RNAi-Mediated Inhibition of Ocular 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

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application is a divisional of U.S. patent application Ser. No. 11/345,361 filed Feb. 1, 2006, which claims benefit to U.S. Provisional Patent Application having Ser. Nos. 60/648,926 filed Feb. 1, 2005, and 60/753,364 filed Dec. 22, 2005.

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 .alpha.1 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 (miRNAs), 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, miRNAs, 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 .alpha.-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 .alpha.1, variant 1, is known from SEQ ID NO:124, the mRNA sequence of Na.sup.+/K.sup.+-ATPase .alpha.1, 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 .beta.2, 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 .alpha. and .beta. mRNA (ATP-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 (.alpha. 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 ATP1 B2 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 ATP1 B3 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.sup.- 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:

TABLE-US-00001 5'-CCCTGAGGATCCTCAACAA-3'. SEQ ID NO: 8

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-00002 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., UL, 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.

[0127] 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-00003 5'-CCCUGAGGAUCCUCAACAAUU-3' SEQ ID NO: 11 3'-UUGGGACUCCUAGGAGUUGUU-5'. SEQ ID NO: 12

[0128] 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-00004 5'-CCCUGAGGAUCCUCAACAA-3' SEQ ID NO: 722 3'-GGGACUCCUAGGAGUUGUU-5'. SEQ ID NO: 723

[0129] 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:

##STR00001##

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.

[0130] 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:

TABLE-US-00005 5'-CCCTGAGGATCCTCAACAATGGTCA-3'. SEQ ID NO: 724

A dicer-substrate 27-mer duplex of the invention for targeting a corresponding mRNA sequence of SEQ ID NO:724 is:

TABLE-US-00006 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.

[0131] 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.

[0132] 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-00007 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 and Nucleotide with SEQ 2 Common Target reference to ID 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 Nucleotide with SEQ CA12, variant 1 reference to ID Target 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 Nucleotide with SEQ CA12, variant 2 reference to ID Target 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

[0133] 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-00008 TABLE 2 ADRB1 and ADRB2 Target Sequences for siRNAs # of Starting Nucleotide with SEQ reference to ID ADRB1 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 ADRB2 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

[0134] 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-00009 TABLE 3 ACHE Target Sequences for siRNAs # of Starting Nucleotide with SEQ ACHE E4-E5 Target reference to ID 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-ES and E4- Nucleotide with SEQ E6 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

[0135] 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-00010 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 TGCCAAGGCCTGCGTAGTA 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 Target reference to ID 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 Target reference to ID 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 Target reference to ID 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 Target reference to ID 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

[0136] 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-00011 TABLE 5 SLC12A1 Target Sequences for siRNAs # of Starting Nucleotide with SEQ SLC12A1 Target reference to ID 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 Target reference to ID 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 GATGTTTGCTAAAGGTTAT 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.

[0137] 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.

[0138] 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.

[0139] "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).

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.).

[0155] 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.

[0156] 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.

[0157] "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 formamide, or raising the hybridization temperature.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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-00012 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 Interfering RNA up to 99; 0.1-99; 0.1-50; 0.5-10.0 Phosphate Buffered Saline 1.0 Benzalkonium Chloride 0.01 Polysorbate 80 0.5 Purified water (RNase-free) q.s. to 100% Interfering RNA up to 99; 0.1-99; 0.1-50; 0.5-10.0 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% Interfering RNA up to 99; 0.1-99; 0.1-50; 0.5-10.0 Phosphate Buffered Saline 1.0 Hydroxypropyl-.beta.-cyclodextrin 4.0 Purified water (RNase-free) q.s. to 100%

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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 DHARMAFECT.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.

[0171] 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.

[0172] For ophthalmic delivery, an interfering RNA may be combined with opthalmologically 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 opthalmologically 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.

[0173] 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 monolaurate, Sigma Aldrich, St. Louis, Mo.), in the event the interfering RNA is less penetrating in the eye.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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

[0178] The present study examines the ability of CA2-interfering RNA to knock down the levels of endogenous CA2 expression in cultured HeLa cells.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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

72411551DNAHomo sapiens 1ggcgcccaag ccgccgccgc cagatcggtg ccgattcctg ccctgccccg accgccagcg 60cgaccatgtc ccatcactgg gggtacggca aacacaacgg acctgagcac tggcataagg 120acttccccat tgccaaggga gagcgccagt cccctgttga catcgacact catacagcca 180agtatgaccc ttccctgaag cccctgtctg tttcctatga tcaagcaact tccctgagga 240tcctcaacaa tggtcatgct ttcaacgtgg agtttgatga ctctcaggac aaagcagtgc 300tcaagggagg acccctggat ggcacttaca gattgattca gtttcacttt cactggggtt 360cacttgatgg acaaggttca gagcatactg tggataaaaa gaaatatgct gcagaacttc 420acttggttca ctggaacacc aaatatgggg attttgggaa agctgtgcag caacctgatg 480gactggccgt tctaggtatt tttttgaagg ttggcagcgc taaaccgggc cttcagaaag 540ttgttgatgt gctggattcc attaaaacaa agggcaagag tgctgacttc actaacttcg 600atcctcgtgg cctccttcct gaatccctgg attactggac ctacccaggc tcactgacca 660cccctcctct tctggaatgt gtgacctgga ttgtgctcaa ggaacccatc agcgtcagca 720gcgagcaggt gttgaaattc cgtaaactta acttcaatgg ggagggtgaa cccgaagaac 780tgatggtgga caactggcgc ccagctcagc cactgaagaa caggcaaatc aaagcttcct 840tcaaataaga tggtcccata gtctgtatcc aaataatgaa tcttcgggtg tttcccttta 900gctaagcaca gatctacctt ggtgatttgg accctggttg ctttgtgtct agttttctag 960acccttcatc tcttacttga tagacttact aataaaatgt gaagactaga ccaattgtca 1020tgcttgacac aactgctgtg gctggttggt gctttgttta tggtagtagt ttttctgtaa 1080cacagaatat aggataagaa ataagaataa agtaccttga ctttgttcac agcatgtagg 1140gtgatgagca ctcacaattg ttgactaaaa tgctgctttt aaaacatagg aaagtagaat 1200ggttgagtgc aaatccatag cacaagataa attgagctag ttaaggcaaa tcaggtaaaa 1260tagtcatgat tctatgtaat gtaaaccaga aaaaataaat gttcatgatt tcaagatgtt 1320atattaaaga aaaactttaa aaattattat atatttatag caaagttatc ttaaatatga 1380attctgttgt aatttaatga cttttgaatt acagagatat aaatgaagta ttatctgtaa 1440aaattgttat aattagagtt gtgatacaga gtatatttcc attcagacaa tatatcataa 1500cttaataaat attgtatttt agatatattc tctaataaaa ttcagaattc t 155121104DNAHomo sapiens 2ctcggtgcgc gaccccggct cagaggactc tttgctgtcc cgcaagatgc ggatgctgct 60ggcgctcctg gccctctccg cggcgcggcc atcggccagt gcagagtcac actggtgcta 120cgaggttcaa gccgagtcct ccaactaccc ctgcttggtg ccagtcaagt ggggtggaaa 180ctgccagaag gaccgccagt cccccatcaa catcgtcacc accaaggcaa aggtggacaa 240aaaactggga cgcttcttct tctctggcta cgataagaag caaacgtgga ctgtccaaaa 300taacgggcac tcagtgatga tgttgctgga gaacaaggcc agcatttctg gaggaggact 360gcctgcccca taccaggcca aacagttgca cctgcactgg tccgacttgc catataaggg 420ctcggagcac agcctcgatg gggagcactt tgccatggag atgcacatag tacatgagaa 480agagaagggg acatcgagga atgtgaaaga ggcccaggac cctgaagacg aaattgcggt 540gctggccttt ctggtggagg ctggaaccca ggtgaacgag ggcttccagc cactggtgga 600ggcactgtct aatatcccca aacctgagat gagcactacg atggcagaga gcagcctgtt 660ggacctgctc cccaaggagg agaaactgag gcactacttc cgctacctgg gctcactcac 720cacaccgacc tgcgatgaga aggtcgtctg gactgtgttc cgggagccca ttcagcttca 780cagagaacag atcctggcat tctctcagaa gctgtactac gacaaggaac agacagtgag 840catgaaggac aatgtcaggc ccctgcagca gctggggcag cgcacggtga taaagtccgg 900ggccccgggt cggccgctgc cctgggccct gcctgccctg ctgggcccca tgctggcctg 960cctgctggcc ggcttcctgc gatgatggct cacttctgca cgcagcctct ctgttgcctc 1020agctctccaa gttccaggct tccggtcctt agccttccca ggtgggactt taggcatgat 1080taaaatatgg acatattttt ggag 110431723DNAHomo sapiens 3tgctacccgc gcccgggctt ctggggtgtt ccccaaccac ggcccagccc tgccacaccc 60cccgcccccg gcctccgcag ctcggcatgg gcgcgggggt gctcgtcctg ggcgcctccg 120agcccggtaa cctgtcgtcg gccgcaccgc tccccgacgg cgcggccacc gcggcgcggc 180tgctggtgcc cgcgtcgccg cccgcctcgt tgctgcctcc cgccagcgaa agccccgagc 240cgctgtctca gcagtggaca gcgggcatgg gtctgctgat ggcgctcatc gtgctgctca 300tcgtggcggg caatgtgctg gtgatcgtgg ccatcgccaa gacgccgcgg ctgcagacgc 360tcaccaacct cttcatcatg tccctggcca gcgccgacct ggtcatgggg ctgctggtgg 420tgccgttcgg ggccaccatc gtggtgtggg gccgctggga gtacggctcc ttcttctgcg 480agctgtggac ctcagtggac gtgctgtgcg tgacggccag catcgagacc ctgtgtgtca 540ttgccctgga ccgctacctc gccatcacct cgcccttccg ctaccagagc ctgctgacgc 600gcgcgcgggc gcggggcctc gtgtgcaccg tgtgggccat ctcggccctg gtgtccttcc 660tgcccatcct catgcactgg tggcgggcgg agagcgacga ggcgcgccgc tgctacaacg 720accccaagtg ctgcgacttc gtcaccaacc gggcctacgc catcgcctcg tccgtagtct 780ccttctacgt gcccctgtgc atcatggcct tcgtgtacct gcgggtgttc cgcgaggccc 840agaagcaggt gaagaagatc gacagctgcg agcgccgttt cctcggcggc ccagcgcggc 900cgccctcgcc ctcgccctcg cccgtccccg cgcccgcgcc gccgcccgga cccccgcgcc 960ccgccgccgc cgccgccacc gccccgctgg ccaacgggcg tgcgggtaag cggcggccct 1020cgcgcctcgt ggccctacgc gagcagaagg cgctcaagac gctgggcatc atcatgggcg 1080tcttcacgct ctgctggctg cccttcttcc tggccaacgt ggtgaaggcc ttccaccgcg 1140agctggtgcc cgaccgcctc ttcgtcttct tcaactggct gggctacgcc aactcggcct 1200tcaaccccat catctactgc cgcagccccg acttccgcaa ggccttccag ggactgctct 1260gctgcgcgcg cagggctgcc cgccggcgcc acgcgaccca cggagaccgg ccgcgcgcct 1320cgggctgtct ggcccggccc ggacccccgc catcgcccgg ggccgcctcg gacgacgacg 1380acgacgatgt cgtcggggcc acgccgcccg cgcgcctgct ggagccctgg gccggctgca 1440acggcggggc ggcggcggac agcgactcga gcctggacga gccgtgccgc cccggcttcg 1500cctcggaatc caaggtgtag ggcccggcgc ggggcgcgga ctccgggcac ggcttcccag 1560gggaacgagg agatctgtgt ttacttaaga ccgatagcag gtgaactcga agcccacaat 1620cctcgtctga atcatccgag gcaaagagaa aagccacgga ccgttgcaca aaaaggaaag 1680tttgggaagg gatgggagag tggcttgctg atgttccttg ttg 172342015DNAHomo sapiens 4actgcgaagc ggcttcttca gagcacgggc tggaactggc aggcaccgcg agcccctagc 60acccgacaag ctgagtgtgc aggacgagtc cccaccacac ccacaccaca gccgctgaat 120gaggcttcca ggcgtccgct cgcggcccgc agagccccgc cgtgggtccg cccgctgagg 180cgcccccagc cagtgcgctt acctgccaga ctgcgcgcca tggggcaacc cgggaacggc 240agcgccttct tgctggcacc caatagaagc catgcgccgg accacgacgt cacgcagcaa 300agggacgagg tgtgggtggt gggcatgggc atcgtcatgt ctctcatcgt cctggccatc 360gtgtttggca atgtgctggt catcacagcc attgccaagt tcgagcgtct gcagacggtc 420accaactact tcatcacttc actggcctgt gctgatctgg tcatgggcct ggcagtggtg 480ccctttgggg ccgcccatat tcttatgaaa atgtggactt ttggcaactt ctggtgcgag 540ttttggactt ccattgatgt gctgtgcgtc acggccagca ttgagaccct gtgcgtgatc 600gcagtggatc gctactttgc cattacttca cctttcaagt accagagcct gctgaccaag 660aataaggccc gggtgatcat tctgatggtg tggattgtgt caggccttac ctccttcttg 720cccattcaga tgcactggta ccgggccacc caccaggaag ccatcaactg ctatgccaat 780gagacctgct gtgacttctt cacgaaccaa gcctatgcca ttgcctcttc catcgtgtcc 840ttctacgttc ccctggtgat catggtcttc gtctactcca gggtctttca ggaggccaaa 900aggcagctcc agaagattga caaatctgag ggccgcttcc atgtccagaa ccttagccag 960gtggagcagg atgggcggac ggggcatgga ctccgcagat cttccaagtt ctgcttgaag 1020gagcacaaag ccctcaagac gttaggcatc atcatgggca ctttcaccct ctgctggctg 1080cccttcttca tcgttaacat tgtgcatgtg atccaggata acctcatccg taaggaagtt 1140tacatcctcc taaattggat aggctatgtc aattctggtt tcaatcccct tatctactgc 1200cggagcccag atttcaggat tgccttccag gagcttctgt gcctgcgcag gtcttctttg 1260aaggcctatg ggaatggcta ctccagcaac ggcaacacag gggagcagag tggatatcac 1320gtggaacagg agaaagaaaa taaactgctg tgtgaagacc tcccaggcac ggaagacttt 1380gtgggccatc aaggtactgt gcctagcgat aacattgatt cacaagggag gaattgtagt 1440acaaatgact cactgctgta aagcagtttt tctactttta aagacccccc cccccccaac 1500agaacactaa acagactatt taacttgagg gtaataaact tagaataaaa ttgtaaaaat 1560tgtatagaga tatgcagaag gaagggcatc cttctgcctt ttttattttt ttaagctgta 1620aaaagagaga aaacttattt gagtgattat ttgttatttg tacagttcag ttcctctttg 1680catggaattt gtaagtttat gtctaaagag ctttagtcct agaggacctg agtctgctat 1740attttcatga cttttccatg tatctacctc actattcaag tattaggggt aatatattgc 1800tgctggtaat ttgtatctga aggagatttt ccttcctaca cccttggact tgaggatttt 1860gagtatctcg gacctttcag ctgtgaacat ggactcttcc cccactcctc ttatttgctc 1920acacggggta ttttaggcag ggatttgagg agcagcttca gttgttttcc cgagcaaagg 1980tctaaagttt acagtaaata aaatgtttga ccatg 201552909DNAHomo sapiens 5cagcctgcgc cggggaacat cggccgcctc cagctcccgg cgcggcccgg cccggcccgg 60ctcggccgcc tcagacgccg cctgccctgc agccatgagg cccccgcagt gtctgctgca 120cacgccttcc ctggcttccc cactccttct cctcctcctc tggctcctgg gtggaggagt 180gggggctgag ggccgggagg atgcagagct gctggtgacg gtgcgtgggg gccggctgcg 240gggcattcgc ctgaagaccc ccgggggccc tgtctctgct ttcctgggca tcccctttgc 300ggagccaccc atgggacccc gtcgctttct gccaccggag cccaagcagc cttggtcagg 360ggtggtagac gctacaacct tccagagtgt ctgctaccaa tatgtggaca ccctataccc 420aggttttgag ggcaccgaga tgtggaaccc caaccgtgag ctgagcgagg actgcctgta 480cctcaacgtg tggacaccat acccccggcc tacatccccc acccctgtcc tcgtctggat 540ctatgggggt ggcttctaca gtggggcctc ctccttggac gtgtacgatg gccgcttctt 600ggtacaggcc gagaggactg tgctggtgtc catgaactac cgggtgggag cctttggctt 660cctggccctg ccggggagcc gagaggcccc gggcaatgtg ggtctcctgg atcagaggct 720ggccctgcag tgggtgcagg agaacgtggc agccttcggg ggtgacccga catcagtgac 780gctgtttggg gagagcgcgg gagccgcctc ggtgggcatg cacctgctgt ccccgcccag 840ccggggcctg ttccacaggg ccgtgctgca gagcggtgcc cccaatggac cctgggccac 900ggtgggcatg ggagaggccc gtcgcagggc cacgcagctg gcccaccttg tgggctgtcc 960tccaggcggc actggtggga atgacacaga gctggtagcc tgccttcgga cacgaccagc 1020gcaggtcctg gtgaaccacg aatggcacgt gctgcctcaa gaaagcgtct tccggttctc 1080cttcgtgcct gtggtagatg gagacttcct cagtgacacc ccagaggccc tcatcaacgc 1140gggagacttc cacggcctgc aggtgctggt gggtgtggtg aaggatgagg gctcgtattt 1200tctggtttac ggggccccag gcttcagcaa agacaacgag tctctcatca gccgggccga 1260gttcctggcc ggggtgcggg tcggggttcc ccaggtaagt gacctggcag ccgaggctgt 1320ggtcctgcat tacacagact ggctgcatcc cgaggacccg gcacgcctga gggaggccct 1380gagcgatgtg gtgggcgacc acaatgtcgt gtgccccgtg gcccagctgg ctgggcgact 1440ggctgcccag ggtgcccggg tctacgccta cgtctttgaa caccgtgctt ccacgctctc 1500ctggcccctg tggatggggg tgccccacgg ctacgagatc gagttcatct ttgggatccc 1560cctggacccc tctcgaaact acacggcaga ggagaaaatc ttcgcccagc gactgatgcg 1620atactgggcc aactttgccc gcacagggga tcccaatgag ccccgagacc ccaaggcccc 1680acaatggccc ccgtacacgg cgggggctca gcagtacgtt agtctggacc tgcggccgct 1740ggaggtgcgg cgggggctgc gcgcccaggc ctgcgccttc tggaaccgct tcctccccaa 1800attgctcagc gccaccgcct cggaggctcc cagcacctgc ccaggcttca cccatgggga 1860ggctgctccg aggcccggcc tccccctgcc cctcctcctc ctccaccagc ttctcctcct 1920cttcctctcc cacctccggc ggctgtgaac acggcctctt cccctacggc cacaggggcc 1980cctcctctaa tgagtggtcg gaccgtgggg aagggcccca ctcagggatc tcagacctag 2040tgctcccttc ctcctcaaac cgagagactc acactggaca gggcaggagg agggggccgt 2100gcctcccacc cttctcaggg acccccacgc ctttgttgtt tgaatggaaa tggaaaagcc 2160agtattcttt tataaaatta tcttttggaa cctgagcctg acattggggg gaagtgggag 2220gccccggacg gggtagcacc ccccattggg gctataacgg tcaaccattt ctgtctcttc 2280tttttccccc aacctccccc tcctgtcccc tctgttcccg tcttccggtc attcttttct 2340cctcctctct ccttcctgct gtccttctcc ggccccgcct ctgccctcat cctccctctc 2400gtctttcgca cattctcctg atcctcttgc caccgtccca cgtggtcgcc tgcatttctc 2460cgtgcgtcct ccctgcactg aaaccccccc ttcaacccgc ccaaatgtcc gatccccgac 2520cttcctcgtg ccgtcctccc ctcccgcctc gctgggcgcc ctggccgcag acacgctcga 2580cgaggcggag cgccagtgga aggccgagtt ccaccgctgg agctcctaca tggtgcactg 2640gaagaaccag ttcgaccact acagcaagca ggatcgctgc tcagacctgt gaccccggcg 2700ggacccccat gtcctccgct ccgcccggcc ccctagctgt atatactatt tatttcaggg 2760ctgggctata acacagacga gccccagact ctgcccatcc ccaccccacc ccgacgtccc 2820ccggggctcc cggtcctctg gcatgtcttc aggctgagct cctccccgcg tgccttcgcc 2880ctctggctgc aaataaactg ttacaggcc 290965468DNAHomo sapiens 6tctctgtctg ccagggtctc cgactgtccc agacgggctg gtgtgggctt gggatcctcc 60tggtgacctc tcccgctaag gtccctcagc cactctgccc caagatgggc cgtggggctg 120gccgtgagta ctcacctgcc gccaccacgg cagagaatgg gggcggcaag aagaaacaga 180aggagaagga actggatgag ctgaagaagg aggtggcaat ggatgaccac aagctgtcct 240tggatgagct gggccgcaaa taccaagtgg acctgtccaa gggcctcacc aaccagcggg 300ctcaggacgt tctggctcga gatgggccca acgccctcac accacctccc acaacccctg 360agtgggtcaa gttctgccgt cagcttttcg gggggttctc catcctgctg tggattgggg 420ctatcctctg cttcctggcc tacggcatcc aggctgccat ggaggatgaa ccatccaacg 480acaatctata tctgggtgtg gtgctggcag ctgtggtcat tgtcactggc tgcttctcct 540actaccagga ggccaagagc tccaagatca tggattcctt caagaacatg gtacctcagc 600aagcccttgt gatccgggag ggagagaaga tgcagatcaa cgcagaggaa gtggtggtgg 660gagacctggt ggaggtgaag ggtggagacc gcgtccctgc tgacctccgg atcatctctt 720ctcatggctg taaggtggat aactcatcct taacaggaga gtcggagccc cagacccgct 780cccccgagtt cacccatgag aaccccctgg agacccgcaa tatctgtttc ttctccacca 840actgtgttga aggcactgcc aggggcattg tgattgccac aggagaccgg acggtgatgg 900gccgcatagc tactctcgcc tcaggcctgg aggttgggcg gacacccata gcaatggaga 960ttgaacactt catccagctg atcacagggg tcgctgtatt cctgggggtc tccttcttcg 1020tgctctccct catcctgggc tacagctggc tggaggcagt catcttcctc atcggcatca 1080tagtggccaa cgtgcctgag gggcttctgg ccactgtcac tgtgtgcctg accctgacag 1140ccaagcgcat ggcacggaag aactgcctgg tgaagaacct ggaggcggtg gagacgctgg 1200gctccacgtc caccatctgc tcggacaaga cgggcaccct cacccagaac cgcatgaccg 1260tcgcccacat gtggttcgac aaccaaatcc atgaggctga caccaccgaa gatcagtctg 1320gggccacttt tgacaaacga tcccctacgt ggacggccct gtctcgaatt gctggtctct 1380gcaaccgcgc cgtcttcaag gcaggacagg agaacatctc cgtgtctaag cgggacacag 1440ctggtgatgc ctctgagtca gctctgctca agtgcattga gctctcctgt ggctcagtga 1500ggaaaatgag agacagaaac cccaaggtgg cagagattcc tttcaactct accaacaagt 1560accagctgtc tatccacgag cgagaagaca gcccccagag ccacgtgctg gtgatgaagg 1620gggccccaga gcgcattctg gaccggtgct ccaccatcct ggtgcagggc aaggagatcc 1680cgctcgacaa ggagatgcaa gatgcctttc aaaatgccta catggagctg gggggacttg 1740gggagcgtgt gctgggattc tgtcaactga atctgccatc tggaaagttt cctcggggct 1800tcaaattcga cacggatgag ctgaactttc ccacggagaa gctttgcttt gtggggctca 1860tgtctatgat tgaccctccc cgggctgctg tgccagatgc tgtgggcaag tgccgaagcg 1920caggcatcaa ggtgatcatg gtaaccgggg atcaccctat cacagccaag gccattgcca 1980aaggcgtggg catcatatca gagggtaacg agactgtgga ggacattgca gcccggctca 2040acattcccat gagtcaagtc aaccccagag aagccaaggc atgcgtggtg cacggctctg 2100acctgaagga catgacatcg gagcagctcg atgagatcct caagaaccac acagagatcg 2160tctttgctcg aacgtctccc cagcagaagc tcatcattgt ggagggatgt cagaggcagg 2220gagccattgt ggccgtgacg ggtgacgggg tgaacgactc ccctgcattg aagaaggctg 2280acattggcat tgccatgggc atctctggct ctgacgtctc taagcaggca gccgacatga 2340tcctgctgga tgacaacttt gcctccatcg tcacgggggt ggaggagggc cgcctgatct 2400ttgacaactt gaagaaatcc atcgcctaca ccctgaccag caacatcccc gagatcaccc 2460ccttcctgct gttcatcatt gccaacatcc ccctacctct gggcactgtg accatccttt 2520gcattgacct gggcacagat atggtccctg ccatctcctt ggcctatgag gcagctgaga 2580gtgatatcat gaagcggcag ccacgaaact cccagacgga caagctggtg aatgagaggc 2640tcatcagcat ggcctacgga cagatcggga tgatccaggc actgggtggc ttcttcacct 2700actttgtgat cctggcagag aacggtttcc tgccatcacg gctactggga atccgcctcg 2760actgggatga ccggaccatg aatgatctgg aggacagcta tggacaggag tggacctatg 2820agcagcggaa ggtggtggag ttcacgtgcc acacggcatt ctttgccagc atcgtggtgg 2880tgcagtgggc tgacctcatc atctgcaaga cccgccgcaa ctcagtcttc cagcagggca 2940tgaagaacaa gatcctgatt tttgggctcc tggaggagac ggcgttggct gcctttctct 3000cttactgccc aggcatgggt gtagccctcc gcatgtaccc gctcaaagtc acctggtggt 3060tctgcgcctt cccctacagc ctcctcatct tcatctatga tgaggtccga aagctcatcc 3120tgcggcggta tcctggtggc tgggtggaga aggagacata ctactgaccc cattggaaga 3180agaaccaggc atggaaagat ggggagctct ggaggtgttg tggggatggt gatggagagg 3240gatggaaata acgggtggca ttgggtggca acatttgggg agagataatg aggcaactca 3300gcaggctaag ttgcggggta tataaattgg ggtgatgacc ccatagacct aactgtgaac 3360aatcagatta gacactatgt gttagagtcc ccccgaccag atccttttcc atcccactcc 3420actatgttgt ctattttttc tgaggaatta agggttaccc caccctgccc actcccatcc 3480cttcaacccc acttcctact gtaatagatc agcatccaaa agcaggaacc catctaaacc 3540agaaggaagc cctctcagat caccccagcc tcactccatt tcccacttcc acccccgtta 3600gcttcctgca ggactctatc cctggcttcc ccttcagacc ttgcaatcac aaaaggttct 3660tctggtgagt gcaagagcct gagactggaa aaggtggact tgtctcccag tcgaggctgg 3720taagggacct tcagggagag ctgggcagac aggtgggaga tggaggtagg gctggctgga 3780ggaaggaaac aacaaaggaa gtgaggtagt gccaatgaca ggacatttga catgagtctc 3840cagatagatg tcgtggactc cagctctacg tcccacattt tagaataccc caccagcaga 3900acaaactcag atctcatcag ggtagcagca gaggcaggac cagaaggcaa tcaagagctt 3960ccagaaatgc cacacttgtg tgccacagag ttccccgctg acccttggtt aggggtcctc 4020ttagtccaca aggtccggat gtcactcatg tacttaataa cacttcacct tctgtaatac 4080taagtcctca gagctccatg ctgttctgaa agggatggcc acaagttctt tcccagcctc 4140ttccattccc tttcttttca tgcccatccc gatgaacctg catcattccc cgacactgcc 4200aagccaaccc tggaaaagga gttcgctggc cattggctag aatcagggtg gagaagttcc 4260ctgaaccttc ctgtctccca gggacatgta tgcttccagg gacaagctta ggtcatgaac 4320atggtcagaa cctttggaca agaggaaaaa tactaagaga tttgcttttt ctgggtgcgg 4380tggctcatgc ctgtaatccc agcactttgg gaggccgagg caggtggatc atgaggtcag 4440gagttcgagg cgagcctggc caacatggtg aaaccctgtc tctactaaaa gtacaaaaaa 4500ttagccagtc atggtggcac acgcctgtaa tctcagctac tcaggaggct gaggcaggag 4560aattgcttga acctgtgagg aagaggttgc agtgagctga gatcgtgcca ttacactcca 4620gcctgggcga aagggtgaga ctccatctca aaaaaaaaaa aaatgatttg cttttgacgt 4680cttaggtggc agggctgttc cctccaggca aatgcccttc aaaccgacga tcattgtgcc 4740cacttaccct gggctggaga gttggtttca ggttcctaca ggagatagct ttctttccct 4800tactccctat ctaacacttt tgctctgcag gcagccttgc ccattctcta agcctggctt 4860agaaggcact gggaatgtcc tgtagagaga gacctagata ggtcatgcaa gtgagaaaga 4920catctgagga aaatggaaga cctaaggcag acaggaagga agcacaaaag acaagcattg 4980ggtcagaccc ataaaccacc tcccaaaggc tgtcatttca ttgcactgga attttgcttt 5040atcagaagca aggaagtaag ggagtcattg ccttgggcct gggaatctaa gtgggagaca 5100atattaattt ggatccgatt aattggagat tactaactgt ggacaaaagt ttatctttgc 5160acaatcaata aaaatggcat ttttttagta aattaagagc ataaacaata ttgctagagg 5220tggcatgttt agtctaccaa aaacaatact tttcaggcac tttagaaata tccttttaga 5280agcagcgagt gcatgggcta attatcatca atctttatgt atttgttaaa gaaacatcta 5340caggatcttt attggtgacc ttttgtaaga cattagtttg aggtactacc tatgtacttg 5400aaaataataa agtggcattt ctttatgaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 5460aaaaaaaa

