 2650, 2794, 2803, 3116, 3124, 3126, 3129, or 3377, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:126; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:127 comprising nucleotide 113, 612, 702, 833, 1101, 1732, 1733, 1836, 2070, 2071, 2143, 2328, 2475, 2861, 2862, 2952, 3203, 3281, 3377, 3379, 3470, 3471, 3554, 3614, 3615, 3616, 3617, 3625, 3626, 3642, 3646, 3647, 3653, 3655, 3797, 3801, 3803, 3809 or 3810, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:127; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:128 comprising nucleotide 126, 251, 252, 253, 331, 427, 429, 520, 521, 530, 601, 602, 603, 604, 664, 665, 666, 667, 675, 676, 692, 696, 697, 702, 703, 705, 707, 847, 851, 853, 859, or 860, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:128; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:129 comprising nucleotide 1096, 1099, 1130, 1131, 1167, 1299, 1441, 1450, 1451, 1452, 1564, 1746, 1750, 1751, 1752, 1795, 203, 204, 214, 222, 224, 225, 226, 380, 525, 591, 612, 613, 615, 635, 636, 663, 664, 669, 699, 765, 790, 839, 840, 841, 900, 909, 933, or 947, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:129; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:130 comprising nucleotide 1063, 1102, 1106, 1107, 1108, 1109, 1111, or 1151, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:130; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:131 comprising nucleotide 653, 654, 771, 773, 841, 849, 853, 917, 918, 926, 927, 931, 981, 983, 984, 996, 998, 1022, 1023, 1160, 1214, 1355, 1356, 1381, 1394, 1425, 1474, 1550, 1620, 1707, 1740, 1753, 1825, 1956, 1965, 2598, 2599, 2608, 2828, 2829, 2888, 3012, or 3251, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:131; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:132 comprising nucleotide 292, 434, 438, 457, 459, 488, 490, 498, 499, 592, 639, 723, 774, 775, 788, 857, 858, 910, 911, 930, 931, 932, 1009, 1010, 1023, 1024, 1111, 1146, 1147, 1220, 1246, 1321, 1325, 1326, 1327, 1331, 1437, 1548, 1571, 1785, 1786, or 1787, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:132; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:7 comprising nucleotide 675, 974, 1373, 1780, 2102, 2151, 2315, 2542, 2609, 3197, 67, 71, 73, 353, 405, 864, 911, 912, 913, 1409, 1748, 1811, 1935, 1937, 1993, 2012, 2346, 2388, 2437, 2586, 3007, 3008, 3022, 3130, 3210, 3237, or 3271, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:7; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:133 comprising nucleotide 748, 749, 753, 1119, 1169, 1499, 1509, 1820, 2081, 2118, 2147, 2615, 2644, 2659, 2663, 2671, 2672, 2793, 2812, 2914, 2948, 3044, 3334, 3391, 3480, 3520, 3549, 3639, 3840, 3941, 3944, 4001, 4995, 4997, 5141, 5143, 5249, 5375, 5834, 5852, 5981, or 6678, and the interfering RNA has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the hybridizing portion of mRNA corresponding to SEQ ID NO:133; wherein the expression of an ocular hypertension target mRNA is thereby attenuated.

95. The method of claim 94 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

96. The method of claim 94 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

97. The method of claim 94 wherein the interfering RNA is an mRNA.

98. The method of claim 94 wherein the interfering RNA is an siRNA.

99. A composition comprising interfering RNA having a length of 19 to 49 nucleotides and having a nucleotide sequence of any one of SEQ ID NO:33-SEQ ID NO:82, and SEQ ID NO:220-SEQ ID NO:717, or a complement thereof, and a pharmaceutically acceptable carrier.

100. The composition of claim 99 wherein the interfering RNA is an shRNA.

101. The composition of claim 99 wherein the interfering RNA is an siRNA.

102. The composition of claim 99 wherein the interfering RNA is an miRNA.