546873362DNAHomo sapiens 7aaaaaatcaa ttttggaaga tgtcactgaa caactcttcc aatgtatttc tggattcagt 60gcccagtaat accaatcgct ttcaagttag tgtcataaat gagaaccatg agagcagtgc 120agctgcagat gacaatactg acccaccaca ttatgaagaa acctcttttg gggatgaagc 180tcagaaaaga ctcagaatca gctttaggcc tgggaatcag gagtgctatg acaatttcct 240ccacagtgga gaaactgcta aaacagatgc cagttttcac gcttatgatt ctcacacaaa 300cacatactat ctacaaactt ttggccacaa caccatggat gccgttccca agatagagta 360ctatcgtaac accggcagca tcagtgggcc caaggtcaac cgacccagcc tgcttgagat 420tcacgagcaa ctcgcaaaga atgtggcagt caccccaagt tcagctgaca gagttgctaa 480cggtgatggg atacctggag atgaacaagc tgaaaataag gaagatgatc aagctggtgt 540tgtgaagttt ggatgggtga aaggtgtgct ggtaagatgc atgctgaaca tctggggagt 600catgctcttc attcgcctct cctggattgt tggagaagct ggaattggtc ttggagttat 660catcattggc ctatccacca tagtaacgac aatcacaggt atgtccacgt ctgctattgc 720cacgaacgga gttgttagag gaggtggggc ctactatctt atttccagaa gtttagggcc 780cgagttcggt gggtcaatag gcctgatctt tgcttttgct aatgcagtgg ctgttgctat 840gtatgtggtg ggattcgctg aaactgtagt agatctactt aaggagagtg attcgatgat 900ggtggatcca accaatgaca tccggattat aggctccatc acagtggtga ttcttctagg 960aatttcagta gctggaatgg aatgggaggc aaaggcccaa gtcattcttc tggtcattct 1020tctaattgct attgcaaact tcttcattgg aactgtcatt ccatccaaca atgagaaaaa 1080gtccagaggt ttctttaatt accaagcatc aatatttgca gaaaactttg ggccacgctt 1140cacaaagggt gaaggcttct tctctgtctt tgccattttt ttcccagcag ctactgggat 1200tcttgctggt gccaatatct caggagattt ggaggatccc caagatgcca tccccagagg 1260aaccatgctg gccattttca tcaccactgt tgcctactta ggggttgcaa tttgtgtagg 1320ggcctgtgtg gtccgagatg ccaccgggaa catgaatgac accatcattt ctgggatgaa 1380ctgcaatggt tcagcagcat gtgggttggg ctatgacttc tcaagatgtc gacatgaacc 1440atgtcagtac gggctgatga acaatttcca ggtcatgagc atggtatcag ggttcggccc 1500cctcatcact gcgggaatct tttctgcaac actctcctcc gccctggcct cccttgtcag 1560cgcacccaaa gtgttccagg ctctgtgcaa ggacaacatc tacaaagccc tgcagttttt 1620tgcaaaggga tatgggaaaa acaatgaacc cctgagagga tatattctca cttttcttat 1680agccatggca tttattctta ttgcggaact gaacaccatt gctcccatca tctccaactt 1740tttcctggcc tcatatgcac ttattaattt ctcctgcttc catgcctctt atgccaaatc 1800tccaggatgg agacctgcgt atggaattta caacatgtgg gtatctcttt ttggagctgt 1860tttgtgctgt gcagtcatgt ttgtcatcaa ctggtgggca gctgtcatca cctatgtcat 1920tgaattcttc ctttacgtct atgtgacttg taagaagcca gatgtgaact ggggctcctc 1980cacacaggct ctttcctacg tgagtgcttt agacaatgct ctggaattaa ccacagtgga 2040agaccacgta aaaaacttca ggccccagtg cattgtctta acagggggac ccatgacaag 2100acctgctctc ctggacataa ctcacgcctt taccaagaac agtggccttt gcatctgctg 2160tgaagtcttt gtgggaccgc gcaaactgtg tgttaaggag atgaacagtg gcatggcgaa 2220aaaacaggcc tggcttataa agaacaaaat caaggctttt tatgctgcag tggcggcaga 2280ctgtttcagg gatggtgtcc gaagtcttct tcaggcctca ggcttaggaa gaatgaaacc 2340aaacactctg gtgattggat ataagaaaaa ctggaggaaa gctcccttga cagagattga 2400gaactacgtg ggaatcatac atgatgcatt tgattttgag attggcgtgg ttatagtcag 2460aatcagccaa ggatttgaca tctctcaggt tcttcaggtg caagaggaat tagagagatt 2520agaacaggag agactagcat tggaagcgac tatcaaagat aatgagtgtg aagaggaaag 2580tggaggcatc cgaggcttgt ttaaaaaagc tggcaagttg aacattacta agacaacgcc 2640taaaaaagat ggcagcatta acacaagcca gtcgatgcat gtgggagagt tcaaccagaa 2700actggtggaa gccagcactc aatttaaaaa gaaacaagaa aaaggcacaa ttgatgtttg 2760gtggttgttt gatgatggag ggttaacact tcttatcccc tatatcttaa ctctcagaaa 2820aaaatggaaa gactgtaaat taagaatcta tgtgggaggg aagatcaacc gcattgaaga 2880agaaaaaatt gcaatggctt cccttctgag caaatttagg ataaaatttg cagacatcca 2940tatcatcggt gacatcaaca ttaggccaaa caaagagagc tggaaagtct ttgaagagat 3000gattgaacca tatcgtctcc atgaaagctg caaagattta acaactgctg agaaattaaa 3060aagagaaact ccgtggaaaa ttacagatgc agaactggaa gcagtcaagg aaaagagtta 3120ccgccaagtt cgactgaatg aactcttaca ggagcactcc agagctgcta atctcattgt 3180cctgagcctt cccgtggcaa gaaagggatc catatcggat ttgttgtata tggcttggtt 3240ggaaatcctc acaaagaacc tcccacctgt cttactagtt agaggaaatc acaaaaatgt 3300cttgacattt tactcttaaa acatgaaaga ttggaataca ttttaactta atgtaatgca 3360ta 3362819DNAArtificial SequenceTARGETING SEQUENCE 8ccctgaggat cctcaacaa 19921DNAArtificial SequenceSENSE STRAND 9cccugaggau ccucaacaan n 211021DNAArtificial SequenceANTISENSE STRAND 10uuguugagga uccucagggn n 211121RNAArtificial SequenceSENSE STRAND 11cccugaggau ccucaacaau u 211221RNAArtificial SequenceANTISENSE STRAND 12uuguugagga uccucagggu u 211348DNAArtificial SequenceHAIRPIN DUPLEX WITH LOOP 13cccugaggau ccucaacaan nnnnnnnuug uugaggaucc ucaggguu 481419DNAArtificial SequenceTARGETING SEQUENCE 14gggccttcag aaagttgtt 191519DNAArtificial SequenceTARGETING SEQUENCE 15gcgagcaggt gttgaaatt 191619DNAArtificial SequenceTARGETING SEQUENCE 16ggtgttgaaa ttccgtaaa 191719DNAArtificial SequenceTARGETING SEQUENCE 17gccactgaag aacaggcaa 191819DNAArtificial SequenceTARGETING SEQUENCE 18ccactgaaga acaggcaaa 191919DNAArtificial SequenceTARGETING SEQUENCE 19cccatagtct gtatccaaa 192019DNAArtificial SequenceTARGETING SEQUENCE 20ccatagtctg tatccaaat 192119DNAArtificial SequenceTARGETING SEQUENCE 21ggtgatttgg accctggtt 192219DNAArtificial SequenceTARGETING SEQUENCE 22gggtgatgag cactcacaa 192319DNAArtificial SequenceTARGETING SEQUENCE 23tcgtcaccac caaggcaaa 192419DNAArtificial SequenceTARGETING SEQUENCE 24gcttcttctt ctctggcta 192519DNAArtificial SequenceTARGETING SEQUENCE 25tcttctctgg ctacgataa 192619DNAArtificial SequenceTARGETING SEQUENCE 26ggctacgata agaagcaaa 192719DNAArtificial SequenceTARGETING SEQUENCE 27ggtccgactt gccatataa 192819DNAArtificial SequenceTARGETING SEQUENCE 28ggagatgcac atagtacat 192919DNAArtificial SequenceTARGETING SEQUENCE 29gcacatagta catgagaaa 193019DNAArtificialTARGETING SEQUENCE 30gacatcgagg aatgtgaaa 193119DNAArtificial SequenceTARGETING SEQUENCE 31ggtggaggca ctgtctaat 193219DNAArtificial SequenceTARGETING SEQUENCE 32gggactttag gcatgatta 193319DNAArtificial SequenceTARGETING SEQUENCE 33tccttcttct gcgagctgt 193419DNAArtificial SequenceTARGETING SEQUENCE 34tcgagaccct gtgtgtcat 193519DNAArtificialTARGETING SEQUENCE 35gcatcatggc cttcgtgta 193619DNAArtificial SequenceTARGETING SEQUENCE 36gaacgaggag atctgtgtt 193719DNAArtificial SequenceTARGETING SEQUENCE 37acgaggagat ctgtgttta 193819DNAArtificial SequenceTARGETING SEQUENCE 38ggagatctgt gtttactta 193919DNAArtificial SequenceTARGETING SEQUENCE 39gatagcaggt gaactcgaa 194019DNAArtificial SequenceTARGETING SEQUENCE 40cccacaatcc tcgtctgaa 194119DNAArtificial SequenceTARGETING SEQUENCE 41ccacaatcct cgtctgaat 194219DNAArtificial SequenceTARGETING SEQUENCE 42tctgaatcat ccgaggcaa 194319DNAArtificial SequenceTARGETING SEQUENCE 43gcatcgtcat gtctctcat 194419DNAArtificial SequenceTARGETING SEQUENCE 44gctggtcatc acagccatt 194519DNAArtificial SequenceTARGETING SEQUENCE 45ccctcaagac gttaggcat 194619DNAArtificial SequenceTARGETING SEQUENCE 46gcatcatcat gggcacttt 194719DNAArtificial SequenceTARGETING SEQUENCE 47cctaaattgg ataggctat 194819DNAArtificial SequenceTARGETING SEQUENCE 48gctatgtcaa ttctggttt 194919DNAArtificial SequenceTARGETING SEQUENCE 49ggaagacttt gtgggccat 195019DNAArtificial SequenceTARGETING SEQUENCE 50gcctagcgat aacattgat 195119DNAArtificial SequenceTARGETING SEQUENCE 51gggaggaatt gtagtacaa 195219DNAArtificial SequenceTARGETING SEQUENCE 52gctgtgaaca tggactctt 195319DNAArtificial SequenceTARGETING SEQUENCE 53ccagagtgtc tgctaccaa 195419DNAArtificial SequenceTARGETING SEQUENCE 54gctaccaata tgtggacac 195519DNAArtificial SequenceTARGETING SEQUENCE 55ccaatatgtg gacacccta 195619DNAArtificial SequenceTARGETING SEQUENCE 56gctggtgtcc atgaactac 195719DNAArtificial SequenceTARGETING SEQUENCE 57tcatcaacgc gggagactt 195819DNAArtificialTARGETING SEQUENCE 58ggtctacgcc tacgtcttt 195919DNAArtificial SequenceTARGETING SEQUENCE 59gctacgagat cgagttcat 196019DNAArtificial SequenceTARGETING SEQUENCE 60gctataacgg tcaaccatt 196119DNAArtificial SequenceTARGETING SEQUENCE 61ggctgcaaat aaactgtta 196219DNAArtificial SequenceTARGETING SEQUENCE 62gctgcaaata aactgttac 196319DNAArtificial SequenceTARGETING SEQUENCE 63ccatccaacg acaatctat 196419DNAArtificial SequenceTARGETING SEQUENCE 64gcatcatatc agagggtaa 196519DNAArtificial SequenceTARGETING SEQUENCE 65cctcctcatc ttcatctat 196619DNAArtificial SequenceTARGETING SEQUENCE 66ggaagtgagg tagtgccaa 196719DNAArtificial SequenceTARGETING SEQUENCE 67ggatgtcact catgtactt 196819DNAArtificial SequenceTARGETING SEQUENCE 68gctccatgct gttctgaaa 196919DNAArtificial SequenceTARGETING SEQUENCE 69gctggccatt ggctagaat 197019DNAArtificial SequenceTARGETING SEQUENCE 70ggtcagaacc tttggacaa 197119DNAArtificial SequenceTARGETING SEQUENCE 71gctagaggtg gcatgttta 197219DNAArtificial SequenceTARGETING SEQUENCE 72gcgagtgcat gggctaatt 197319DNAArtificial SequenceTARGETING SEQUENCE 73ccaccatagt aacgacaat 197419DNAArtificial SequenceTARGETING SEQUENCE 74ggaatggaat gggaggcaa 197519DNAArtificial SequenceTARGETING SEQUENCE 75gggatgaact gcaatggtt 197619DNAArtificial SequenceTARGETING SEQUENCE 76ccatgcctct tatgccaaa 197719DNAArtificial SequenceTARGETING SEQUENCE 77cctgctctcc tggacataa 197819DNAArtificial SequenceTARGETING SEQUENCE 78gcatctgctg tgaagtctt 197919DNAArtificial SequenceTARGETING SEQUENCE 79gcctcaggct taggaagaa 198019DNAArtificial SequenceTARGETING SEQUENCE 80ggaagcgact atcaaagat 198119DNAArtificial SequenceTARGETING SEQUENCE 81gctggcaagt tgaacatta 198219DNAArtificial SequenceTARGETING SEQUENCE 82gcaagaaagg gatccatat 198319DNAArtificial SequenceTARGETING SEQUENCE 83gaaggttggc agcgctaaa 198419DNAArtificial SequenceTARGETING SEQUENCE 84atgtgctgga ttccattaa 198519DNAArtificial SequenceTARGETING SEQUENCE 85tgtgctggat tccattaaa 198619DNAArtificial SequenceTARGETING SEQUENCE 86ccgtaaactt aacttcaat 198719DNAArtificial SequenceTARGETING SEQUENCE 87gatctacctt ggtgatttg 198819DNAArtificial SequenceTARGETING SEQUENCE 88gaccaattgt catgcttga 198919DNAArtificial SequenceTARGETING SEQUENCE 89ggtgatgagc actcacaat 199019DNAArtificial SequenceTARGETING SEQUENCE 90cactcacaat tgttgacta 199119DNAArtificial SequenceTARGETING SEQUENCE 91actcacaatt gttgactaa 199219DNAArtificial SequenceTARGETING SEQUENCE 92ctcacaattg ttgactaaa 199319DNAArtificial SequenceTARGETING SEQUENCE 93aggaaagtag aatggttga 199419DNAArtificial SequenceTARGETING SEQUENCE 94gtagaatggt tgagtgcaa 199519DNAArtificial SequenceTARGETING SEQUENCE 95tagaatggtt gagtgcaaa 199619DNAArtificial SequenceTARGETING SEQUENCE 96caagataaat tgagctagt 199719DNAArtificial SequenceTARGETING SEQUENCE 97agttaaggca aatcaggta 199819DNAArtificial SequenceTARGETING SEQUENCE 98gagttgtgat acagagtat 199919DNAArtificial SequenceTARGETING SEQUENCE 99agttgtgata cagagtata 1910019DNAArtificial SequenceTARGETING SEQUENCE 100gttgtgatac agagtatat 191013992DNAHomo sapiens 101ataaaagctg cccggggaag ccaggagagc gaagggcgga cgtactcgcc acggcaccca 60ggctgcgcgc acgcggtccc ggtgtgcagc tggagagcga gcggccaccg ggagcccccg 120gcacagcccg cgcccgcccc gcaggagccc gcgaagatgc cccggcgcag cctgcacgcg 180gcggccgtgc tcctgctggt gatcttaaag gaacagcctt ccagcccggc cccagtgaac 240ggttccaagt ggacttattt tggtcctgat ggggagaata gctggtccaa gaagtacccg 300tcgtgtgggg gcctgctgca gtcccccata gacctgcaca gtgacatcct ccagtatgac 360gccagcctca cgcccctcga gttccaaggc tacaatctgt ctgccaacaa gcagtttctc 420ctgaccaaca atggccattc agtgaagctg aacctgccct cggacatgca catccagggc 480ctccagtctc gctacagtgc cacgcagctg cacctgcact gggggaaccc gaatgacccg 540cacggctctg agcacaccgt cagcggacag cacttcgccg ccgagctgca cattgtccat 600tataactcag acctttatcc tgacgccagc actgccagca acaagtcaga aggcctcgct 660gtcctggctg ttctcattga gatgggctcc ttcaatccgt cctatgacaa gatcttcagt 720caccttcaac atgtaaagta caaaggccag gaagcattcg tcccgggatt caacattgaa 780gagctgcttc cggagaggac cgctgaatat taccgctacc gggggtccct gaccacaccc 840ccttgcaacc ccactgtgct ctggacagtt ttccgaaacc ccgtgcaaat ttcccaggag 900cagctgctgg ctttggagac agccctgtac tgcacacaca tggacgaccc ttcccccaga 960gaaatgatca acaacttccg gcaggtccag aagttcgatg agaggctggt atacacctcc 1020ttctcccaag tgcaagtctg tactgcggca ggactgagtc tgggcatcat cctctcactg 1080gccctggctg gcattcttgg catctgtatt gtggtggtgg tgtccatttg gcttttcaga 1140aggaagagta tcaaaaaagg tgataacaag ggagtcattt acaagccagc caccaagatg 1200gagactgagg cccacgcttg aggtccccgg agctcccggg cacatccagg aaggaccttg 1260ctttggaccc tacacacttc ggctctctgg acacttgcga cacctcaagg tgttctctgt 1320agctcaatct gcaaacatgc caggcctcag ggatcctctg ctgggtgcct ccttgccttg 1380ggaccatggc caccccagag ccatccgatc gatggatggg atgcactctc agaccaagca 1440gcaggaattc aaagctgctt gctgtaactg tgtgagattg tgaagtggtc tgaattctgg 1500aatcacaaac caagccatgc tggtgggcca ttaatggttg gaaaacactt tcatccgggg 1560ctttgccaga gcgtgctttc aagtgtcctg gaaattctgc tgcttctcca agctttcaga 1620caagaatgtg cactctctgc ttaggttttg cttgggaaac tcaacttctt tcctctggag 1680acggggcatc tccctctgat ttccttctgc tatgacaaaa cctttaatct gcaccttaca 1740actcggggac aaatggggac aggaaggatc aagttgtaga gagaaaaaga aaacaagaga 1800tatacattgt gatatattag ggacactttc acagtcctgt cctctggatc acagacactg 1860cacagacctt agggaatggc aggttcaagt tccacttctt ggtggggatg agaagggaga 1920gagagctaga gggacaaaga gaatgagaag acatggatga tctgggagag tctcactttg 1980gaatcagaat tggaatcaca ttctgtttat caagccataa tgtaaggaca gaataataca 2040atattaagtc caaatccaac ctcctgtcag tggagcagtt atgttttata ctctacagat 2100tttacaaata atgaggctgt tccttgaaaa tgtgttgttg ctgtgtcctg gaggagacat 2160gagttccgag atgacccaat ctgcctttga atctggagga aataggcaga aacaaaatga 2220ctgtagaact tattctctgt aggccaaatt tcatttcagc cacttctgca ggatccctac

2280tgccaacctg gaatggagac ttttatctac ttctctctct ctgaagatgt caaatcgtgg 2340tttagatcaa atatatttca agctataaaa gcaggaggtt atctgtgcag ggggctggca 2400tcatgtattt aggggcaagt aataatggaa tgctactaag atactccata ttcttccccg 2460aatcacacag acagtttctg acaggcgcaa ctcctccatt ttcctcccgc aggtgagaac 2520cctgtggaga tgagtcagtg ccatgactga gaaggaaccg acccctagtt gagagcacct 2580tgcagttccc cgagaacttt ctgattcaca gtctcatttt gacagcatga aatgtcctct 2640tgaagcatag ctttttaaat atctttttcc ttctactcct ccctctgact ctaagaattc 2700tctcttctgg aatcgcttga acccaggagg cggaggttgc agtaagccaa ggtcatgcca 2760ctgcactcta gcctgggtga cagagcgaga ctccatctca aaaaaaaaaa aaaaaaaatt 2820attctgtacc atcacaactt ttcacaacga tggcaagcct tatgtcttgg gagcctgttt 2880tgctaggcaa agttacaagt gacctaatgg gagctcaaat gtgtgtgtgt ctctctgtgt 2940gtttgtgtgt gtgtgtgcac tcaagacctc taacagcctc gaagcctggg gtggcatccc 3000ggccttgcca ttagcatgcc tcatgcatca tcagatgaca aggacaaccc tcatgacgaa 3060gcaacatgaa ttagggggcc tcttggcctt ggtccaaaat tgtcaatcag aaatgaacat 3120aaaggactcc agagcagtgg gactgtctgt caaaagactc tgtatatctt ttgtggatga 3180gttttgtgag agaacagaga gaccattgta cctggcacaa gggctgttca tgaaaaggga 3240gacttactgg gaggtgcaag acagtggcat ttctcctctc ctcttgctgc tcagcacagc 3300cctggattgc agccccgagg ctgagaccag acaaagcccg ggaggcagaa agatgctcca 3360agaaccaaca ctatcaatgt ctttgcaaat cctcacagga ttcctgtggg tccagctttg 3420gaactgggaa acctttcttc ggatccgcac tcattccact gatgccagct gcccctgaag 3480gatgccagta ctgtggtgtg tgagtctcag cagccgccca cacgctccta actctgctgc 3540atggcagatg cctaggtgga aatagcaaaa acaaggccca ggctggggcc agggccagag 3600gggaaggccc tggattctca ctcatgtgag atcttgaatc tctttctttg ttctgtttgt 3660ttagttagta tcatctggta aaatagttaa aaaacaacaa aaaactctgt atctgtttct 3720agcatgtgct gcattgactc tattaatcac atttcaaatt caccctacat tcctctcctc 3780ttcactagcc tctctgaagg tgtcctggcc agccctggag aagcactggt gtctgcagca 3840cccctcagtt cctgtgcctc agcccacagg ccactgtgat aatggtctgt ttagcacttc 3900tgtatttatt gtaagaatga ttataatgaa gatacacact gtaactacaa gaaattataa 3960atgtttttca catcaaaaaa aaaaaaaaaa aa 399210219DNAArtificial SequenceTARGETING SEQUENCE 102tcctgctggt gatcttaaa 1910319DNAArtificial SequenceTARGETING SEQUENCE 103acggttccaa gtggactta 1910419DNAArtificial SequenceTARGETING SEQUENCE 104gagaatagct ggtccaaga 1910519DNAArtificial SequenceTARGETING SEQUENCE 105agaatagctg gtccaagaa 1910619DNAArtificial SequenceTARGETING SEQUENCE 106gtgacatcct ccagtatga 1910719DNAArtificial SequenceTARGETING SEQUENCE 107gctacaatct gtctgccaa 1910819DNAArtificial SequenceTARGETING SEQUENCE 108cagtttctcc tgaccaaca 1910919DNAArtificial SequenceTARGETING SEQUENCE 109agtttctcct gaccaacaa 1911019DNAArtificial SequenceTARGETING SEQUENCE 110gaccaacaat ggccattca 1911119DNAArtificial SequenceTARGETING SEQUENCE 111ctccttcaat ccgtcctat 1911219DNAArtificial SequenceTARGETING SEQUENCE 112ccttcaatcc gtcctatga 1911319DNAArtificial SequenceTARGETING SEQUENCE 113atccgtccta tgacaagat 1911419DNAArtificial SequenceTARGETING SEQUENCE 114agatcttcag tcaccttca 1911519DNAArtificial SequenceTARGETING SEQUENCE 115cggagaggac cgctgaata 1911619DNAArtificial SequenceTARGETING SEQUENCE 116ggagaggacc gctgaatat 1911719DNAArtificial SequenceTARGETING SEQUENCE 117agaggaccgc tgaatatta 1911819DNAArtificial SequenceTARGETING SEQUENCE 118aggtccagaa gttcgatga 1911919DNAArtificial SequenceTARGETING SEQUENCE 119gttcgatgag aggctggta 1912019DNAArtificial SequenceTARGETING SEQUENCE 120ttcgatgaga ggctggtat 1912119DNAArtificial SequenceTARGETING SEQUENCE 121tcgatgagag gctggtata 1912219DNAArtificial SequenceTARGETING SEQUENCE 122tgtactgcgg caggactga 191232156DNAHomo sapiens 123cagcctgcgc cggggaacat cggccgcctc cagctcccgg cgcggcccgg cccggcccgg 60ctcggccgcc tcagacgccg cctgccctgc agccatgagg cccccgcagt gtctgctgca 120cacgccttcc ctggcttccc cactccttct cctcctcctc tggctcctgg gtggaggagt 180gggggctgag ggccgggagg atgcagagct gctggtgacg gtgcgtgggg gccggctgcg 240gggcattcgc ctgaagaccc ccgggggccc tgtctctgct ttcctgggca tcccctttgc 300ggagccaccc atgggacccc gtcgctttct gccaccggag cccaagcagc cttggtcagg 360ggtggtagac gctacaacct tccagagtgt ctgctaccaa tatgtggaca ccctataccc 420aggttttgag ggcaccgaga tgtggaaccc caaccgtgag ctgagcgagg actgcctgta 480cctcaacgtg tggacaccat acccccggcc tacatccccc acccctgtcc tcgtctggat 540ctatgggggt ggcttctaca gtggggcctc ctccttggac gtgtacgatg gccgcttctt 600ggtacaggcc gagaggactg tgctggtgtc catgaactac cgggtgggag cctttggctt 660cctggccctg ccggggagcc gagaggcccc gggcaatgtg ggtctcctgg atcagaggct 720ggccctgcag tgggtgcagg agaacgtggc agccttcggg ggtgacccga catcagtgac 780gctgtttggg gagagcgcgg gagccgcctc ggtgggcatg cacctgctgt ccccgcccag 840ccggggcctg ttccacaggg ccgtgctgca gagcggtgcc cccaatggac cctgggccac 900ggtgggcatg ggagaggccc gtcgcagggc cacgcagctg gcccaccttg tgggctgtcc 960tccaggcggc actggtggga atgacacaga gctggtagcc tgccttcgga cacgaccagc 1020gcaggtcctg gtgaaccacg aatggcacgt gctgcctcaa gaaagcgtct tccggttctc 1080cttcgtgcct gtggtagatg gagacttcct cagtgacacc ccagaggccc tcatcaacgc 1140gggagacttc cacggcctgc aggtgctggt gggtgtggtg aaggatgagg gctcgtattt 1200tctggtttac ggggccccag gcttcagcaa agacaacgag tctctcatca gccgggccga 1260gttcctggcc ggggtgcggg tcggggttcc ccaggtaagt gacctggcag ccgaggctgt 1320ggtcctgcat tacacagact ggctgcatcc cgaggacccg gcacgcctga gggaggccct 1380gagcgatgtg gtgggcgacc acaatgtcgt gtgccccgtg gcccagctgg ctgggcgact 1440ggctgcccag ggtgcccggg tctacgccta cgtctttgaa caccgtgctt ccacgctctc 1500ctggcccctg tggatggggg tgccccacgg ctacgagatc gagttcatct ttgggatccc 1560cctggacccc tctcgaaact acacggcaga ggagaaaatc ttcgcccagc gactgatgcg 1620atactgggcc aactttgccc gcacagggga tcccaatgag ccccgagacc ccaaggcccc 1680acaatggccc ccgtacacgg cgggggctca gcagtacgtt agtctggacc tgcggccgct 1740ggaggtgcgg cgggggctgc gcgcccaggc ctgcgccttc tggaaccgct tcctccccaa 1800attgctcagc gccaccgaca cgctcgacga ggcggagcgc cagtggaagg ccgagttcca 1860ccgctggagc tcctacatgg tgcactggaa gaaccagttc gaccactaca gcaagcagga 1920tcgctgctca gacctgtgac cccggcggga cccccatgtc ctccgctccg cccggccccc 1980tagctgtata tactatttat ttcagggctg ggctataaca cagacgagcc ccagactctg 2040cccatcccca ccccaccccg acgtcccccg gggctcccgg tcctctggca tgtcttcagg 2100ctgagctcct ccccgcgtgc cttcgccctc tggctgcaaa taaactgtta caggcc 21561243713DNAHomo sapiens 124attttaggaa gtgaggagga ggcgcgggct ggagctgcgg cggggtctgg ggcgcagagc 60agcggcggga ggaggcggac acgtggcaac agcggtagca gcccgggcgg cggcagcaac 120agcggcggcg gcatcggccc gagccgccgg ccgccctccc accctcccgc cccgcggcag 180ccctagctcc ctccacttgg ctcccctggt cccgctcgct cggccgggag ctgctctgtg 240cttttctctc tgattctcca gcgacaggac ccggcgccgg gcactgagca ccgccaccat 300ggggaagggg gttggacgtg ataagtatga gcctgcagct gtttcagaac aaggtgataa 360aaagggcaaa aagggcaaaa aagacaggga catggatgaa ctgaagaaag aagtttctat 420ggatgatcat aaacttagcc ttgatgaact tcatcgtaaa tatggaacag acttgagccg 480gggattaaca tctgctcgtg cagctgagat cctggcgcga gatggtccca acgccctcac 540tccccctccc actactcctg aatggatcaa gttttgtcgg cagctctttg gggggttctc 600aatgttactg tggattggag cgattctttg tttcttggct tatagcatcc aagctgctac 660agaagaggaa cctcaaaacg ataatctgta cctgggtgtg gtgctatcag ccgttgtaat 720cataactggt tgcttctcct actatcaaga agctaaaagt tcaaagatca tggaatcctt 780caaaaacatg gtccctcagc aagcccttgt gattcgaaat ggtgagaaaa tgagcataaa 840tgcggaggaa gttgtggttg gggatctggt ggaagtaaaa ggaggagacc gaattcctgc 900tgacctcaga atcatatctg caaatggctg caaggtggat aactcctcgc tcactggtga 960atcagaaccc cagactaggt ctccagattt cacaaatgaa aaccccctgg agacgaggaa 1020cattgccttc ttttcaacca attgtgttga aggcaccgca cgtggtattg ttgtctacac 1080tggggatcgc actgtgatgg gaagaattgc cacacttgct tctgggctgg aaggaggcca 1140gacccccatt gctgcagaaa ttgaacattt tatccacatc atcacgggtg tggctgtgtt 1200cctgggtgtg tctttcttca tcctttctct catccttgag tacacctggc ttgaggctgt 1260catcttcctc atcggtatca tcgtagccaa tgtgccggaa ggtttgctgg ccactgtcac 1320ggtctgtctg acacttactg ccaaacgcat ggcaaggaaa aactgcttag tgaagaactt 1380agaagctgtg gagaccttgg ggtccacgtc caccatctgc tctgataaaa ctggaactct 1440gactcagaac cggatgacag tggcccacat gtggtttgac aatcaaatcc atgaagctga 1500tacgacagag aatcagagtg gtgtctcttt tgacaagact tcagctacct ggcttgctct 1560gtccagaatt gcaggtcttt gtaacagggc agtgtttcag gctaaccagg aaaacctacc 1620tattcttaag cgggcagttg caggagatgc ctctgagtca gcactcttaa agtgcataga 1680gctgtgctgt ggttccgtga aggagatgag agaaagatac gccaaaatcg tcgagatacc 1740cttcaactcc accaacaagt accagttgtc tattcataag aaccccaaca catcggagcc 1800ccaacacctg ttggtgatga agggcgcccc agaaaggatc ctagaccgtt gcagctctat 1860cctcctccac ggcaaggagc agcccctgga tgaggagctg aaagacgcct ttcagaacgc 1920ctatttggag ctggggggcc tcggagaacg agtcctaggt ttctgccacc tctttctgcc 1980agatgaacag tttcctgaag ggttccagtt tgacactgac gatgtgaatt tccctatcga 2040taatctgtgc tttgttgggc tcatctccat gattgaccct ccacgggcgg ccgttcctga 2100tgccgtgggc aaatgtcgaa gtgctggaat taaggtcatc atggtcacag gagaccatcc 2160aatcacagct aaagctattg ccaaaggtgt gggcatcatc tcagaaggca atgagaccgt 2220ggaagacatt gctgcccgcc tcaacatccc agtcagccag gtgaacccca gggatgccaa 2280ggcctgcgta gtacacggca gtgatctaaa ggacatgacc tccgagcagc tggatgacat 2340tttgaagtac cacactgaga tagtgtttgc caggacctcc cctcagcaga agctcatcat 2400tgtggaaggc tgccaaagac agggtgctat cgtggctgtg actggtgacg gtgtgaatga 2460ctctccagct ttgaagaaag cagacattgg ggttgctatg gggattgctg gctcagatgt 2520gtccaagcaa gctgctgaca tgattcttct ggatgacaac tttgcctcaa ttgtgactgg 2580agtagaggaa ggtcgtctga tctttgataa cttgaagaaa tccattgctt ataccttaac 2640cagtaacatt cccgagatca ccccgttcct gatatttatt attgcaaaca ttccactacc 2700actggggact gtcaccatcc tctgcattga cttgggcact gacatggttc ctgccatctc 2760cctggcttat gagcaggctg agagtgacat catgaagaga cagcccagaa atcccaaaac 2820agacaaactt gtgaatgagc ggctgatcag catggcctat gggcagattg gaatgatcca 2880ggccctggga ggcttcttta cttactttgt gattctggct gagaacggct tcctcccaat 2940tcacctgttg ggcctccgag tggactggga tgaccgctgg atcaacgatg tggaagacag 3000ctacgggcag cagtggacct atgagcagag gaaaatcgtg gagttcacct gccacacagc 3060cttcttcgtc agtatcgtgg tggtgcagtg ggccgacttg gtcatctgta agaccaggag 3120gaattcggtc ttccagcagg ggatgaagaa caagatcttg atatttggcc tctttgaaga 3180gacagccctg gctgctttcc tttcctactg ccctggaatg ggtgttgctc ttaggatgta 3240tcccctcaaa cctacctggt ggttctgtgc cttcccctac tctcttctca tcttcgtata 3300tgacgaagtc agaaaactca tcatcaggcg acgccctggc ggctgggtgg agaaggaaac 3360ctactattag ccccccgtcc tgcacgccgt ggagcatcag gccacacact ctgcatccga 3420cacccacccc ctctttgtgt acttcagtct tggagtttgg aactctaccc tggtaggaaa 3480gcaccgcagc atgtggggaa gcaagacgtc ctggaatgaa gcatgtagct ctatgggggg 3540aggggggagg gctgcctgaa aaccatccat ctgtggaaat gacagcgggg aaggttttta 3600tgtgcctttt tgtttttgta aaaaaggaac acccggaaag actgaaagaa tacattttat 3660atctggattt ttacaaataa agatggctat tataatggaa aaaaaaaaaa aaa 37131252911DNAHomo sapiens 125attttaggaa gtgaggagga ggcgcgggct ggagctgcgg cggggtctgg ggcgcagagc 60agcggcggga ggaggcggac acgtggcaac agcggtagca gcccgggcgg cggcagcaac 120agcggcggcg gcatcggccc gagccgccgg ccgccctccc accctcccgc cccgcggcag 180ccctagctcc ctccacttgg ctcccctggt cccgctcgct cggccgggag ctgctctgtg 240cttttctctc tgattctcca gcgacaggac ccggcgccgg gcactgagca ccgccaccat 300ggggaagggg gttggacgtg ataagtatga gcctgcagct gtttcagaac aaggtgataa 360aaagggcaaa aagggcaaaa aagacaggga catggatgaa ctgaagaaag aagtttctat 420ggatgatcat aaacttagcc ttgatgaact tcatcgtaaa tatggaacag acttgagccg 480gggattaaca tctgctcgtg cagctgagat cctggcgcga gatggtccca acgccctcac 540tccccctccc actactcctg aatggatcaa gttttgtcgg cagctctttg gggggttctc 600aatgttactg tggattggag cgattctttg tttcttggct tatagcatcc aagctgctac 660agaagaggaa cctcaaaacg ataatctgta cctgggtgtg gtgctatcag ccgttgtaat 720cataactggt tgcttctcct actatcaaga agctaaaagt tcaaagatca tggaatcctt 780caaaaacatg gtccctcagc aagcccttgt gattcgaaat ggtgagaaaa tgagcataaa 840tgcggaggaa gttgtggttg gggatctggt ggaagtaaaa ggaggagacc gaattcctgc 900tgacctcaga atcatatctg caaatggctg caaggtggat aactcctcgc tcactggtga 960atcagaaccc cagactaggt ctccagattt cacaaatgaa aaccccctgg agacgaggaa 1020cattgccttc ttttcaacca attgtgttga aggcaccgca cgtggtattg ttgtctacac 1080tggggatcgc actgtgatgg gaagaattgc cacacttgct tctgggctgg aaggaggcca 1140gacccccatt gctgcagaaa ttgaacattt tatccacatc atcacgggtg tggctgtgtt 1200cctgggtgtg tctttcttca tcctttctct catccttgag tacacctggc ttgaggctgt 1260catcttcctc atcggtatca tcgtagccaa tgtgccggaa ggtttgctgg ccactgtcac 1320ggtctgtctg acacttactg ccaaacgcat ggcaaggaaa aactgcttag tgaagaactt 1380agaagctgtg gagaccttgg ggtccacgtc caccatctgc tctgataaaa ctggaactct 1440gactcagaac cggatgacag tggcccacat gtggtttgac aatcaaatcc atgaagctga 1500tacgacagag aatcagagtg gtgtctcttt tgacaagact tcagctacct ggcttgctct 1560gtccagaatt gcaggtcttt gtaacagggc agtgtttcag gctaaccagg aaaacctacc 1620tattcttaag cgggcagttg caggagatgc ctctgagtca gcactcttaa agtgcataga 1680gctgtgctgt ggttccgtga aggagatgag agaaagatac gccaaaatcg tcgagatacc 1740cttcaactcc accaacaagt accagttgtc tattcataag aaccccaaca catcggagcc 1800ccaacacctg ttggtgatga agggcgcccc agaaaggatc ctagaccgtt gcagctctat 1860cctcctccac ggcaaggagc agcccctgga tgaggagctg aaagacgcct ttcagaacgc 1920ctatttggag ctggggggcc tcggagaacg agtcctaggt ttctgccacc tctttctgcc 1980agatgaacag tttcctgaag ggttccagtt tgacactgac gatgtgaatt tccctatcga 2040taatctgtgc tttgttgggc tcatctccat gattgaccct ccacgggcgg ccgttcctga 2100tgccgtgggc aaatgtcgaa gtgctggaat taaggtcatc atggtcacag gagaccatcc 2160aatcacagct aaagctattg ccaaaggtgt gggcatcatc tcagaaggca atggacctat 2220gagcagagga aaatcgtgga gttcacctgc cacacagcct tcttcgtcag tatcgtggtg 2280gtgcagtggg ccgacttggt catctgtaag accaggagga attcggtctt ccagcagggg 2340atgaagaaca agatcttgat atttggcctc tttgaagaga cagccctggc tgctttcctt 2400tcctactgcc ctggaatggg tgttgctctt aggatgtatc ccctcaaacc tacctggtgg 2460ttctgtgcct tcccctactc tcttctcatc ttcgtatatg acgaagtcag aaaactcatc 2520atcaggcgac gccctggcgg ctgggtggag aaggaaacct actattagcc ccccgtcctg 2580cacgccgtgg agcatcaggc cacacactct gcatccgaca cccaccccct ctttgtgtac 2640ttcagtcttg gagtttggaa ctctaccctg gtaggaaagc accgcagcat gtggggaagc 2700aagacgtcct ggaatgaagc atgtagctct atggggggag gggggagggc tgcctgaaaa 2760ccatccatct gtggaaatga cagcggggaa ggtttttatg tgcctttttg tttttgtaaa 2820aaaggaacac ccggaaagac tgaaagaata cattttatat ctggattttt acaaataaag 2880atggctatta taatggaaaa aaaaaaaaaa a 29111263587DNAHomo sapiens 126agcctctgtg cggtgggacc aacggacgga cggacggacg cgcgcaccta ccgaggcgcg 60ggcgctgcag aggctcccag cccaagcctg agcctgagcc cgccccgagg tccccgcccc 120gcccgcctgg ctctctcgcc gcggagccgc caagatgggg gacaagaaag atgacaagga 180ctcacccaag aagaacaagg gcaaggagcg ccgggacctg gatgacctca agaaggaggt 240ggctatgaca gagcacaaga tgtcagtgga agaggtctgc cggaaataca acacagactg 300tgtgcagggt ttgacccaca gcaaagccca ggagatcctg gcccgggatg ggcctaacgc 360actcacgcca ccgcctacca ccccagagtg ggtcaagttt tgccggcagc tcttcggggg 420cttctccatc ctgctgtgga tcggggctat cctctgcttc ctggcctacg gtatccaggc 480gggcaccgag gacgacccct ctggtgacaa cctgtacctg ggcatcgtgc tggcggccgt 540ggtgatcatc actggctgct tctcctacta ccaggaggcc aagagctcca agatcatgga 600gtccttcaag aacatggtgc cccagcaagc cctggtgatc cgggaaggtg agaagatgca 660ggtgaacgct gaggaggtgg tggtcgggga cctggtggag atcaagggtg gagaccgagt 720gccagctgac ctgcggatca tctcagccca cggctgcaag gtggacaact cctccctgac 780tggcgaatcc gagccccaga ctcgctctcc cgactgcact cacgacaacc ccttggagac 840tcggaacatc accttctttt ccaccaactg tgtggaaggc acggctcggg gcgtggtggt 900ggccacgggc gaccgcactg tcatgggccg tatcgccacc ctggcatcag ggctggaggt 960gggcaagacg cccatcgcca tcgagattga gcacttcatc cagctcatca ccggcgtggc 1020tgtcttcctg ggtgtctcct tcttcatcct ctccctcatt ctcggataca cctggcttga 1080ggctgtcatc ttcctcatcg gcatcatcgt ggccaatgtc ccagagggtc tgctggccac 1140tgtcactgtg tgtctgacgc tgaccgccaa gcgcatggcc cggaagaact gcctggtgaa 1200gaacctggag gctgtagaaa ccctgggctc cacgtccacc atctgctcag ataagacagg 1260gaccctcact cagaaccgca tgacagtcgc ccacatgtgg tttgacaacc agatccacga 1320ggctgacacc actgaggacc agtcagggac ctcatttgac aagagttcgc acacctgggt 1380ggccctgtct cacatcgctg ggctctgcaa tcgcgctgtc ttcaagggtg gtcaggacaa 1440catccctgtg ctcaagaggg atgtggctgg ggatgcgtct gagtctgccc tgctcaagtg 1500catcgagctg tcctctggct ccgtgaagct gatgcgtgaa cgcaacaaga aagtggctga 1560gattcccttc aattccacca acaaatacca gctctccatc catgagaccg aggaccccaa 1620cgacaaccga tacctgctgg tgatgaaggg tgcccccgag cgcatcctgg accgctgctc 1680caccatcctg ctacagggca aggagcagcc tctggacgag gaaatgaagg aggccttcca 1740gaatgcctac cttgagctcg gtggcctggg cgagcgcgtg cttggtttct gccattatta 1800cctgcccgag gagcagttcc ccaagggctt tgccttcgac tgtgatgacg tgaacttcac 1860cacggacaac ctctgctttg tgggcctcat gtccatgatc gacccacccc gggcagccgt 1920ccctgacgcg gtgggcaagt gtcgcagcgc aggcatcaag gtcatcatgg tcaccggcga 1980tcaccccatc acggccaagg ccattgccaa gggtgtgggc atcatctctg agggcaacga 2040gactgtggag gacatcgccg cccggctcaa cattcccgtc agccaggtta acccccggga 2100tgccaaggcc tgcgtgatcc acggcaccga cctcaaggac ttcacctccg agcaaatcga 2160cgagatcctg cagaatcaca ccgagatcgt cttcgcccgc acatcccccc agcagaagct 2220catcattgtg gagggctgtc agagacaggg tgcaattgtg gctgtgaccg gggatggtgt 2280gaacgactcc cccgctctga

agaaggccga cattggggtg gccatgggca tcgctggctc 2340tgacgtctcc aagcaggcag ctgacatgat cctgctggac gacaactttg cctccatcgt 2400cacaggggtg gaggagggcc gcctgatctt cgacaaccta aagaagtcca ttgcctacac 2460cctgaccagc aatatcccgg agatcacgcc cttcctgctg ttcatcatgg ccaacatccc 2520gctgcccctg ggcaccatca ccatcctctg catcgatctg ggcactgaca tggtccctgc 2580catctcactg gcgtacgagg ctgccgaaag cgacatcatg aagagacagc ccaggaaccc 2640gcggacggac aaattggtca atgagagact catcagcatg gcctacgggc agattggaat 2700gatccaggct ctcggtggct tcttctctta ctttgtgatc ctggcagaaa atggcttctt 2760gcccggcaac ctggtgggca tccggctgaa ctgggatgac cgcaccgtca atgacctgga 2820agacagttac gggcagcagt ggacatacga gcagaggaag gtggtggagt tcacctgcca 2880cacggccttc tttgtgagca tcgttgtcgt ccagtgggcc gatctgatca tctgcaagac 2940ccggaggaac tcggtcttcc agcagggcat gaagaacaag atcctgatct tcgggctgtt 3000tgaggagacg gccctggctg ccttcctgtc ctactgcccc ggcatggacg tggccctgcg 3060catgtaccct ctcaagccca gctggtggtt ctgtgccttc ccctacagtt tcctcatctt 3120cgtctacgac gaaatccgca aactcatcct gcgcaggaac ccagggggtt gggtggagaa 3180ggaaacctac tactgacctc agccccacca catcgcccat ctcttccccg tcccccaggc 3240ccaggaccgc ccctgtcagt ccccccaatt ttgtattctg gggggaggag ccctctcttc 3300ctgtggcccc accttggccc ccaccccctc cactatctcc tgccgccccc actctggctg 3360gcttctctcc cctgccccaa acctctctcc tctctctttt ctgtgtcagt ttctctccct 3420ctcctcaccc ctctatccat tcctcccgcc ccagccacct ccctgggctc ttttttactc 3480cccttcagcc ccccggctga tgccatctct ggttctggac aattatcaaa tatatcagtg 3540gggagagaga aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 35871273873DNAHomo sapiens 127aaccacaggg cctgggactg gggggttccc agatccttga agctcactcc gcctcctcac 60tctcactgca tttcccacct tcctgtgggc cttgcggcat cttcatcact gaggcacctg 120gttacgcttc acctcttgtt tcctgccctc actgcattcc ctcacctcta cctttttatc 180cttccaccct aggcttctct cctccctctt ccctcactcc tgactcttcc tcttcccagc 240ggacggctgg aggaccgctc agtctctcct ctctcacttc ccttcctctc tctcaccttc 300accacccaac acctccctcc ctgcctcttt ctttctgctc cctcattctc tccccaccac 360tctcttctcg tggccccctt gcccgcgcgc cctcttccct tccccttgcc tcactctctc 420agctttcttc ccacagttga gctcgggcag ctctttctgg ggatagctat ggggctttgg 480gggaagaaag ggacagtggc tccccatgac cagagtccaa gacgaagacc taaaaaaggg 540cttatcaaga aaaaaatggt gaagagggaa aaacagaagc gcaatatgga ggaactgaag 600aaggaagtgg tcatggatga tcacaaatta accttggaag agctgagcac caagtactcc 660gtggacctga caaagggcca tagccaccaa agggcaaagg aaatcctgac tcgagatgga 720cccaatactg ttaccccacc ccccaccact ccagaatggg tcaaattctg taagcaactg 780ttcggaggct tctccctcct actatggact ggggccattc tctgctttgt ggcctacagc 840atccagatat atttcaatga ggagcctacc aaagacaacc tctacctgag catcgtactg 900tccgtcgtgg tcatcgtcac tggctgcttc tcctattatc aggaggccaa gagctccaag 960atcatggagt cttttaagaa catggtgcct cagcaagctc tggtaattcg aggaggagag 1020aagatgcaaa ttaatgtaca agaggtggtg ttgggagacc tggtggaaat caagggtgga 1080gaccgagtcc ctgctgacct ccggcttatc tctgcacaag gatgtaaggt ggacaactca 1140tccttgactg gggagtcaga accccagagc cgctcccctg acttcaccca tgagaaccct 1200ctggagaccc gaaacatctg cttcttttcc accaactgtg tggaaggaac cgcccggggt 1260attgtgattg ctacgggaga ctccacagtg atgggcagaa ttgcctccct gacgtcaggc 1320ctggcggttg gccagacacc tatcgctgct gagatcgaac acttcatcca tctgatcact 1380gtggtggccg tcttccttgg tgtcactttt tttgcgctct cacttctctt gggctatggt 1440tggctggagg ctatcatttt tctcattggc atcattgtgg ccaatgtgcc tgaggggctg 1500ttggccacag tcactgtgtg cctgaccctc acagccaagc gcatggcgcg gaagaactgc 1560ctggtgaaga acctggaggc ggtggagacg ctgggctcca cgtccaccat ctgctcagac 1620aagacgggca ccctcaccca gaaccgcatg accgtcgccc acatgtggtt tgatatgacc 1680gtgtatgagg ccgacaccac tgaagaacag actggaaaaa catttaccaa gagctctgat 1740acctggttta tgctggcccg aatcgctggc ctctgcaacc gggctgactt taaggctaat 1800caggagatcc tgcccattgc taagagggcc acaacaggtg atgcttccga gtcagccctc 1860ctcaagttca tcgagcagtc ttacagctct gtggcggaga tgagagagaa aaaccccaag 1920gtggcagaga ttccctttaa ttctaccaac aagtaccaga tgtccatcca ccttcgggag 1980gacagctccc agacccacgt actgatgatg aagggtgctc cggagaggat cttggagttt 2040tgttctacct ttcttctgaa tgggcaggag tactcaatga acgatgaaat gaaggaagcc 2100ttccaaaatg cctatttaga actgggaggt ctgggggaac gtgtgctagg cttctgcttc 2160ttgaatctgc ctagcagctt ctccaaggga ttcccattta atacagatga aataaatttc 2220cccatggaca acctttgttt tgtgggcctc atatccatga ttgaccctcc ccgagctgca 2280gtgcctgatg ctgtgagcaa gtgtcgcagt gcaggaatta aggtgatcat ggtaacagga 2340gatcatccca ttacagctaa ggccattgcc aagggtgtgg gcatcatctc agaaggcact 2400gagacggcag aggaagtcgc tgcccggctt aagatcccta tcagcaaggt cgatgccagt 2460gctgccaaag ccattgtggt gcatggtgca gaactgaagg acatacagtc caagcagctt 2520gatcagatcc tccagaacca ccctgagatc gtgtttgctc ggacctcccc tcagcagaag 2580ctcatcattg tcgagggatg tcagaggctg ggagccgttg tggccgtgac aggtgacggg 2640gtgaacgact cccctgcgct gaagaaggct gacattggca ttgccatggg catctctggc 2700tctgacgtct ctaagcaggc agccgacatg atcctgctgg atgacaactt tgcctccatc 2760gtcacggggg tggaggaggg ccgcctgatc tttgacaacc tgaagaaatc catcatgtac 2820accctgacca gcaacatccc cgagatcacg cccttcctga tgttcatcat cctcggtata 2880cccctgcctc tgggaaccat aaccatcctc tgcattgatc tcggcactga catggtccct 2940gccatctcct tggcttatga gtcagctgaa agcgacatca tgaagaggct tccaaggaac 3000ccaaagacgg ataatctggt gaaccaccgt ctcattggca tggcctatgg acagattggg 3060atgatccagg ctctggctgg attctttacc tactttgtaa tcctggctga gaatggtttt 3120aggcctgttg atctgctggg catccgcctc cactgggaag ataaatactt gaatgacctg 3180gaggacagct acggacagca gtggacctat gagcaacgaa aagttgtgga gttcacatgc 3240caaacggcct tttttgtcac catcgtggtt gtgcagtggg cggatctcat catctccaag 3300actcgccgca actcactttt ccagcagggc atgagaaaca aagtcttaat atttgggatc 3360ctggaggaga cactcttggc tgcatttctg tcctacactc caggcatgga cgtggccctg 3420cgaatgtacc cactcaagat aacctggtgg ctctgtgcca ttccctacag tattctcatc 3480ttcgtctatg atgaaatcag aaaactcctc atccgtcagc acccggatgg ctgggtggaa 3540agggagacgt actactaaac tcagcagatg aagagcttca tgtgacacag gggtgttgtg 3600agagctggga tggggccaga gattataagt ttgacacaac atctgagaca ctaggatgaa 3660ttatcttgga tgagaaagat gggcaatcct gggctggctt gagggaatca tgggcagagg 3720atgaggtggg ctgaagggaa gcccagcctg catctagctg gagccccgca gggaggggca 3780tggtcctgct gaatcccgta gccagtctag acagtaaatg tctggaaaag ccaaaaaaaa 3840aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 3873128951DNAHomo sapiens 128caccagccca gccagaagca agtcccagcc cccagccctc ccctggccta ccttttgggg 60cccttctctg aaccaggctc ccctgtcctg caactctgtc attcacaggg atgatccagg 120ctctggctgg attctttacc tactttgtaa tcctggctga gaatggtttt aggcctgttg 180atctgctggg catccgcctc cactgggaag ataaatactt gaatgacctg gaggacagct 240acggacagca gtggacctat gagcaacgaa aagttgtgga gttcacatgc caaacggcct 300tttttgtcac catcgtggtt gtgcagtggg cggatctcat catctccaag actcgccgca 360actcactttt ccagcagggc atgagaaaca aagtcttaat atttgggatc ctggaggaga 420cactcttggc tgcatttctg tcctacactc caggcatgga cgtggccctg cgaatgtacc 480cactcaagat aacctggtgg ctctgtgcca ttccctacag tattctcatc ttcgtctatg 540atgaaatcag aaaactcctc atccgtcagc acccggatgg ctgggtggaa agggagacgt 600actactaaac tcagcagatg aagagcttca tgtgacacag gggtgttgtg agagctggga 660tggggccaga gattataagt ttgacacaac atctgagaca ctaggatgaa ttatcttgga 720tgagaaagat gggcaatcct gggctggctt gagggaatca tgggcagagg atgaggtggg 780ctgaagggaa gcccagcctg catctagctg gagccccgca gggaggggca tggtcctgct 840gaatcccgta gccagtctag acagtaaatg tctggaaaag ccctcaaaaa aaaaaaaaaa 900aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 9511292212DNAHomo sapiens 129cagcggcgcg tcctgcctgc agagagccag gccggagaag ccgagcggcg cagaggacgc 60cagggcgcgc gccgcagcca cccaccctcc ggaccgcggc agctgctgac ccgccatcgc 120catggcccgc gggaaagcca aggaggaggg cagctggaag aaattcatct ggaactcaga 180gaagaaggag tttctgggca ggaccggtgg cagttggttt aagatccttc tattctacgt 240aatattttat ggctgcctgg ctggcatctt catcggaacc atccaagtga tgctgctcac 300catcagtgaa tttaagccca catatcagga ccgagtggcc ccgccaggat taacacagat 360tcctcagatc cagaagactg aaatttcctt tcgtcctaat gatcccaaga gctatgaggc 420atatgtactg aacatagtta ggttcctgga aaagtacaaa gattcagccc agagggatga 480catgattttt gaagattgtg gcgatgtgcc cagtgaaccg aaagaacgag gagactttaa 540tcatgaacga ggagagcgaa aggtctgcag attcaagctt gaatggctgg gaaattgctc 600tggattaaat gatgaaactt atggctacaa agagggcaaa ccgtgcatta ttataaagct 660caaccgagtt ctaggcttca aacctaagcc tcccaagaat gagtccttgg agacttaccc 720agtgatgaag tataacccaa atgtccttcc cgttcagtgc actggcaagc gagatgaaga 780taaggataaa gttggaaatg tggagtattt tggactgggc aactcccctg gttttcctct 840gcagtattat ccgtactatg gcaaactcct gcagcccaaa tacctgcagc ccctgctggc 900cgtacagttc accaatctta ccatggacac tgaaattcgc atagagtgta aggcgtacgg 960tgagaacatt gggtacagtg agaaagaccg ttttcaggga cgttttgatg taaaaattga 1020agttaagagc tgatcacaag cacaaatctt tcccactagc catttaataa gttaaaaaaa 1080gatacaaaaa caaaaaccta ctagtcttga acaaactgtc atacgtatgg gacctacact 1140taatctatat gctttacact agctttctgc atttaatagg ttagaatgta aattaaagtg 1200tagcaatagc aacaaaatat ttattctact gtaaatgaca aaagaaaaag aaaaattgag 1260ccttgggacg tgcccatttt tactgtaaat tatgattccg taactgactt gtagtaagca 1320gtgtttctgg cccctaagta ttgctgcctt gtgtatttta tttagtgtac agtactacag 1380gtgcatactc tggtcatttt tcaagccatg ttttattgta tctgttttct actttatgtg 1440agcaaggttt gctgtccaag gtgtaaatat tcaacgggaa taaaactggc atggtaattt 1500tttttttttt tttttttttg ttttttggct ctttcaaagg taatggccca tcgatgagca 1560tttttaacat actccatagt cttttcctgt ggtgttaggt ctttattttt atttttttcc 1620tgggggctgg ggtgggggtt tgtcatgggg gaactgccct ttaaatttta agtgacacta 1680cagaaaaaca caaaaaggtg atgggttgtg ttatgcttgt attgaatgct gtcttgacat 1740ctcttgcctt gtcctccggt atgttctaaa gctgtgtctg agatctggat ctgcccatca 1800ctttggctag tgacagggct aattaatttg ctttatacat tttcttttac tttccttttt 1860tcctttctgg aggcatcaca tgctggtgct gtgtctttat gaatgtttta accattttca 1920tggtggaaga attttatatt tatgcagttg tacaatttta tttttttctg caagaaaaag 1980tgtaatgtat gaaataaacc aaagtcactt gtttgaaaat aaatctttat tttgaacttt 2040ataaaaagca atgcagtacc ccatagactg gtgttaaatg ttgtctacag tgcaaaatcc 2100atgttctaac atatgtaata attgccagga gtacagtgct cttgttgatc ttgtattcag 2160tcaggttaaa acaacggaca ataaaagaat gaacacattc aaaaaaaaaa aa 22121301568DNAHomo sapiens 130cagcggcgcg tcctgcctgc agagagccag gccggagaag ccgagcggcg cagaggacgc 60cagggcgcgc gccgcagcca cccaccctcc ggaccgcggc agctgctgac ccgccatcgc 120catggcccgc gggaaagcca aggaggaggg cagctggaag aaattcatct ggaactcaga 180gaagaaggag tttctgggca ggaccggtgg cagttggttt aagatccttc tattctacgt 240aatattttat ggctgcctgg ctggcatctt catcggaacc atccaagtga tgctgctcac 300catcagtgaa tttaagccca catatcagga ccgagtggcc ccgccaggat taacacagat 360tcctcagatc cagaagactg aaatttcctt tcgtcctaat gatcccaaga gctatgaggc 420atatgtactg aacatagtta ggttcctgga aaagtacaaa gattcagccc agagggatga 480catgattttt gaagattgtg gcgatgtgcc cagtgaaccg aaagaacgag gagactttaa 540tcatgaacga ggagagcgaa aggtctgcag attcaagctt gaatggctgg gaaattgctc 600tggattaaat gatgaaactt atggctacaa agagggcaaa ccgtgcatta ttataaagct 660caaccgagtt ctaggcttca aacctaagcc tcccaagaat gagtccttgg agacttaccc 720agtgatgaag tataacccaa atgtccttcc cgttcagtgc actggcaagc gagatgaaga 780taaggataaa gttggaaatg tggagtattt tggactgggc aactcccctg gttttcctct 840gcagtattat ccgtactatg gcaaactcct gcagcccaaa tacctgcagc ccctgctggc 900cgtacagttc accaatctta ccatggacac tgaaattcgc atagagtgta aggcgtacgg 960tgagaacatt gggtacagtg agaaagaccg ttttcaggga cgttttgatg taaaaattaa 1020attttaagtg acactacaga aaaacacaaa aaggtgatgg gttgtgttat gcttgtattg 1080aatgctgtct tgacatctct tgccttgtcc tccggtatgt tctaaagctg tgtctgagat 1140ctggatctgc ccatcacttt ggctagtgac agggctaatt aatttgcttt atacattttc 1200ttttactttc cttttttcct ttctggaggc atcacatgct ggtgctgtgt ctttatgaat 1260gttttaacca ttttcatggt ggaagaattt tatatttatg cagttgtaca attttatttt 1320tttctgcaag aaaaagtgta atgtatgaaa taaaccaaag tcacttgttt gaaaataaat 1380ctttattttg aactttataa aaagcaatgc agtaccccat agactggtgt taaatgttgt 1440ctacagtgca aaatccatgt tctaacatat gtaataattg ccaggagtac agtgctcttg 1500ttgatcttgt attcagtcag gttaaaacaa cggacaataa aagaatgaac acattcaaaa 1560aaaaaaaa 15681313350DNAHomo sapiens 131ggagcggagc ctccgcctgg ggggcccccc atccctggct gtcccccagc tgcgcgtccc 60cgccccaccc ccgcggctga gccaccaccg gtgcagtggt ctccgcttgg cggagcgagc 120cttgagcttc gttccacagc ttctttgcat cttggatttc ggggcggccc cctcccccac 180ctctctctgc ctttttgtac cccgcttttt ttctgcgttc tgctcggttt ttgtagccgt 240ctgtttttgc accccatttc gttttgtttc tagacggttt ggtggggggt gaagctgcat 300tcatacccct tcctcttgtt attctcccct gctctgacag cacccctttt catcgcagtt 360ggggggccta ggatcggtgc atcttccgcc gcgctgccag caccccgcag cgcgtggtcg 420tgcaccccgg aatctgcagc agctgcatat ctgagggggg tctcctttgc ccgcgccgcc 480ttcgctcccc gtgcttttgg gtgtgtggag ggcttcagcg cgcggcgccc ccgcttctcc 540gcaacccccc gccccgcgcc cggactcgcc ccgcgccacc aagatggtca tccagaaaga 600gaagaagagc tgcgggcagg tggttgagga gtggaaggag ttcgtgtgga acccgaggac 660gcaccagttt atgggccgca ccgggaccag ctgggccttt atcctcctct tctacctcgt 720tttttatggg ttcctcaccg ccatgttcac cctcaccatg tgggtgatgc tgcagactgt 780ctccgaccat acccccaagt accaggaccg actggccaca ccgggcttga tgattcgccc 840caagactgag aaccttgatg tcattgtcaa tgtcagtgac actgaaagct gggaccagca 900tgttcagaag ctcaacaagt tcttggagcc ttacaacgac tctatccaag cccaaaagaa 960tgatgtctgc cgccctgggc gctattacga acagccagat aatggagtcc tcaactaccc 1020caaacgtgcc tgccaattca accggaccca gctgggcaac tgctccggca ttggggactc 1080cacccactat ggttacagca ctgggcagcc ctgtgtcttc atcaagatga accgggtcat 1140caacttctat gcaggagcaa accagagcat gaatgttacc tgtgctggga agcgagatga 1200agatgctgag aatctcggca acttcgtcat gttccccgcc aacggcaaca tcgacctcat 1260gtacttcccc tactatggca aaaagttcca cgtgaactac acacagcccc tggtggctgt 1320gaagttcctg aatgtgaccc ccaacgtgga ggtgaatgta gaatgtcgca tcaacgccgc 1380caacatcgcc acagacgatg agcgagacaa gttcgccggc cgcgtggcct tcaaactccg 1440catcaacaaa acctgaggcc ccttcctccc accccatctc tctcctgtgg atgctcctgg 1500aatgtccctg accctgcctg atccctccct cacccacccc aaaggtattt ttgataacag 1560agctatgact tgtctgagcc tcacatcctt ttccttgact tctcaaccca gcctgaagtc 1620cattgcggtt ccgtcactcg cctttcccac caacttctcc caacctcaga tcagtcagac 1680agggagctgg gctaagatgg ccacggagga gttaggagcc tttctagttc tggtttagct 1740gtgagagcta tccactctcc tgcctgcata tcccctgaga gttataggaa gtgcccactg 1800acccacccac ccacctacac cccccgccac acacacacac aaacgtgcac acgcgtctca 1860tttgacccct ttgcttccag agatgaatgt ggcactccct ccttccattc ctaagctcta 1920gccaccgtcc cttgatctct catactttct ccctgtctac acagtcgcca tcttggtgac 1980tttgaattta tctggctcct gggcaggtct tctcctcctc tccatcccta ttccctcctc 2040tgaaatgcac ccctttgtaa ttgaggacaa ggtggttctg tggccttttc cctctttgct 2100ggcacgttct gcttctcacc ctctggtgac tctgtgagct gggaaatgag ggactggaag 2160tgaggcctgt gttgaccctt cctgaaaatc ctctagcagc ccccgacttc agcagtttct 2220ttctttgttt ttttgagatg gagtttcgct cttgttgccc aggctggagt gcaatggtgc 2280aatctcagct cactgcaact tccgcatccc aggttcaagc gattctcccg cctcaggttc 2340ccgagtagct gggactacag gcatgtgcca ccatgcccgg ctaatttctt tctttctttt 2400tttttttttt tgcatttttt agtagagatg ggggtttctc cttgttggtc aggctggtct 2460cgaactcccg acctcaggtg atccacctgc ctcggcctcc caaagtgttg ggattacagg 2520cgtgagccac cgcgcccggc cttcagtttc ttcctaggcc gttctgtcac ccaaatagct 2580gctacccaga ggggcggggt tgacctaggc tgaatatcca ctttgttttt atggatggct 2640cccttccccc attcgccttc ccagaatatc cttcaagttc cacttcccag ggagctctgg 2700gggaggggcg gccattctgg ctccgtcccc agtggccacc ttggaaacat cggctggctt 2760tgggactatt ccacctcctt cccctgagcc cagatctgcc cccaccatcc tttctctggc 2820ttcttttagc aagttatcaa ctaatcacta actccttcct tttcctctgc atgccagcct 2880gaaaattcca aatctagcct ctgaatgtct tggctccatc tcttcagacc cctttgcctt 2940taaaaaaaaa acaaaaacaa aaacaaaaaa acccataatg cccacagaat gtcaaatgag 3000gggcctcctg cctcctgctc tgaatattct gtagctgtag aggcatttta accctttgtc 3060ctccagcatc ccttcacttc ctcatcctct ctaacctcct ttttcttttt ttaatgctgc 3120agcctccaca ctccacccac aggtggaccc ttcccttttt ctctagctgg atctgtgttt 3180cttcccttcg ggcccccatg ttttcctgca cccgccctac catggtctct ctctgcagtt 3240atttaatgcc tgtgtcagat ctactgtaaa aagaggatta agtaaaataa aatgagagca 3300attatatata taaatatata tcatacacag agaaaaaaaa aaaaaaaaaa 33501321853DNAHomo sapiens 132ggcgcggcgc ggcgcagtcg gctcgagtac tccccgtaac gaggaggtgt tctcggccgt 60cccacccttc actgccgtct ccgggctgcg ccgccggagc cgggacgcgc ctccgcagcc 120ctcgccgcct ccatccccgc ggccgcagct cctctcgccg tccgcgcgca caccatgacg 180aagaacgaga agaagtccct caaccagagc ctggccgagt ggaagctctt catctacaac 240ccgaccaccg gagaattcct ggggcgcacc gccaagagct ggggtttgat cttgctcttc 300tacctagttt tttatgggtt cctggctgca ctcttctcat tcacgatgtg ggttatgctt 360cagactctca acgatgaggt tccaaaatac cgtgaccaga ttcctagccc aggactcatg 420gtttttccaa aaccagtgac cgcattggaa tatacattca gtaggtctga tccaacttcg 480tatgcagggt acattgaaga ccttaagaag tttctaaaac catatacttt agaagaacag 540aagaacctca cagtctgtcc tgatggagca ctttttgaac agaagggtcc agtttatgtt 600gcatgtcagt ttcctatttc attacttcaa gcatgcagtg gtatgaatga tcctgatttt 660ggctattctc aaggaaaccc ttgtattctt gtgaaaatga acagaataat tggattaaag 720cctgaaggag tgccaaggat agattgtgtt tcaaagaatg aagatatacc aaatgtagca 780gtttatcctc ataatggaat gatagactta aaatatttcc catattatgg gaaaaaactg 840catgttgggt atctacagcc attggttgct gttcaggtca gctttgctcc taacaacact 900gggaaagaag taacagttga gtgcaagatt gatggatcag ccaacctaaa aagtcaggat 960gatcgtgaca agtttttggg acgagttatg ttcaaaatca cagcacgtgc atagtatgag 1020taggatatct ccacagagta aatgttgtgt tgtctgtctt cattttgtaa cagctggacc 1080ttccattcta gaattatgag accaccttgg agaaaggtgt gtggtacatg acattgggtt 1140acatcataac gtgcttccag atcatagtgt tcagtgtcct ctgaagtaac tgcctgttgc 1200ctctgctgcc ctttgaacca gtgtacagtc gccagatagg gaccggtgaa cacctgattc 1260caaacatgta ggatgggggt cttgtcctct ttttatgtgg tttaattgcc aagtgtctaa 1320agcttaatat gccgtgctat gtaaatattt tatggatata acaactgtca tattttgatg 1380tcaacagagt tttagggata aaatggtacc cggccaacat caagtgactt tatagctgca 1440agaaatgtgg tatgtggaga agttctgtat gtgaggaagg aaaaaaagaa aataaaagtg 1500tgtttgaaaa atattatctt gggttctttg taaaatttat tttttacatg ctgaattagc

1560ctcgatcttt ttgattaaga gcacaaactt ttttttgtaa aacatgtaaa aaaaaaaact 1620gggattaatt tttagtgttg gaactgcctc ttattttagg ctgtagataa aatagcattt 1680ttaggttagc cagtgtgact atgcacctaa ttttttatga gattaaattc ataagactta 1740atttgtacaa tagtttgtga aatatcttgt tactgctttt atttagcaga ctgtggactg 1800taataaagta tataaattgt gaaatataaa aacttggaac ttattcaaag ctt 18531336891DNAHomo sapiens 133ggtggcctct gtggccgtcc aggctagcgg cggcccgcag gcggcgggga gaaagactct 60ctcacctggt cttgcggctg tggccaccgc cggccagggg tgtggagggc gtgctgccgg 120agacgtccgc cgggctctgc agttccgccg ggggtcgggc agctatggag ccgcggccca 180cggcgccctc ctccggcgcc ccgggactgg ccggggtcgg ggagacgccg tcagccgctg 240cgctggccgc agccagggtg gaactgcccg gcacggctgt gccctcggtg ccggaggatg 300ctgcgcccgc gagccgggac ggcggcgggg tccgcgatga gggccccgcg gcggccgggg 360acgggctggg cagacccttg gggcccaccc cgagccagag ccgtttccag gtggacctgg 420tttccgagaa cgccgggcgg gccgctgctg cggcggcggc ggcggcggcg gcagcggcgg 480cggctggtgc tggggcgggg gccaagcaga cccccgcgga cggggaagcc agcggcgaga 540gcgagccggc taaaggcagc gaggaagcca agggccgctt ccgcgtgaac ttcgtggacc 600cagctgcctc ctcgtcggct gaagacagcc tgtcagatgc tgccggggtc ggagtcgacg 660ggcccaacgt gagcttccag aacggcgggg acacggtgct gagcgagggc agcagcctgc 720actccggcgg cggcggcggc agtgggcacc accagcacta ctattatgat acccacacca 780acacctacta cctgcgcacc ttcggccaca acaccatgga cgctgtgccc aggatcgatc 840actaccggca cacagccgcg cagctgggcg agaagctgct ccggcctagc ctggcggagc 900tccacgacga gctggaaaag gaaccttttg aggatggctt tgcaaatggg gaagaaagta 960ctccaaccag agatgctgtg gtcacgtata ctgcagaaag taaaggagtc gtgaagtttg 1020gctggatcaa gggtgtatta gtacgttgta tgttaaacat ttggggtgtg atgcttttca 1080ttagattgtc atggattgtg ggtcaagctg gaataggtct atcagtcctt gtaataatga 1140tggccactgt tgtgacaact atcacaggat tgtctacttc agcaatagca actaatggat 1200ttgtaagagg aggaggagca tattatttaa tatctagaag tctagggcca gaatttggtg 1260gtgcaattgg tctaatcttc gcctttgcca acgctgttgc agttgctatg tatgtggttg 1320gatttgcaga aaccgtggtg gagttgctta aggaacattc catacttatg atagatgaaa 1380tcaatgatat ccgaattatt ggagccatta cagtcgtgat tcttttaggt atctcagtag 1440ctggaatgga gtgggaagca aaagctcaga ttgttctttt ggtgatccta cttcttgcta 1500ttggtgattt cgtcatagga acatttatcc cactggagag caagaagcca aaagggtttt 1560ttggttataa atctgaaata tttaatgaga actttgggcc cgattttcga gaggaagaga 1620ctttcttttc tgtatttgcc atcttttttc ctgctgcaac tggtattctg gctggagcaa 1680atatctcagg tgatcttgca gatcctcagt cagccatacc caaaggaaca ctcctagcca 1740ttttaattac tacattggtt tacgtaggaa ttgcagtatc tgtaggttct tgtgttgttc 1800gagatgccac tggaaacgtt aatgacacta tcgtaacaga gctaacaaac tgtacttctg 1860cagcctgcaa attaaacttt gatttttcat cttgtgaaag cagtccttgt tcctatggcc 1920taatgaacaa cttccaggta atgagtatgg tgtcaggatt tacaccacta atttctgcag 1980gtatattttc agccactctt tcttcagcat tagcatccct agtgagtgct cccaaaatat 2040ttcaggctct atgtaaggac aacatctacc cagctttcca gatgtttgct aaaggttatg 2100ggaaaaataa tgaacctctt cgtggctaca tcttaacatt cttaattgca cttggattca 2160tcttaattgc tgaactgaat gttattgcac caattatctc aaacttcttc cttgcatcat 2220atgcattgat caatttttca gtattccatg catcacttgc aaaatctcca ggatggcgtc 2280ctgcattcaa atactacaac atgtggatat cacttcttgg agcaattctt tgttgcatag 2340taatgttcgt cattaactgg tgggctgcat tgctaacata tgtgatagtc cttgggctgt 2400atatttatgt tacctacaaa aaaccagatg tgaattgggg atcctctaca caagccctga 2460cttacctgaa tgcactgcag cattcaattc gtctttctgg agtggaagac cacgtgaaaa 2520actttaggcc acagtgtctt gttatgacag gtgctccaaa ctcacgtcca gctttacttc 2580atcttgttca tgatttcaca aaaaatgttg gtttgatgat ctgtggccat gtacatatgg 2640gtcctcgaag acaagccatg aaagagatgt ccatcgatca agccaaatat cagcgatggc 2700ttattaagaa caaaatgaag gcattttatg ctccagtaca tgcagatgac ttgagagaag 2760gtgcacagta tttgatgcag gctgctggtc ttggtcgtat gaagccaaac acacttgtcc 2820ttggatttaa gaaagattgg ttgcaagcag atatgaggga tgtggatatg tatataaact 2880tatttcatga tgcttttgac atacaatatg gagtagtggt tattcgccta aaagaaggtc 2940tggatatatc tcatcttcaa ggacaagaag aattattgtc atcacaagag aaatctcctg 3000gcaccaagga tgtggtagta agtgtggaat atagtaaaaa gtccgattta gatacttcca 3060aaccactcag tgaaaaacca attacacaca aagttgagga agaggatggc aagactgcaa 3120ctcaaccact gttgaaaaaa gaatccaaag gccctattgt gcctttaaat gtagctgacc 3180aaaagcttct tgaagctagt acacagtttc agaaaaaaca aggaaagaat actattgatg 3240tctggtggct ttttgatgat ggaggtttga ccttattgat accttacctt ctgacgacca 3300agaaaaaatg gaaagactgt aagatcagag tattcattgg tggaaagata aacagaatag 3360accatgaccg gagagcgatg gctactttgc ttagcaagtt ccggatagac ttttctgata 3420tcatggttct aggagatatc aataccaaac caaagaaaga aaatattata gcttttgagg 3480aaatcattga gccatacaga cttcatgaag atgataaaga gcaagatatt gcagataaaa 3540tgaaagaaga tgaaccatgg cgaataacag ataatgagct tgaactttat aagaccaaga 3600cataccggca gatcaggtta aatgagttat taaaggaaca ttcaagcaca gctaatatta 3660ttgtcatgag tctcccagtt gcacgaaaag gtgctgtgtc tagtgctctc tacatggcat 3720ggttagaagc tctatctaag gacctaccac caatcctcct agttcgtggg aatcatcaga 3780gtgtccttac cttctattca taaatgttct atacagtgga cagccctcca gaatggtact 3840tcagtgccta gtgtagtaac tgaaatcttc aatgacacat taacatcaca atggcgaatg 3900gtgacttttc tttcacgatt tcattaattt gaaagcacac aggaaagttg ctccattgat 3960aacgtgtatg gagacttcgg ttttagtcaa ttccatatct caatcttaat ggtgattctt 4020ctctgttgaa ctgaagtttg tgagagtagt tttcctttgc tacttgaata gcaataaaag 4080cgtgttaact ttttgattga tgaaagaagt acaaaaagcc tttagccttg aggtgccttc 4140tgaaattaac caaatttcat ccatatatcc tcttttataa acttatagaa tgtcaaactt 4200tgccttcaac tgtttttatt tctagtctct tccactttaa aacaaaatga acactgcttg 4260tcttcttcca ttgaccattt agtgttgagt actgtatgtg ttttgttaat tctataaagg 4320tatctgttag atattaaagg tgagaattag ggcaggttaa tcaaaaatgg ggaaggggaa 4380atggtaacca aaaagtaacc ccatggtaag gtttatatga gtatatgtga atatagagct 4440aggaaaaaaa gcccccccaa ataccttttt aacccctctg attggctatt attactatat 4500ttattattat ttattgaaac cttagggaag attgaagatt catcccatac ttctatatac 4560catgcttaaa aatcacgtca ttctttaaac aaaaatactc aagatcattt atatttattt 4620ggagagaaaa ctgtcctaat ttagaatttc cctcaaatct gagggacttt taagaaatgc 4680taacagattt ttctggagga aatttagaca aaacaatgtc atttagtaga atatttcagt 4740atttaagtgg aatttcagta tactgtacta tcctttataa gtcattaaaa taatgtttca 4800tcaaatggtt aaatggacca ctggtttctt agagaaatgt ttttaggctt aattcattca 4860attgtcaagt acacttagtc ttaatacact caggtttgaa cagattattc tgaatattaa 4920aatttaatcc attcttaata ttttaaaact tttgttaaga aaaactgcca gtttgtgctt 4980ttgaaatgtc tgttttgaca tcatagtcta gtaaaatttt gacagtgcat atgtactgtt 5040actaaaagct ttatatgaaa ttattaatgt gaagtttttc atttataatt caaggaagga 5100tttcctgaaa acatttcaag ggatttatgt ctacatattt gtgtgtgtgt gtgtatatat 5160atgtaatatg catacacaga tgcatatgtg tatatataat gaaatttatg ttgctggtat 5220tttgcatttt aaagtgatca agattcatta ggcaaacttt ggtttaagta aacatatgtt 5280caaaatcaga ttaacagata caggtttcat agagaacaaa ggtgatcatt tgaagggcat 5340gctgtaattt cacacaattt tccagttcaa aaatggagaa tacttcgcct aaaatactgt 5400taagtgggtt aattgataca agtttctgtg gtggaaaatt tatgcaggtt ttcacgaatc 5460cttttttttt tttttttttt tttttgagac ggagtcttgc tctgttgcca cgctggaatg 5520cagtaacgtg atcttggctc actgcgacct ccacctcccc agttcaagcg attctcctgc 5580ctcagcctcc ctagtagctg ggactacggg tgcacgccac catgcccagc taatttttgt 5640attttgagta gagacagggt ttcaccgtgt tggctaggat ggtgtctatc tcttgacctt 5700gtgatccacc cgcctcagcc tcccagagtg ctgggattac aggtgcgagc cactgcgcct 5760ggctggtttt catgaatctt gatagacatc tataacgtta ttattttcag tggtgtgcag 5820catttttgct tcatgagtat gacctaggta tagagatctg ataacttgaa ttcagaatat 5880taagaaaatg aagtaactga ttttctaaaa aaaaaaaaaa aaaaaatttc tacattataa 5940ctcacagcat tgttccattg caggttttgc aatgtttggg ggtaaagaca gtagaaatat 6000tattcagtaa acaataatgt gtgaactttt aagatggata atagggcatg gactgagtgc 6060tgctatcttg aaatgtgcac aggtacactt accttttttt tttttttttt taagtttttc 6120ccattcagga aaacaacatt gtgatctgta ctacaggaac caaatgtcat gcgtcataca 6180tgtgggtata aagtacataa aatatatcta actattcata atgtggggtg ggtaatactg 6240tctgtgaaat aatgtaagaa gcttttcact taaaaaaaat gcattacttt cacttaacac 6300tagacaccag gtcgaaaatt ttcaaggtta tagtacttat ttcaacaatt cttagagatg 6360ctagctagtg ttgaagctaa aaatagcttt atttatgctg aattgtgatt tttttatgcc 6420aaattttttt tagttctaat cattgatgat agcttggaaa taaataatta tgccatggca 6480tttgacagtt cattattcct ataagaatta aattgagttt agagagaatg gtggtgttga 6540gctgattatt aacagttact gaaatcaaat atttatttgt tacattattc catttgtatt 6600ttaggtttcc ttttacattc tttttatatg cattctgaca ttacatattt tttaagacta 6660tggaaataat ttaaagattt aagctctggt ggatgattat ctgctaagta agtctgaaaa 6720tgtaatattt tgataatact gtaatatacc tgtcacacaa atgcttttct aatgttttaa 6780ccttgagtat tgcagttgct gctttgtaca gaggttactg caataaagga agtggattca 6840ttaaacctat ttaatgtcca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 68911343959DNAHomo sapiens 134ataaaagctg cccggggaag ccaggagagc gaagggcgga cgtactcgcc acggcaccca 60ggctgcgcgc acgcggtccc ggtgtgcagc tggagagcga gcggccaccg ggagcccccg 120gcacagcccg cgcccgcccc gcaggagccc gcgaagatgc cccggcgcag cctgcacgcg 180gcggccgtgc tcctgctggt gatcttaaag gaacagcctt ccagcccggc cccagtgaac 240ggttccaagt ggacttattt tggtcctgat ggggagaata gctggtccaa gaagtacccg 300tcgtgtgggg gcctgctgca gtcccccata gacctgcaca gtgacatcct ccagtatgac 360gccagcctca cgcccctcga gttccaaggc tacaatctgt ctgccaacaa gcagtttctc 420ctgaccaaca atggccattc agtgaagctg aacctgccct cggacatgca catccagggc 480ctccagtctc gctacagtgc cacgcagctg cacctgcact gggggaaccc gaatgacccg 540cacggctctg agcacaccgt cagcggacag cacttcgccg ccgagctgca cattgtccat 600tataactcag acctttatcc tgacgccagc actgccagca acaagtcaga aggcctcgct 660gtcctggctg ttctcattga gatgggctcc ttcaatccgt cctatgacaa gatcttcagt 720caccttcaac atgtaaagta caaaggccag gaagcattcg tcccgggatt caacattgaa 780gagctgcttc cggagaggac cgctgaatat taccgctacc gggggtccct gaccacaccc 840ccttgcaacc ccactgtgct ctggacagtt ttccgaaacc ccgtgcaaat ttcccaggag 900cagctgctgg ctttggagac agccctgtac tgcacacaca tggacgaccc ttcccccaga 960gaaatgatca acaacttccg gcaggtccag aagttcgatg agaggctggt atacacctcc 1020ttctcccaag gcatcatcct ctcactggcc ctggctggca ttcttggcat ctgtattgtg 1080gtggtggtgt ccatttggct tttcagaagg aagagtatca aaaaaggtga taacaaggga 1140gtcatttaca agccagccac caagatggag actgaggccc acgcttgagg tccccggagc 1200tcccgggcac atccaggaag gaccttgctt tggaccctac acacttcggc tctctggaca 1260cttgcgacac ctcaaggtgt tctctgtagc tcaatctgca aacatgccag gcctcaggga 1320tcctctgctg ggtgcctcct tgccttggga ccatggccac cccagagcca tccgatcgat 1380ggatgggatg cactctcaga ccaagcagca ggaattcaaa gctgcttgct gtaactgtgt 1440gagattgtga agtggtctga attctggaat cacaaaccaa gccatgctgg tgggccatta 1500atggttggaa aacactttca tccggggctt tgccagagcg tgctttcaag tgtcctggaa 1560attctgctgc ttctccaagc tttcagacaa gaatgtgcac tctctgctta ggttttgctt 1620gggaaactca acttctttcc tctggagacg gggcatctcc ctctgatttc cttctgctat 1680gacaaaacct ttaatctgca ccttacaact cggggacaaa tggggacagg aaggatcaag 1740ttgtagagag aaaaagaaaa caagagatat acattgtgat atattaggga cactttcaca 1800gtcctgtcct ctggatcaca gacactgcac agaccttagg gaatggcagg ttcaagttcc 1860acttcttggt ggggatgaga agggagagag agctagaggg acaaagagaa tgagaagaca 1920tggatgatct gggagagtct cactttggaa tcagaattgg aatcacattc tgtttatcaa 1980gccataatgt aaggacagaa taatacaata ttaagtccaa atccaacctc ctgtcagtgg 2040agcagttatg ttttatactc tacagatttt acaaataatg aggctgttcc ttgaaaatgt 2100gttgttgctg tgtcctggag gagacatgag ttccgagatg acccaatctg cctttgaatc 2160tggaggaaat aggcagaaac aaaatgactg tagaacttat tctctgtagg ccaaatttca 2220tttcagccac ttctgcagga tccctactgc caacctggaa tggagacttt tatctacttc 2280tctctctctg aagatgtcaa atcgtggttt agatcaaata tatttcaagc tataaaagca 2340ggaggttatc tgtgcagggg gctggcatca tgtatttagg ggcaagtaat aatggaatgc 2400tactaagata ctccatattc ttccccgaat cacacagaca gtttctgaca ggcgcaactc 2460ctccattttc ctcccgcagg tgagaaccct gtggagatga gtcagtgcca tgactgagaa 2520ggaaccgacc cctagttgag agcaccttgc agttccccga gaactttctg attcacagtc 2580tcattttgac agcatgaaat gtcctcttga agcatagctt tttaaatatc tttttccttc 2640tactcctccc tctgactcta agaattctct cttctggaat cgcttgaacc caggaggcgg 2700aggttgcagt aagccaaggt catgccactg cactctagcc tgggtgacag agcgagactc 2760catctcaaaa aaaaaaaaaa aaaaattatt ctgtaccatc acaacttttc acaacgatgg 2820caagccttat gtcttgggag cctgttttgc taggcaaagt tacaagtgac ctaatgggag 2880ctcaaatgtg tgtgtgtctc tctgtgtgtt tgtgtgtgtg tgtgcactca agacctctaa 2940cagcctcgaa gcctggggtg gcatcccggc cttgccatta gcatgcctca tgcatcatca 3000gatgacaagg acaaccctca tgacgaagca acatgaatta gggggcctct tggccttggt 3060ccaaaattgt caatcagaaa tgaacataaa ggactccaga gcagtgggac tgtctgtcaa 3120aagactctgt atatcttttg tggatgagtt ttgtgagaga acagagagac cattgtacct 3180ggcacaaggg ctgttcatga aaagggagac ttactgggag gtgcaagaca gtggcatttc 3240tcctctcctc ttgctgctca gcacagccct ggattgcagc cccgaggctg agaccagaca 3300aagcccggga ggcagaaaga tgctccaaga accaacacta tcaatgtctt tgcaaatcct 3360cacaggattc ctgtgggtcc agctttggaa ctgggaaacc tttcttcgga tccgcactca 3420ttccactgat gccagctgcc cctgaaggat gccagtactg tggtgtgtga gtctcagcag 3480ccgcccacac gctcctaact ctgctgcatg gcagatgcct aggtggaaat agcaaaaaca 3540aggcccaggc tggggccagg gccagagggg aaggccctgg attctcactc atgtgagatc 3600ttgaatctct ttctttgttc tgtttgttta gttagtatca tctggtaaaa tagttaaaaa 3660acaacaaaaa actctgtatc tgtttctagc atgtgctgca ttgactctat taatcacatt 3720tcaaattcac cctacattcc tctcctcttc actagcctct ctgaaggtgt cctggccagc 3780cctggagaag cactggtgtc tgcagcaccc ctcagttcct gtgcctcagc ccacaggcca 3840ctgtgataat ggtctgttta gcacttctgt atttattgta agaatgatta taatgaagat 3900acacactgta actacaagaa attataaatg tttttcacat caaaaaaaaa aaaaaaaaa 395913519DNAArtificial SequenceTARGETING SEQUENCE 135gacctgagca ctggcataa 1913619DNAArtificial SequenceTARGETING SEQUENCE 136tgacatcgac actcataca 1913719DNAArtificial SequenceTARGETING SEQUENCE 137acactcatac agccaagta 1913819DNAArtificial SequenceTARGETING SEQUENCE 138acaatggtca tgctttcaa 1913919DNAArtificial SequenceTARGETING SEQUENCE 139aggacaaagc agtgctcaa 1914019DNAArtificial SequenceTARGETING SEQUENCE 140gatggcactt acagattga 1914119DNAArtificial SequenceTARGETING SEQUENCE 141gcacttacag attgattca 1914219DNAArtificial SequenceTARGETING SEQUENCE 142acagattgat tcagtttca 1914319DNAArtificial SequenceTARGETING SEQUENCE 143acaaggttca gagcatact 1914419DNAArtificial SequenceTARGETING SEQUENCE 144cagaacttca cttggttca 1914519DNAArtificial SequenceTARGETING SEQUENCE 145actggccgtt ctaggtatt 1914619DNAArtificial SequenceTARGETING SEQUENCE 146ttgaaggttg gcagcgcta 1914719DNAArtificial SequenceTARGETING SEQUENCE 147tgaaggttgg cagcgctaa 1914819DNAArtificial SequenceTARGETING SEQUENCE 148ttgttgatgt gctggattc 1914919DNAArtificial SequenceTARGETING SEQUENCE 149gaaattccgt aaacttaac 1915019DNAArtificial SequenceTARGETING SEQUENCE 150ccgaagaact gatggtgga 1915119DNAArtificial SequenceTARGETING SEQUENCE 151gaactgatgg tggacaact 1915219DNAArtificial SequenceTARGETING SEQUENCE 152tgaagaacag gcaaatcaa 1915319DNAArtificial SequenceTARGETING SEQUENCE 153cttacttgat agacttact 1915419DNAArtificial SequenceTARGETING SEQUENCE 154tgtgaagact agaccaatt 1915519DNAArtificial SequenceTARGETING SEQUENCE 155ttgagctagt taaggcaaa 1915619DNAArtificial SequenceTARGETING SEQUENCE 156acactggtgc tacgaggtt 1915719DNAArtificial SequenceTARGETING SEQUENCE 157ctggtgctac gaggttcaa 1915819DNAArtificial SequenceTARGETING SEQUENCE 158gttcaagccg agtcctcca 1915919DNAArtificial SequenceTARGETING SEQUENCE 159ttcaagccga gtcctccaa 1916019DNAArtificial SequenceTARGETING SEQUENCE 160cctgcttggt gccagtcaa 1916119DNAArtificial SequenceTARGETING SEQUENCE 161tctctggcta cgataagaa 1916219DNAArtificial SequenceTARGETING SEQUENCE 162tggctacgat aagaagcaa 1916319DNAArtificial SequenceTARGETING SEQUENCE 163gcaaacgtgg actgtccaa 1916419DNAArtificial SequenceTARGETING SEQUENCE 164tggtccgact tgccatata 1916519DNAArtificial SequenceTARGETING SEQUENCE 165ccatggagat gcacatagt 1916619DNAArtificial SequenceTARGETING SEQUENCE 166agatgcacat agtacatga 1916719DNAArtificial SequenceTARGETING SEQUENCE 167tgcacatagt acatgagaa 1916819DNAArtificial SequenceTARGETING SEQUENCE 168atagtacatg agaaagaga 1916919DNAArtificial SequenceTARGETING SEQUENCE 169catcgaggaa tgtgaaaga 1917019DNAArtificial SequenceTARGETING SEQUENCE 170ttgcggtgct ggcctttct 1917119DNAArtificial SequenceTARGETING SEQUENCE 171gaacagatcc tggcattct 1917219DNAArtificial SequenceTARGETING SEQUENCE 172tctctcagaa gctgtacta 1917319DNAArtificial SequenceTARGETING SEQUENCE

173aggaacagac agtgagcat 1917419DNAArtificial SequenceTARGETING SEQUENCE 174gaacagacag tgagcatga 1917519DNAArtificial SequenceTARGETING SEQUENCE 175ggcagcgcac ggtgataaa 1917619DNAArtificial SequenceTARGETING SEQUENCE 176cagcctctct gttgcctca 1917719DNAArtificial SequenceTARGETING SEQUENCE 177tgttgcctca gctctccaa 1917819DNAArtificial SequenceTARGETING SEQUENCE 178ttcaatccgt cctatgaca 1917919DNAArtificial SequenceTARGETING SEQUENCE 179agagcgtgct ttcaagtgt 1918019DNAArtificial SequenceTARGETING SEQUENCE 180gatgtcaaat cgtggttta 1918119DNAArtificial SequenceTARGETING SEQUENCE 181aaatcgtggt ttagatcaa 1918219DNAArtificial SequenceTARGETING SEQUENCE 182atggaatgct actaagata 1918319DNAArtificial SequenceTARGETING SEQUENCE 183ctactaagat actccatat 1918419DNAArtificial SequenceTARGETING SEQUENCE 184acaacgatgg caagcctta 1918519DNAArtificial SequenceTARGETING SEQUENCE 185caacgatggc aagccttat 1918619DNAArtificial SequenceTARGETING SEQUENCE 186ttgctaggca aagttacaa 1918719DNAArtificial SequenceTARGETING SEQUENCE 187taggcaaagt tacaagtga 1918819DNAArtificial SequenceTARGETING SEQUENCE 188agttacaagt gacctaatg 1918919DNAArtificial SequenceTARGETING SEQUENCE 189tgtgcactca agacctcta 1919019DNAArtificial SequenceTARGETING SEQUENCE 190gtgcactcaa gacctctaa 1919119DNAArtificial SequenceTARGETING SEQUENCE 191tgcactcaag acctctaac 1919219DNAArtificial SequenceTARGETING SEQUENCE 192gcactcaaga cctctaaca 1919319DNAArtificial SequenceTARGETING SEQUENCE 193agacctctaa cagcctcga 1919419DNAArtificial SequenceTARGETING SEQUENCE 194gacctctaac agcctcgaa 1919519DNAArtificial SequenceTARGETING SEQUENCE 195tgccattagc atgcctcat 1919619DNAArtificial SequenceTARGETING SEQUENCE 196gccattagca tgcctcatg 1919719DNAArtificial SequenceTARGETING SEQUENCE 197tagcatgcct catgcatca 1919819DNAArtificial SequenceTARGETING SEQUENCE 198catcatcaga tgacaagga 1919919DNAArtificial SequenceTARGETING SEQUENCE 199ctccttcaat ccgtcctat 1920019DNAArtificial SequenceTARGETING SEQUENCE 200agagcgtgct ttcaagtgt 1920119DNAArtificial SequenceTARGETING SEQUENCE 201gatgtcaaat cgtggttta 1920219DNAArtificial SequenceTARGETING SEQUENCE 202aaatcgtggt ttagatcaa 1920319DNAArtificial SequenceTARGETING SEQUENCE 203atggaatgct actaagata 1920419DNAArtificial SequenceTARGETING SEQUENCE 204ctactaagat actccatat 1920519DNAArtificial SequenceTARGETING SEQUENCE 205acaacgatgg caagcctta 1920619DNAArtificial SequenceTARGETING SEQUENCE 206caacgatggc aagccttat 1920719DNAArtificial SequenceTARGETING SEQUENCE 207ttgctaggca aagttacaa 1920819DNAArtificial SequenceTARGETING SEQUENCE 208taggcaaagt tacaagtga 1920919DNAArtificial SequenceTARGETING SEQUENCE 209agttacaagt gacctaatg 1921019DNAArtificial SequenceTARGETING SEQUENCE 210tgtgcactca agacctcta 1921119DNAArtificial SequenceTARGETING SEQUENCE 211gtgcactcaa gacctctaa 1921219DNAArtificial SequenceTARGETING SEQUENCE 212tgcactcaag acctctaac 1921319DNAArtificial SequenceTARGETING SEQUENCE 213gcactcaaga cctctaaca 1921419DNAArtificial SequenceTARGETING SEQUENCE 214agacctctaa cagcctcga 1921519DNAArtificial SequenceTARGETING SEQUENCE 215gacctctaac agcctcgaa 1921619DNAArtificial SequenceTARGETING SEQUENCE 216tgccattagc atgcctcat 1921719DNAArtificial SequenceTARGETING SEQUENCE 217gccattagca tgcctcatg 1921819DNAArtificial SequenceTARGETING SEQUENCE 218tagcatgcct catgcatca 1921919DNAArtificial SequenceTARGETING SEQUENCE 219catcatcaga tgacaagga 1922019DNAArtificial SequenceTARGETING SEQUENCE 220gcaatgtgct ggtgatcgt 1922119DNAArtificial SequenceTARGETING SEQUENCE 221tgatcgtggc catcgccaa 1922219DNAArtificial SequenceTARGETING SEQUENCE 222aagtgctgcg acttcgtca 1922319DNAArtificial SequenceTARGETING SEQUENCE 223cgtccgtagt ctccttcta 1922419DNAArtificial SequenceTARGETING SEQUENCE 224ccgtagtctc cttctacgt 1922519DNAArtificial SequenceTARGETING SEQUENCE 225atcatggcct tcgtgtacc 1922619DNAArtificial SequenceTARGETING SEQUENCE 226tcatggcctt cgtgtacct 1922719DNAArtificial SequenceTARGETING SEQUENCE 227cctcggaatc caaggtgta 1922819DNAArtificial SequenceTARGETING SEQUENCE 228tgtgtttact taagaccga 1922919DNAArtificial SequenceTARGETING SEQUENCE 229gtgtttactt aagaccgat 1923019DNAArtificial SequenceTARGETING SEQUENCE 230gtttacttaa gaccgatag 1923119DNAArtificial SequenceTARGETING SEQUENCE 231tttacttaag accgatagc 1923219DNAArtificial SequenceTARGETING SEQUENCE 232ttacttaaga ccgatagca 1923319DNAArtificial SequenceTARGETING SEQUENCE 233taagaccgat agcaggtga 1923419DNAArtificial SequenceTARGETING SEQUENCE 234accgatagca ggtgaactc 1923519DNAArtificial SequenceTARGETING SEQUENCE 235cgatagcagg tgaactcga 1923619DNAArtificial SequenceTARGETING SEQUENCE 236atagcaggtg aactcgaag 1923719DNAArtificial SequenceTARGETING SEQUENCE 237cacaatcctc gtctgaatc 1923819DNAArtificial SequenceTARGETING SEQUENCE 238acaatcctcg tctgaatca 1923919DNAArtificial SequenceTARGETING SEQUENCE 239tcatccgagg caaagagaa 1924019DNAArtificial SequenceTARGETING SEQUENCE 240catccgaggc aaagagaaa 1924119DNAArtificial SequenceTARGETING SEQUENCE 241ccacggaccg ttgcacaaa 1924219DNAArtificial SequenceTARGETING SEQUENCE 242cacgacgtca cgcagcaaa 1924319DNAArtificial SequenceTARGETING SEQUENCE 243gatcgctact ttgccatta 1924419DNAArtificial SequenceTARGETING SEQUENCE 244atcgctactt tgccattac 1924519DNAArtificial SequenceTARGETING SEQUENCE 245tcgctacttt gccattact 1924619DNAArtificial SequenceTARGETING SEQUENCE 246gccattactt cacctttca 1924719DNAArtificial SequenceTARGETING SEQUENCE 247ttacttcacc tttcaagta 1924819DNAArtificial SequenceTARGETING SEQUENCE 248ccattcagat gcactggta 1924919DNAArtificial SequenceTARGETING SEQUENCE 249tgatcatggt cttcgtcta 1925019DNAArtificial SequenceTARGETING SEQUENCE 250agacgttagg catcatcat 1925119DNAArtificial SequenceTARGETING SEQUENCE 251tcgttaacat tgtgcatgt 1925219DNAArtificial SequenceTARGETING SEQUENCE 252aggataacct catccgtaa 1925319DNAArtificial SequenceTARGETING SEQUENCE 253tcatccgtaa ggaagttta 1925419DNAArtificial SequenceTARGETING SEQUENCE 254aagtttacat cctcctaaa 1925519DNAArtificial SequenceTARGETING SEQUENCE 255agtttacatc ctcctaaat 1925619DNAArtificial SequenceTARGETING SEQUENCE 256taaattggat aggctatgt 1925719DNAArtificial SequenceTARGETING SEQUENCE 257ctatgtcaat tctggtttc 1925819DNAArtificial SequenceTARGETING SEQUENCE 258ggtactgtgc ctagcgata 1925919DNAArtificial SequenceTARGETING SEQUENCE 259gtactgtgcc tagcgataa 1926019DNAArtificial SequenceTARGETING SEQUENCE 260tactgtgcct agcgataac 1926119DNAArtificial SequenceTARGETING SEQUENCE 261gcgataacat tgattcaca 1926219DNAArtificial SequenceTARGETING SEQUENCE 262cgataacatt gattcacaa 1926319DNAArtificial SequenceTARGETING SEQUENCE 263ggaggaattg tagtacaaa 1926419DNAArtificial SequenceTARGETING SEQUENCE 264gaggaattgt agtacaaat 1926519DNAArtificial SequenceTARGETING SEQUENCE 265aggaattgta gtacaaatg 1926619DNAArtificial SequenceTARGETING SEQUENCE 266caaatgactc actgctgta 1926719DNAArtificial SequenceTARGETING SEQUENCE 267gacctgagtc tgctatatt 1926819DNAArtificial SequenceTARGETING SEQUENCE 268acctgagtct gctatattt 1926919DNAArtificial SequenceTARGETING SEQUENCE 269ccatgtatct acctcacta 1927019DNAArtificial SequenceTARGETING SEQUENCE 270catgtatcta cctcactat 1927119DNAArtificial SequenceTARGETING SEQUENCE 271atgtatctac ctcactatt 1927219DNAArtificial SequenceTARGETING SEQUENCE 272cctcactatt caagtatta 1927319DNAArtificial SequenceTARGETING SEQUENCE 273taatatattg ctgctggta 1927419DNAArtificial SequenceTARGETING SEQUENCE 274aatatattgc tgctggtaa 1927519DNAArtificial SequenceTARGETING SEQUENCE 275atatattgct gctggtaat 1927619DNAArtificial SequenceTARGETING SEQUENCE 276tatattgctg ctggtaatt 1927719DNAArtificial SequenceTARGETING SEQUENCE 277ctggtaattt gtatctgaa 1927819DNAArtificial SequenceTARGETING SEQUENCE 278gagtatctcg gacctttca 1927919DNAArtificial SequenceTARGETING SEQUENCE 279cggacctttc agctgtgaa 1928019DNAArtificial SequenceTARGETING SEQUENCE 280cgagcaaagg tctaaagtt 1928119DNAArtificial SequenceTARGETING SEQUENCE 281gagcaaaggt ctaaagttt 1928219DNAArtificial SequenceTARGETING SEQUENCE 282ggtctaaagt ttacagtaa 1928319DNAArtificial SequenceTARGETING SEQUENCE 283agtgtctgct accaatatg 1928419DNAArtificial SequenceTARGETING SEQUENCE 284agacaacgag tctctcatc 1928519DNAArtificial SequenceTARGETING SEQUENCE 285ggctgtggtc ctgcattac 1928619DNAArtificial SequenceTARGETING SEQUENCE 286cttcctcctc aaaccgaga 1928719DNAArtificial SequenceTARGETING SEQUENCE 287tcctcctcaa accgagaga 1928819DNAArtificial SequenceTARGETING SEQUENCE 288cctcaaaccg agagactca 1928919DNAArtificial SequenceTARGETING SEQUENCE 289tcaaaccgag agactcaca 1929019DNAArtificial SequenceTARGETING SEQUENCE 290aaaccgagag actcacact 1929119DNAArtificial SequenceTARGETING SEQUENCE 291ccacgccttt gttgtttga 1929219DNAArtificial SequenceTARGETING SEQUENCE 292cacgcctttg ttgtttgaa 1929319DNAArtificial SequenceTARGETING SEQUENCE 293acgcctttgt tgtttgaat 1929419DNAArtificial SequenceTARGETING SEQUENCE 294ggctataacg gtcaaccat 1929519DNAArtificial SequenceTARGETING SEQUENCE 295tataacggtc aaccatttc 1929619DNAArtificial SequenceTARGETING SEQUENCE 296cggtcaacca tttctgtct 1929719DNAArtificial SequenceTARGETING SEQUENCE 297gtcaaccatt tctgtctct 1929819DNAArtificial SequenceTARGETING SEQUENCE 298ccgtcttccg gtcattctt 1929919DNAArtificial SequenceTARGETING SEQUENCE 299cctctcgtct ttcgcacat 1930019DNAArtificial SequenceTARGETING SEQUENCE 300tctcgtcttt cgcacattc 1930119DNAArtificial SequenceTARGETING SEQUENCE 301tttcgcacat tctcctgat 1930219DNAArtificial SequenceTARGETING SEQUENCE 302ttcgcacatt ctcctgatc 1930319DNAArtificial SequenceTARGETING SEQUENCE 303agaaccagtt cgaccacta 1930419DNAArtificial SequenceTARGETING SEQUENCE 304aaccagttcg accactaca 1930519DNAArtificial SequenceTARGETING SEQUENCE 305ctgcaaataa actgttaca 1930619DNAArtificial SequenceTARGETING SEQUENCE 306tagacgctac aaccttcca 1930719DNAArtificial SequenceTARGETING SEQUENCE 307cgctacaacc ttccagagt 1930819DNAArtificial SequenceTARGETING SEQUENCE 308agagtgtctg ctaccaata 1930919DNAArtificial SequenceTARGETING SEQUENCE 309gagtgtctgc taccaatat 1931019DNAArtificial SequenceTARGETING SEQUENCE 310ctgtcctcgt ctggatcta 1931119DNAArtificial SequenceTARGETING SEQUENCE 311atggccgctt cttggtaca 1931219DNAArtificial SequenceTARGETING SEQUENCE 312cgacatcagt gacgctgtt 1931319DNAArtificial SequenceTARGETING SEQUENCE 313gcacgtgctg cctcaagaa 1931419DNAArtificial SequenceTARGETING SEQUENCE 314cacgtgctgc ctcaagaaa 1931519DNAArtificial SequenceTARGETING SEQUENCE 315gaaagcgtct tccggttct 1931619DNAArtificial SequenceTARGETING SEQUENCE 316tgtggtagat ggagacttc 1931719DNAArtificial SequenceTARGETING SEQUENCE 317gacaacgagt ctctcatca 1931819DNAArtificial SequenceTARGETING SEQUENCE 318aggctgtggt cctgcatta 1931919DNAArtificial SequenceTARGETING SEQUENCE 319gctgtggtcc tgcattaca 1932019DNAArtificial SequenceTARGETING SEQUENCE 320gtctacgcct acgtctttg 1932119DNAArtificial SequenceTARGETING SEQUENCE 321tctacgccta cgtctttga 1932219DNAArtificial SequenceTARGETING SEQUENCE 322ctacgcctac gtctttgaa 1932319DNAArtificial SequenceTARGETING SEQUENCE 323cggctacgag atcgagttc

1932419DNAArtificial SequenceTARGETING SEQUENCE 324cagcgactga tgcgatact 1932519DNAArtificial SequenceTARGETING SEQUENCE 325ggctcagcag tacgttagt 1932619DNAArtificial SequenceTARGETING SEQUENCE 326agtacgttag tctggacct 1932719DNAArtificial SequenceTARGETING SEQUENCE 327acatggtgca ctggaagaa 1932819DNAArtificial SequenceTARGETING SEQUENCE 328agaaccagtt cgaccacta 1932919DNAArtificial SequenceTARGETING SEQUENCE 329gaaccagttc gaccactac 1933019DNAArtificial SequenceTARGETING SEQUENCE 330ggctataaca cagacgagc 1933119DNAArtificial SequenceTARGETING SEQUENCE 331gctataacac agacgagcc 1933219DNAArtificial SequenceTARGETING SEQUENCE 332gctgcaaata aactgttac 1933319DNAArtificial SequenceTARGETING SEQUENCE 333ctgcaaataa actgttaca 1933419DNAArtificial SequenceTARGETING SEQUENCE 334gcaatgagac cgtggaaga 1933519DNAArtificial SequenceTARGETING SEQUENCE 335tgccaaggcc tgcgtagta 1933619DNAArtificial SequenceTARGETING SEQUENCE 336taaaggacat gacctccga 1933719DNAArtificial SequenceTARGETING SEQUENCE 337agcaagctgc tgacatgat 1933819DNAArtificial SequenceTARGETING SEQUENCE 338acatgattct tctggatga 1933919DNAArtificial SequenceTARGETING SEQUENCE 339gtcgtctgat ctttgataa 1934019DNAArtificial SequenceTARGETING SEQUENCE 340cttatacctt aaccagtaa 1934119DNAArtificial SequenceTARGETING SEQUENCE 341ggatcaacga tgtggaaga 1934219DNAArtificial SequenceTARGETING SEQUENCE 342acgatgtgga agacagcta 1934319DNAArtificial SequenceTARGETING SEQUENCE 343ccgacttggt catctgtaa 1934419DNAArtificial SequenceTARGETING SEQUENCE 344taggaaagca ccgcagcat 1934519DNAArtificial SequenceTARGETING SEQUENCE 345agacgtcctg gaatgaagc 1934619DNAArtificial SequenceTARGETING SEQUENCE 346gacgtcctgg aatgaagca 1934719DNAArtificial SequenceTARGETING SEQUENCE 347acgtcctgga atgaagcat 1934819DNAArtificial SequenceTARGETING SEQUENCE 348gaagcatgta gctctatgg 1934919DNAArtificial SequenceTARGETING SEQUENCE 349ttcagaacaa ggtgataaa 1935019DNAArtificial SequenceTARGETING SEQUENCE 350tgatgaactt catcgtaaa 1935119DNAArtificial SequenceTARGETING SEQUENCE 351ggtgctatca gccgttgta 1935219DNAArtificial SequenceTARGETING SEQUENCE 352tcagccgttg taatcataa 1935319DNAArtificial SequenceTARGETING SEQUENCE 353gattcgaaat ggtgagaaa 1935419DNAArtificial SequenceTARGETING SEQUENCE 354cagaatcata tctgcaaat 1935519DNAArtificial SequenceTARGETING SEQUENCE 355cacgtggtat tgttgtcta 1935619DNAArtificial SequenceTARGETING SEQUENCE 356ctgcttagtg aagaactta 1935719DNAArtificial SequenceTARGETING SEQUENCE 357gtttcaggct aaccaggaa 1935819DNAArtificial SequenceTARGETING SEQUENCE 358cactcttaaa gtgcataga 1935919DNAArtificial SequenceTARGETING SEQUENCE 359agtaccagtt gtctattca 1936019DNAArtificial SequenceTARGETING SEQUENCE 360taccagttgt ctattcata 1936119DNAArtificial SequenceTARGETING SEQUENCE 361agctgaaaga cgcctttca 1936219DNAArtificial SequenceTARGETING SEQUENCE 362tcgataatct gtgctttgt 1936319DNAArtificial SequenceTARGETING SEQUENCE 363acaggagacc atccaatca 1936419DNAArtificial SequenceTARGETING SEQUENCE 364tagccttgat gaacttcat 1936519DNAArtificial SequenceTARGETING SEQUENCE 365ttgatgaact tcatcgtaa 1936619DNAArtificial SequenceTARGETING SEQUENCE 366gatgaacttc atcgtaaat 1936719DNAArtificial SequenceTARGETING SEQUENCE 367ctactcctga atggatcaa 1936819DNAArtificial SequenceTARGETING SEQUENCE 368ggagcgattc tttgtttct 1936919DNAArtificial SequenceTARGETING SEQUENCE 369gtgctatcag ccgttgtaa 1937019DNAArtificial SequenceTARGETING SEQUENCE 370tgctatcagc cgttgtaat 1937119DNAArtificial SequenceTARGETING SEQUENCE 371gagcataaat gcggaggaa 1937219DNAArtificial SequenceTARGETING SEQUENCE 372gaaggcaatg gacctatga 1937319DNAArtificial SequenceTARGETING SEQUENCE 373ccgacttggt catctgtaa 1937419DNAArtificial SequenceTARGETING SEQUENCE 374tatatgacga agtcagaaa 1937519DNAArtificial SequenceTARGETING SEQUENCE 375tggcaatgga tgaccacaa 1937619DNAArtificial SequenceTARGETING SEQUENCE 376tgaaccatcc aacgacaat 1937719DNAArtificial SequenceTARGETING SEQUENCE 377accatccaac gacaatcta 1937819DNAArtificial SequenceTARGETING SEQUENCE 378catccaacga caatctata 1937919DNAArtificial SequenceTARGETING SEQUENCE 379atccaacgac aatctatat 1938019DNAArtificial SequenceTARGETING SEQUENCE 380gcagatcaac gcagaggaa 1938119DNAArtificial SequenceTARGETING SEQUENCE 381tgtttcttct ccaccaact 1938219DNAArtificial SequenceTARGETING SEQUENCE 382ccatagcaat ggagattga 1938319DNAArtificial SequenceTARGETING SEQUENCE 383agatgcaaga tgcctttca 1938419DNAArtificial SequenceTARGETING SEQUENCE 384ctgaatctgc catctggaa 1938519DNAArtificial SequenceTARGETING SEQUENCE 385tgaatctgcc atctggaaa 1938619DNAArtificial SequenceTARGETING SEQUENCE 386atcgtctttg ctcgaacgt 1938719DNAArtificial SequenceTARGETING SEQUENCE 387ctgcattgaa gaaggctga 1938819DNAArtificial SequenceTARGETING SEQUENCE 388atgaagcggc agccacgaa 1938919DNAArtificial SequenceTARGETING SEQUENCE 389tgaagcggca gccacgaaa 1939019DNAArtificial SequenceTARGETING SEQUENCE 390ggatgaccgg accatgaat 1939119DNAArtificial SequenceTARGETING SEQUENCE 391gctgcctttc tctcttact 1939219DNAArtificial SequenceTARGETING SEQUENCE 392tctatgatga ggtccgaaa 1939319DNAArtificial SequenceTARGETING SEQUENCE 393gtggagaagg agacatact 1939419DNAArtificial SequenceTARGETING SEQUENCE 394tggagaagga gacatacta 1939519DNAArtificial SequenceTARGETING SEQUENCE 395tagacctaac tgtgaacaa 1939619DNAArtificial SequenceTARGETING SEQUENCE 396agacctaact gtgaacaat 1939719DNAArtificial SequenceTARGETING SEQUENCE 397tccactatgt tgtctattt 1939819DNAArtificial SequenceTARGETING SEQUENCE 398tgagtgcaag agcctgaga 1939919DNAArtificial SequenceTARGETING SEQUENCE 399tgacatgagt ctccagata 1940019DNAArtificial SequenceTARGETING SEQUENCE 400gtcgtggact ccagctcta 1940119DNAArtificial SequenceTARGETING SEQUENCE 401tgtcactcat gtacttaat 1940219DNAArtificial SequenceTARGETING SEQUENCE 402gtcactcatg tacttaata 1940319DNAArtificial SequenceTARGETING SEQUENCE 403cacttcacct tctgtaata 1940419DNAArtificial SequenceTARGETING SEQUENCE 404gtagagagag acctagata 1940519DNAArtificial SequenceTARGETING SEQUENCE 405ctagataggt catgcaagt 1940619DNAArtificial SequenceTARGETING SEQUENCE 406aggtcatgca agtgagaaa 1940719DNAArtificial SequenceTARGETING SEQUENCE 407tatcagaagc aaggaagta 1940819DNAArtificial SequenceTARGETING SEQUENCE 408tccgattaat tggagatta 1940919DNAArtificial SequenceTARGETING SEQUENCE 409ccgattaatt ggagattac 1941019DNAArtificial SequenceTARGETING SEQUENCE 410gattactaac tgtggacaa 1941119DNAArtificial SequenceTARGETING SEQUENCE 411attactaact gtggacaaa 1941219DNAArtificial SequenceTARGETING SEQUENCE 412tcaggcactt tagaaatat 1941319DNAArtificial SequenceTARGETING SEQUENCE 413ggctaattat catcaatct 1941419DNAArtificial SequenceTARGETING SEQUENCE 414agtttgaggt actacctat 1941519DNAArtificial SequenceTARGETING SEQUENCE 415tactacctat gtacttgaa 1941619DNAArtificial SequenceTARGETING SEQUENCE 416actacctatg tacttgaaa 1941719DNAArtificial SequenceTARGETING SEQUENCE 417tggctatgac agagcacaa 1941819DNAArtificial SequenceTARGETING SEQUENCE 418gaggtctgcc ggaaataca 1941919DNAArtificial SequenceTARGETING SEQUENCE 419ctcacgccac cgcctacca 1942019DNAArtificial SequenceTARGETING SEQUENCE 420tcgactgtga tgacgtgaa 1942119DNAArtificial SequenceTARGETING SEQUENCE 421tgaacttcac cacggacaa 1942219DNAArtificial SequenceTARGETING SEQUENCE 422ccaaggcctg cgtgatcca 1942319DNAArtificial SequenceTARGETING SEQUENCE 423ggacttcacc tccgagcaa 1942419DNAArtificial SequenceTARGETING SEQUENCE 424gacttcacct ccgagcaaa 1942519DNAArtificial SequenceTARGETING SEQUENCE 425acttcacctc cgagcaaat 1942619DNAArtificial SequenceTARGETING SEQUENCE 426tcgacgagat cctgcagaa 1942719DNAArtificial SequenceTARGETING SEQUENCE 427cgacgagatc ctgcagaat 1942819DNAArtificial SequenceTARGETING SEQUENCE 428acgagatcct gcagaatca 1942919DNAArtificial SequenceTARGETING SEQUENCE 429gatcttcgac aacctaaag 1943019DNAArtificial SequenceTARGETING SEQUENCE 430ccatctcact ggcgtacga 1943119DNAArtificial SequenceTARGETING SEQUENCE 431ctgccgaaag cgacatcat 1943219DNAArtificial SequenceTARGETING SEQUENCE 432cggacaaatt ggtcaatga 1943319DNAArtificial SequenceTARGETING SEQUENCE 433caaattggtc aatgagaga 1943419DNAArtificial SequenceTARGETING SEQUENCE 434ggatgaccgc accgtcaat 1943519DNAArtificial SequenceTARGETING SEQUENCE 435caccgtcaat gacctggaa 1943619DNAArtificial SequenceTARGETING SEQUENCE 436atcttcgtct acgacgaaa 1943719DNAArtificial SequenceTARGETING SEQUENCE 437ctacgacgaa atccgcaaa 1943819DNAArtificial SequenceTARGETING SEQUENCE 438acgacgaaat ccgcaaact 1943919DNAArtificial SequenceTARGETING SEQUENCE 439acgaaatccg caaactcat 1944019DNAArtificial SequenceTARGETING SEQUENCE 440ccaaacctct ctcctctct 1944119DNAArtificial SequenceTARGETING SEQUENCE 441ggcacctggt tacgcttca 1944219DNAArtificial SequenceTARGETING SEQUENCE 442catggatgat cacaaatta 1944319DNAArtificial SequenceTARGETING SEQUENCE 443aatcctgact cgagatgga 1944419DNAArtificial SequenceTARGETING SEQUENCE 444cctacagcat ccagatata 1944519DNAArtificial SequenceTARGETING SEQUENCE 445ccggcttatc tctgcacaa 1944619DNAArtificial SequenceTARGETING SEQUENCE 446agctctgata cctggttta 1944719DNAArtificial SequenceTARGETING SEQUENCE 447gctctgatac ctggtttat 1944819DNAArtificial SequenceTARGETING SEQUENCE 448aggtgatgct tccgagtca 1944919DNAArtificial SequenceTARGETING SEQUENCE 449gtactcaatg aacgatgaa 1945019DNAArtificial SequenceTARGETING SEQUENCE 450tactcaatga acgatgaaa 1945119DNAArtificial SequenceTARGETING SEQUENCE 451gtgctaggct tctgcttct 1945219DNAArtificial SequenceTARGETING SEQUENCE 452catggtaaca ggagatcat 1945319DNAArtificial SequenceTARGETING SEQUENCE 453tgtggtgcat ggtgcagaa 1945419DNAArtificial SequenceTARGETING SEQUENCE 454tgttcatcat cctcggtat 1945519DNAArtificial SequenceTARGETING SEQUENCE 455gttcatcatc ctcggtata 1945619DNAArtificial SequenceTARGETING SEQUENCE 456ggcttatgag tcagctgaa 1945719DNAArtificial SequenceTARGETING SEQUENCE 457ggacctatga gcaacgaaa 1945819DNAArtificial SequenceTARGETING SEQUENCE 458cggatctcat catctccaa 1945919DNAArtificial SequenceTARGETING SEQUENCE 459tggctgcatt tctgtccta 1946019DNAArtificial SequenceTARGETING SEQUENCE 460gctgcatttc tgtcctaca 1946119DNAArtificial SequenceTARGETING SEQUENCE 461gtattctcat cttcgtcta 1946219DNAArtificial SequenceTARGETING SEQUENCE 462tattctcatc ttcgtctat 1946319DNAArtificial SequenceTARGETING SEQUENCE 463actaaactca gcagatgaa 1946419DNAArtificial SequenceTARGETING SEQUENCE 464ggccagagat tataagttt 1946519DNAArtificial SequenceTARGETING SEQUENCE 465gccagagatt ataagtttg 1946619DNAArtificial SequenceTARGETING SEQUENCE 466ccagagatta taagtttga 1946719DNAArtificial SequenceTARGETING SEQUENCE 467cagagattat aagtttgac 1946819DNAArtificial SequenceTARGETING SEQUENCE 468ataagtttga cacaacatc 1946919DNAArtificial SequenceTARGETING SEQUENCE 469taagtttgac acaacatct 1947019DNAArtificial SequenceTARGETING SEQUENCE 470tctgagacac taggatgaa 1947119DNAArtificial SequenceTARGETING SEQUENCE 471agacactagg atgaattat 1947219DNAArtificial SequenceTARGETING SEQUENCE 472gacactagga tgaattatc 1947319DNAArtificial SequenceTARGETING SEQUENCE 473aggatgaatt atcttggat 1947419DNAArtificial SequenceTARGETING SEQUENCE 474gatgaattat cttggatga

1947519DNAArtificial SequenceTARGETING SEQUENCE 475cgtagccagt ctagacagt 1947619DNAArtificial SequenceTARGETING SEQUENCE 476gccagtctag acagtaaat 1947719DNAArtificial SequenceTARGETING SEQUENCE 477cagtctagac agtaaatgt 1947819DNAArtificial SequenceTARGETING SEQUENCE 478agacagtaaa tgtctggaa 1947919DNAArtificial SequenceTARGETING SEQUENCE 479gacagtaaat gtctggaaa 1948019DNAArtificial SequenceTARGETING SEQUENCE 480gctggattct ttacctact 1948119DNAArtificial SequenceTARGETING SEQUENCE 481gtggacctat gagcaacga 1948219DNAArtificial SequenceTARGETING SEQUENCE 482tggacctatg agcaacgaa 1948319DNAArtificial SequenceTARGETING SEQUENCE 483ggacctatga gcaacgaaa 1948419DNAArtificial SequenceTARGETING SEQUENCE 484cggatctcat catctccaa 1948519DNAArtificial SequenceTARGETING SEQUENCE 485tggctgcatt tctgtccta 1948619DNAArtificial SequenceTARGETING SEQUENCE 486gctgcatttc tgtcctaca 1948719DNAArtificial SequenceTARGETING SEQUENCE 487gtattctcat cttcgtcta 1948819DNAArtificial SequenceTARGETING SEQUENCE 488tattctcatc ttcgtctat 1948919DNAArtificial SequenceTARGETING SEQUENCE 489cttcgtctat gatgaaatc 1949019DNAArtificial SequenceTARGETING SEQUENCE 490actactaaac tcagcagat 1949119DNAArtificial SequenceTARGETING SEQUENCE 491ctactaaact cagcagatg 1949219DNAArtificial SequenceTARGETING SEQUENCE 492tactaaactc agcagatga 1949319DNAArtificial SequenceTARGETING SEQUENCE 493actaaactca gcagatgaa 1949419DNAArtificial SequenceTARGETING SEQUENCE 494ggccagagat tataagttt 1949519DNAArtificial SequenceTARGETING SEQUENCE 495gccagagatt ataagtttg 1949619DNAArtificial SequenceTARGETING SEQUENCE 496ccagagatta taagtttga 1949719DNAArtificial SequenceTARGETING SEQUENCE 497cagagattat aagtttgac 1949819DNAArtificial SequenceTARGETING SEQUENCE 498ataagtttga cacaacatc 1949919DNAArtificial SequenceTARGETING SEQUENCE 499taagtttgac acaacatct 1950019DNAArtificial SequenceTARGETING SEQUENCE 500tctgagacac taggatgaa 1950119DNAArtificial SequenceTARGETING SEQUENCE 501agacactagg atgaattat 1950219DNAArtificial SequenceTARGETING SEQUENCE 502gacactagga tgaattatc 1950319DNAArtificial SequenceTARGETING SEQUENCE 503taggatgaat tatcttgga 1950419DNAArtificial SequenceTARGETING SEQUENCE 504aggatgaatt atcttggat 1950519DNAArtificial SequenceTARGETING SEQUENCE 505gatgaattat cttggatga 1950619DNAArtificial SequenceTARGETING SEQUENCE 506tgaattatct tggatgaga 1950719DNAArtificial SequenceTARGETING SEQUENCE 507cgtagccagt ctagacagt 1950819DNAArtificial SequenceTARGETING SEQUENCE 508gccagtctag acagtaaat 1950919DNAArtificial SequenceTARGETING SEQUENCE 509cagtctagac agtaaatgt 1951019DNAArtificial SequenceTARGETING SEQUENCE 510agacagtaaa tgtctggaa 1951119DNAArtificial SequenceTARGETING SEQUENCE 511gacagtaaat gtctggaaa 1951219DNAArtificial SequenceTARGETING SEQUENCE 512acctactagt cttgaacaa 1951319DNAArtificial SequenceTARGETING SEQUENCE 513tactagtctt gaacaaact 1951419DNAArtificial SequenceTARGETING SEQUENCE 514ggacctacac ttaatctat 1951519DNAArtificial SequenceTARGETING SEQUENCE 515gacctacact taatctata 1951619DNAArtificial SequenceTARGETING SEQUENCE 516ctgcatttaa taggttaga 1951719DNAArtificial SequenceTARGETING SEQUENCE 517cgtaactgac ttgtagtaa 1951819DNAArtificial SequenceTARGETING SEQUENCE 518agcaaggttt gctgtccaa 1951919DNAArtificial SequenceTARGETING SEQUENCE 519tgctgtccaa ggtgtaaat 1952019DNAArtificial SequenceTARGETING SEQUENCE 520gctgtccaag gtgtaaata 1952119DNAArtificial SequenceTARGETING SEQUENCE 521ctgtccaagg tgtaaatat 1952219DNAArtificial SequenceTARGETING SEQUENCE 522ttaacatact ccatagtct 1952319DNAArtificial SequenceTARGETING SEQUENCE 523gccttgtcct ccggtatgt 1952419DNAArtificial SequenceTARGETING SEQUENCE 524tgtcctccgg tatgttcta 1952519DNAArtificial SequenceTARGETING SEQUENCE 525gtcctccggt atgttctaa 1952619DNAArtificial SequenceTARGETING SEQUENCE 526tcctccggta tgttctaaa 1952719DNAArtificial SequenceTARGETING SEQUENCE 527ccatcacttt ggctagtga 1952819DNAArtificial SequenceTARGETING SEQUENCE 528accggtggca gttggttta 1952919DNAArtificial SequenceTARGETING SEQUENCE 529ccggtggcag ttggtttaa 1953019DNAArtificial SequenceTARGETING SEQUENCE 530ttggtttaag atccttcta 1953119DNAArtificial SequenceTARGETING SEQUENCE 531agatccttct attctacgt 1953219DNAArtificial SequenceTARGETING SEQUENCE 532atccttctat tctacgtaa 1953319DNAArtificial SequenceTARGETING SEQUENCE 533tccttctatt ctacgtaat 1953419DNAArtificial SequenceTARGETING SEQUENCE 534ccttctattc tacgtaata 1953519DNAArtificial SequenceTARGETING SEQUENCE 535gaaatttcct ttcgtccta 1953619DNAArtificial SequenceTARGETING SEQUENCE 536aacgaggaga ctttaatca 1953719DNAArtificial SequenceTARGETING SEQUENCE 537gaaattgctc tggattaaa 1953819DNAArtificial SequenceTARGETING SEQUENCE 538atgaaactta tggctacaa 1953919DNAArtificial SequenceTARGETING SEQUENCE 539tgaaacttat ggctacaaa 1954019DNAArtificial SequenceTARGETING SEQUENCE 540aaacttatgg ctacaaaga 1954119DNAArtificial SequenceTARGETING SEQUENCE 541ggcaaaccgt gcattatta 1954219DNAArtificial SequenceTARGETING SEQUENCE 542gcaaaccgtg cattattat 1954319DNAArtificial SequenceTARGETING SEQUENCE 543accgagttct aggcttcaa 1954419DNAArtificial SequenceTARGETING SEQUENCE 544ccgagttcta ggcttcaaa 1954519DNAArtificial SequenceTARGETING SEQUENCE 545ttctaggctt caaacctaa 1954619DNAArtificial SequenceTARGETING SEQUENCE 546atgagtcctt ggagactta 1954719DNAArtificial SequenceTARGETING SEQUENCE 547gcaagcgaga tgaagataa 1954819DNAArtificial SequenceTARGETING SEQUENCE 548agttggaaat gtggagtat 1954919DNAArtificial SequenceTARGETING SEQUENCE 549ctgcagtatt atccgtact 1955019DNAArtificial SequenceTARGETING SEQUENCE 550tgcagtatta tccgtacta 1955119DNAArtificial SequenceTARGETING SEQUENCE 551gcagtattat ccgtactat 1955219DNAArtificial SequenceTARGETING SEQUENCE 552ccgtacagtt caccaatct 1955319DNAArtificial SequenceTARGETING SEQUENCE 553tcaccaatct taccatgga 1955419DNAArtificial SequenceTARGETING SEQUENCE 554aaattcgcat agagtgtaa 1955519DNAArtificial SequenceTARGETING SEQUENCE 555tgtaaggcgt acggtgaga 1955619DNAArtificial SequenceTARGETING SEQUENCE 556tgtgttatgc ttgtattga 1955719DNAArtificial SequenceTARGETING SEQUENCE 557gccttgtcct ccggtatgt 1955819DNAArtificial SequenceTARGETING SEQUENCE 558tgtcctccgg tatgttcta 1955919DNAArtificial SequenceTARGETING SEQUENCE 559gtcctccggt atgttctaa 1956019DNAArtificial SequenceTARGETING SEQUENCE 560tcctccggta tgttctaaa 1956119DNAArtificial SequenceTARGETING SEQUENCE 561cctccggtat gttctaaag 1956219DNAArtificial SequenceTARGETING SEQUENCE 562tccggtatgt tctaaagct 1956319DNAArtificial SequenceTARGETING SEQUENCE 563ccatcacttt ggctagtga 1956419DNAArtificial SequenceTARGETING SEQUENCE 564ccgaggacgc accagttta 1956519DNAArtificial SequenceTARGETING SEQUENCE 565cgaggacgca ccagtttat 1956619DNAArtificial SequenceTARGETING SEQUENCE 566tgcagactgt ctccgacca 1956719DNAArtificial SequenceTARGETING SEQUENCE 567cagactgtct ccgaccata 1956819DNAArtificial SequenceTARGETING SEQUENCE 568caagactgag aaccttgat 1956919DNAArtificial SequenceTARGETING SEQUENCE 569agaaccttga tgtcattgt 1957019DNAArtificial SequenceTARGETING SEQUENCE 570ccttgatgtc attgtcaat 1957119DNAArtificial SequenceTARGETING SEQUENCE 571aagttcttgg agccttaca 1957219DNAArtificial SequenceTARGETING SEQUENCE 572agttcttgga gccttacaa 1957319DNAArtificial SequenceTARGETING SEQUENCE 573gagccttaca acgactcta 1957419DNAArtificial SequenceTARGETING SEQUENCE 574agccttacaa cgactctat 1957519DNAArtificial SequenceTARGETING SEQUENCE 575ttacaacgac tctatccaa 1957619DNAArtificial SequenceTARGETING SEQUENCE 576gctattacga acagccaga 1957719DNAArtificial SequenceTARGETING SEQUENCE 577tattacgaac agccagata 1957819DNAArtificial SequenceTARGETING SEQUENCE 578attacgaaca gccagataa 1957919DNAArtificial SequenceTARGETING SEQUENCE 579cagataatgg agtcctcaa 1958019DNAArtificial SequenceTARGETING SEQUENCE 580gataatggag tcctcaact 1958119DNAArtificial SequenceTARGETING SEQUENCE 581aaacgtgcct gccaattca 1958219DNAArtificial SequenceTARGETING SEQUENCE 582aacgtgcctg ccaattcaa 1958319DNAArtificial SequenceTARGETING SEQUENCE 583aaccagagca tgaatgtta 1958419DNAArtificial SequenceTARGETING SEQUENCE 584ctcggcaact tcgtcatgt 1958519DNAArtificial SequenceTARGETING SEQUENCE 585aatgtagaat gtcgcatca 1958619DNAArtificial SequenceTARGETING SEQUENCE 586atgtagaatg tcgcatcaa 1958719DNAArtificial SequenceTARGETING SEQUENCE 587caacatcgcc acagacgat 1958819DNAArtificial SequenceTARGETING SEQUENCE 588gacgatgagc gagacaagt 1958919DNAArtificial SequenceTARGETING SEQUENCE 589tggccttcaa actccgcat 1959019DNAArtificial SequenceTARGETING SEQUENCE 590ccatctctct cctgtggat 1959119DNAArtificial SequenceTARGETING SEQUENCE 591tttgataaca gagctatga 1959219DNAArtificial SequenceTARGETING SEQUENCE 592ccattgcggt tccgtcact 1959319DNAArtificial SequenceTARGETING SEQUENCE 593aggagttagg agcctttct 1959419DNAArtificial SequenceTARGETING SEQUENCE 594tgtgagagct atccactct 1959519DNAArtificial SequenceTARGETING SEQUENCE 595cactctcctg cctgcatat 1959619DNAArtificial SequenceTARGETING SEQUENCE 596cgccacacac acacacaaa 1959719DNAArtificial SequenceTARGETING SEQUENCE 597tctacacagt cgccatctt 1959819DNAArtificial SequenceTARGETING SEQUENCE 598tcgccatctt ggtgacttt 1959919DNAArtificial SequenceTARGETING SEQUENCE 599ggttgaccta ggctgaata 1960019DNAArtificial SequenceTARGETING SEQUENCE 600gttgacctag gctgaatat 1960119DNAArtificial SequenceTARGETING SEQUENCE 601ggctgaatat ccactttgt 1960219DNAArtificial SequenceTARGETING SEQUENCE 602agcaagttat caactaatc 1960319DNAArtificial SequenceTARGETING SEQUENCE 603gcaagttatc aactaatca 1960419DNAArtificial SequenceTARGETING SEQUENCE 604ccaaatctag cctctgaat 1960519DNAArtificial SequenceTARGETING SEQUENCE 605ctcctgctct gaatattct 1960619DNAArtificial SequenceTARGETING SEQUENCE 606tgtgtcagat ctactgtaa 1960719DNAArtificial SequenceTARGETING SEQUENCE 607ttgctcttct acctagttt 1960819DNAArtificial SequenceTARGETING SEQUENCE 608cagtgaccgc attggaata 1960919DNAArtificial SequenceTARGETING SEQUENCE 609gaccgcattg gaatataca 1961019DNAArtificial SequenceTARGETING SEQUENCE 610ttcagtaggt ctgatccaa 1961119DNAArtificial SequenceTARGETING SEQUENCE 611cagtaggtct gatccaact 1961219DNAArtificial SequenceTARGETING SEQUENCE 612ggtacattga agaccttaa 1961319DNAArtificial SequenceTARGETING SEQUENCE 613tacattgaag accttaaga 1961419DNAArtificial SequenceTARGETING SEQUENCE 614agaccttaag aagtttcta 1961519DNAArtificial SequenceTARGETING SEQUENCE 615gaccttaaga agtttctaa 1961619DNAArtificial SequenceTARGETING SEQUENCE 616gtttatgttg catgtcagt 1961719DNAArtificial SequenceTARGETING SEQUENCE 617tggtatgaat gatcctgat 1961819DNAArtificial SequenceTARGETING SEQUENCE 618tgaaggagtg ccaaggata 1961919DNAArtificial SequenceTARGETING SEQUENCE 619tgtagcagtt tatcctcat 1962019DNAArtificial SequenceTARGETING SEQUENCE 620gtagcagttt atcctcata 1962119DNAArtificial SequenceTARGETING SEQUENCE 621ctcataatgg aatgataga 1962219DNAArtificial SequenceTARGETING SEQUENCE 622agccattggt tgctgttca 1962319DNAArtificial SequenceTARGETING SEQUENCE 623gccattggtt gctgttcag 1962419DNAArtificial SequenceTARGETING SEQUENCE 624gtaacagttg agtgcaaga 1962519DNAArtificial

SequenceTARGETING SEQUENCE 625taacagttga gtgcaagat 1962619DNAArtificial SequenceTARGETING SEQUENCE 626tgatggatca gccaaccta 1962719DNAArtificial SequenceTARGETING SEQUENCE 627gatggatcag ccaacctaa 1962819DNAArtificial SequenceTARGETING SEQUENCE 628atggatcagc caacctaaa 1962919DNAArtificial SequenceTARGETING SEQUENCE 629gcatagtatg agtaggata 1963019DNAArtificial SequenceTARGETING SEQUENCE 630catagtatga gtaggatat 1963119DNAArtificial SequenceTARGETING SEQUENCE 631ggatatctcc acagagtaa 1963219DNAArtificial SequenceTARGETING SEQUENCE 632gatatctcca cagagtaaa 1963319DNAArtificial SequenceTARGETING SEQUENCE 633agaaaggtgt gtggtacat 1963419DNAArtificial SequenceTARGETING SEQUENCE 634ataacgtgct tccagatca 1963519DNAArtificial SequenceTARGETING SEQUENCE 635taacgtgctt ccagatcat 1963619DNAArtificial SequenceTARGETING SEQUENCE 636agtgtacagt cgccagata 1963719DNAArtificial SequenceTARGETING SEQUENCE 637gtgaacacct gattccaaa 1963819DNAArtificial SequenceTARGETING SEQUENCE 638agcttaatat gccgtgcta 1963919DNAArtificial SequenceTARGETING SEQUENCE 639taatatgccg tgctatgta 1964019DNAArtificial SequenceTARGETING SEQUENCE 640aatatgccgt gctatgtaa 1964119DNAArtificial SequenceTARGETING SEQUENCE 641atatgccgtg ctatgtaaa 1964219DNAArtificial SequenceTARGETING SEQUENCE 642gccgtgctat gtaaatatt 1964319DNAArtificial SequenceTARGETING SEQUENCE 643tgcaagaaat gtggtatgt 1964419DNAArtificial SequenceTARGETING SEQUENCE 644atgctgaatt agcctcgat 1964519DNAArtificial SequenceTARGETING SEQUENCE 645ttgattaaga gcacaaact 1964619DNAArtificial SequenceTARGETING SEQUENCE 646agcagactgt ggactgtaa 1964719DNAArtificial SequenceTARGETING SEQUENCE 647gcagactgtg gactgtaat 1964819DNAArtificial SequenceTARGETING SEQUENCE 648cagactgtgg actgtaata 1964919DNAArtificial SequenceTARGETING SEQUENCE 649taataccaat cgctttcaa 1965019DNAArtificial SequenceTARGETING SEQUENCE 650accaatcgct ttcaagtta 1965119DNAArtificial SequenceTARGETING SEQUENCE 651caatcgcttt caagttagt 1965219DNAArtificial SequenceTARGETING SEQUENCE 652atagagtact atcgtaaca 1965319DNAArtificial SequenceTARGETING SEQUENCE 653ccagcctgct tgagattca 1965419DNAArtificial SequenceTARGETING SEQUENCE 654ctgtagtaga tctacttaa 1965519DNAArtificial SequenceTARGETING SEQUENCE 655accaatgaca tccggatta 1965619DNAArtificial SequenceTARGETING SEQUENCE 656ccaatgacat ccggattat 1965719DNAArtificial SequenceTARGETING SEQUENCE 657caatgacatc cggattata 1965819DNAArtificial SequenceTARGETING SEQUENCE 658ggctatgact tctcaagat 1965919DNAArtificial SequenceTARGETING SEQUENCE 659gcctcatatg cacttatta 1966019DNAArtificial SequenceTARGETING SEQUENCE 660agacctgcgt atggaattt 1966119DNAArtificial SequenceTARGETING SEQUENCE 661acgtctatgt gacttgtaa 1966219DNAArtificial SequenceTARGETING SEQUENCE 662gtctatgtga cttgtaaga 1966319DNAArtificial SequenceTARGETING SEQUENCE 663ttcctacgtg agtgcttta 1966419DNAArtificial SequenceTARGETING SEQUENCE 664gacaatgctc tggaattaa 1966519DNAArtificial SequenceTARGETING SEQUENCE 665ctctggtgat tggatataa 1966619DNAArtificial SequenceTARGETING SEQUENCE 666tgacagagat tgagaacta 1966719DNAArtificial SequenceTARGETING SEQUENCE 667tgagattggc gtggttata 1966819DNAArtificial SequenceTARGETING SEQUENCE 668gcatccgagg cttgtttaa 1966919DNAArtificial SequenceTARGETING SEQUENCE 669accatatcgt ctccatgaa 1967019DNAArtificial SequenceTARGETING SEQUENCE 670ccatatcgtc tccatgaaa 1967119DNAArtificial SequenceTARGETING SEQUENCE 671tgaaagctgc aaagattta 1967219DNAArtificial SequenceTARGETING SEQUENCE 672tcgactgaat gaactctta 1967319DNAArtificial SequenceTARGETING SEQUENCE 673ccatatcgga tttgttgta 1967419DNAArtificial SequenceTARGETING SEQUENCE 674ggttggaaat cctcacaaa 1967519DNAArtificial SequenceTARGETING SEQUENCE 675cttactagtt agaggaaat 1967619DNAArtificial SequenceTARGETING SEQUENCE 676accaccagca ctactatta 1967719DNAArtificial SequenceTARGETING SEQUENCE 677ccaccagcac tactattat 1967819DNAArtificial SequenceTARGETING SEQUENCE 678cagcactact attatgata 1967919DNAArtificial SequenceTARGETING SEQUENCE 679ctatcagtcc ttgtaataa 1968019DNAArtificial SequenceTARGETING SEQUENCE 680attgtctact tcagcaata 1968119DNAArtificial SequenceTARGETING SEQUENCE 681tattggtgat ttcgtcata 1968219DNAArtificial SequenceTARGETING SEQUENCE 682ttcgtcatag gaacattta 1968319DNAArtificial SequenceTARGETING SEQUENCE 683taatgacact atcgtaaca 1968419DNAArtificial SequenceTARGETING SEQUENCE 684gatgtttgct aaaggttat 1968519DNAArtificial SequenceTARGETING SEQUENCE 685cttcgtggct acatcttaa 1968619DNAArtificial SequenceTARGETING SEQUENCE 686tgcacttgga ttcatctta 1968719DNAArtificial SequenceTARGETING SEQUENCE 687gatgatctgt ggccatgta 1968819DNAArtificial SequenceTARGETING SEQUENCE 688ctcgaagaca agccatgaa 1968919DNAArtificial SequenceTARGETING SEQUENCE 689tgaaagagat gtccatcga 1969019DNAArtificial SequenceTARGETING SEQUENCE 690agagatgtcc atcgatcaa 1969119DNAArtificial SequenceTARGETING SEQUENCE 691ccatcgatca agccaaata 1969219DNAArtificial SequenceTARGETING SEQUENCE 692catcgatcaa gccaaatat 1969319DNAArtificial SequenceTARGETING SEQUENCE 693ggtcgtatga agccaaaca 1969419DNAArtificial SequenceTARGETING SEQUENCE 694cacttgtcct tggatttaa 1969519DNAArtificial SequenceTARGETING SEQUENCE 695tagtggttat tcgcctaaa 1969619DNAArtificial SequenceTARGETING SEQUENCE 696atctcatctt caaggacaa 1969719DNAArtificial SequenceTARGETING SEQUENCE 697cgatttagat acttccaaa 1969819DNAArtificial SequenceTARGETING SEQUENCE 698tcattggtgg aaagataaa 1969919DNAArtificial SequenceTARGETING SEQUENCE 699ttagcaagtt ccggataga 1970019DNAArtificial SequenceTARGETING SEQUENCE 700gaaatcattg agccataca 1970119DNAArtificial SequenceTARGETING SEQUENCE 701agcaagatat tgcagataa 1970219DNAArtificial SequenceTARGETING SEQUENCE 702gatgaaccat ggcgaataa 1970319DNAArtificial SequenceTARGETING SEQUENCE 703cattcaagca cagctaata 1970419DNAArtificial SequenceTARGETING SEQUENCE 704ttcagtgcct agtgtagta 1970519DNAArtificial SequenceTARGETING SEQUENCE 705aggaaagttg ctccattga 1970619DNAArtificial SequenceTARGETING SEQUENCE 706aaagttgctc cattgataa 1970719DNAArtificial SequenceTARGETING SEQUENCE 707caatcttaat ggtgattct 1970819DNAArtificial SequenceTARGETING SEQUENCE 708ttgacatcat agtctagta 1970919DNAArtificial SequenceTARGETING SEQUENCE 709gacatcatag tctagtaaa 1971019DNAArtificial SequenceTARGETING SEQUENCE 710gtgtgtgtgt gtgtatata 1971119DNAArtificial SequenceTARGETING SEQUENCE 711gtgtgtgtgt gtatatata 1971219DNAArtificial SequenceTARGETING SEQUENCE 712taggcaaact ttggtttaa 1971319DNAArtificial SequenceTARGETING SEQUENCE 713ggagaatact tcgcctaaa 1971419DNAArtificial SequenceTARGETING SEQUENCE 714tgagtatgac ctaggtata 1971519DNAArtificial SequenceTARGETING SEQUENCE 715agagatctga taacttgaa 1971619DNAArtificial SequenceTARGETING SEQUENCE 716ggtaaagaca gtagaaata 1971719DNAArtificial SequenceTARGETING SEQUENCE 717tttaagctct ggtggatga 1971825RNAArtificial SequenceSENSE STRAND 718cccugaggau ccucaacaau gguca 2571927RNAArtificial SequenceANTISENSE STRAND 719ugaccauugu ugaggauccu caggguu 2772019DNAArtificial SequenceTARGETING SEQUENCE 720ggatggcact tacagattg 1972119DNAArtificial SequenceTARGETING SEQUENCE 721gaaatatgct gcagaactt 1972219RNAArtificial SequenceSENSE STRAND 722cccugaggau ccucaacaa 1972319RNAArtificial SequenceANTISENSE STRAND 723uuguugagga uccucaggg 1972425DNAArtificial SequenceTARGETING SEQUENCE 724ccctgaggat cctcaacaat ggtca 25

Claims

1. 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: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, wherein the expression of an ocular hypertension target mRNA is attenuated.

2. The method of claim 1 wherein the subject is a human and the human has ocular hypertension.

3. The method of claim 1 wherein the subject is a human and the human is at risk of developing ocular hypertension.

4. The method of claim 1 wherein the ocular hypertension target mRNA encodes carbonic anhydrase II, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:1 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.

5. The method of claim 1 wherein the ocular hypertension target mRNA encodes carbonic anhydrase IV, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to SEQ ID NO:2 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:2.

6. The method of claim 1 wherein the ocular hypertension target mRNA encodes carbonic anhydrase XII, and the antisense strand hybridizes under physiological conditions to a portion of mRNA corresponding to 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:101 or SEQ ID NO:134, respectively.

7. The method of claim 1 wherein the antisense strand 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.

8. The method of claim 1 wherein the antisense strand 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.

9. The method of claim 1 wherein the antisense strand 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.

10. The method of claim 1 wherein the antisense strand 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.

11. The method of claim 1 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:1, SEQ ID NO:2, SEQ ID NO:101, 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:101, or SEQ ID NO:134, respectively.

12. The method of claim 1 wherein the sense nucleotide strand and the antisense nucleotide strand are connected by a loop nucleotide sequence.

13. 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.

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

15. 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: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, 322, 328, 371, 412, 482, 504, 505, 541, 734, 772, 777, 814, 972, 998, 1232, or 401, and the interfering RNA has a region of at least near-perfect contiguous complementarity with the hybridizing portion of mRNA corresponding to SEQ ID NO:1; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of 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, 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:2; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of 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, 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:101; or wherein the single-stranded interfering RNA hybridizes under physiological conditions to a portion of 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, 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:134; wherein the expression of an ocular hypertension target mRNA is thereby attenuated.

16. The method of claim 15 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.

17. The method of claim 15 wherein the composition is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

18. 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: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:139, SEQ ID NO:141-SEQ ID NO:219, and SEQ ID NO:721, or a complement thereof, and a pharmaceutically acceptable carrier.

19. The composition of claim 18 wherein the interfering RNA is an shRNA, siRNA, or miRNA.