U.S. patent application number 16/877141 was filed with the patent office on 2020-10-15 for methods for distributing agents to areas of brain.
The applicant listed for this patent is Medtronic, Inc.. Invention is credited to Lisa L. Shafer, Greg Stewart, Deepak Ramesh Thakker.
Application Number | 20200323897 16/877141 |
Document ID | / |
Family ID | 1000004918004 |
Filed Date | 2020-10-15 |
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United States Patent
Application |
20200323897 |
Kind Code |
A1 |
Thakker; Deepak Ramesh ; et
al. |
October 15, 2020 |
METHODS FOR DISTRIBUTING AGENTS TO AREAS OF BRAIN
Abstract
Broad cerebrospinal fluid (CSF) distribution of an agent is
achievable by delivering the agent in a liquid formulation to the
CSF at flow rates less than 500 microliters per hour, such as
between about 2 microliters per hour and about 100 microliters per
hour.
Inventors: |
Thakker; Deepak Ramesh;
(Blaine, MN) ; Shafer; Lisa L.; (Stillwater,
MN) ; Stewart; Greg; (Plymouth, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medtronic, Inc. |
Minneapolis |
MN |
US |
|
|
Family ID: |
1000004918004 |
Appl. No.: |
16/877141 |
Filed: |
May 18, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13267243 |
Oct 6, 2011 |
10653713 |
|
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16877141 |
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61405363 |
Oct 21, 2010 |
|
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61390266 |
Oct 6, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 49/143 20130101;
A61K 31/711 20130101; A61M 5/14276 20130101; A61M 5/16804 20130101;
A61M 2205/50 20130101; A61M 2210/0693 20130101; A61K 49/105
20130101 |
International
Class: |
A61K 31/711 20060101
A61K031/711; A61K 49/10 20060101 A61K049/10; A61K 49/14 20060101
A61K049/14; A61M 5/168 20060101 A61M005/168; A61M 5/142 20060101
A61M005/142 |
Claims
1-22. (canceled)
23. A method comprising: selecting a subject for which delivery of
a therapeutic or diagnostic molecule to cerebrospinal fluid (CSF)
of a brain is desired; and administering a liquid formulation
comprising the molecule to an CSF-containing intrathecal space of
the subject at a flow rate of less than 500 microliters per hour,
wherein the liquid formulation is administered for a period of time
sufficient to reach a steady state concentration in CSF of the
brain.
24. A method according to claim 23, wherein the liquid formulation
is administered at a flow rate of less than 200 microliters per
hour.
25. A method according to claim 23, wherein the liquid formulation
is administered at a flow rate of between about 4 microliters per
hour and about 100 microliters per hour.
26. A method according to claim 23, wherein the liquid formulation
is administered at a flow rate of between about 2 microliters per
hour and about 25 microliters per hour.
27. A method according to claim 23, wherein the liquid formulation
is delivered via a catheter having a delivery region placed in the
CSF-containing space.
28. A method according to claim 27, wherein the CSF-containing
space is selected from the group consisting of lumbar intrathecal
space, thoracic intrathecal space, and cervical intrathecal
space.
29. A method according to claim 23, wherein the molecule is a
therapeutic molecule and wherein the steady state concentration is
a therapeutically effective concentration.
30. A method according to claim 29, further comprising
administering the liquid formulation at a second slower rate for a
period of time sufficient to reduce the concentration of the
molecule in the CSF.
31. A method according to claim 30, wherein the liquid formulation
is administered via a catheter, and wherein the second slower rate
is sufficient to keep the catheter patent.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority to US
Provisional Application Nos. 61/390,266 and 61/405,363, filed on
Oct. 6, 2010 and Oct. 21, 2010, which applications are hereby
incorporated herein by reference in their respective entireties to
the extent that they do not conflict with the present
disclosure.
FIELD
[0002] This disclosure relates to methods for delivering agents,
such as therapeutic or diagnostic agents, to a brain; and, more
particularly, to methods of achieving distribution of the agent to
desired locations of the brain and spinal cord, collectively
comprising the Central Nervous System (CNS).
BACKGROUND
[0003] A variety of agents have been administered to the
cerebrospinal fluid (CSF), such as through intracerebroventricular
(ICV) or intrathecal (IT) bolus infusion. Typically, these agents
are administered acutely through a single, bolus infusion at flow
rates in the range of about 0.5 to 12 ml/min. At such high delivery
rates, the agents can achieve wider distribution within the central
nervous system (CNS), albeit transiently.
[0004] However, at lower flow rates, such as less than 1 ml/day,
studies report that the distribution of the agent in the CSF is
limited. For example, one study reported the distribution of a
small molecule agent within the CSF following IT infusion at a rate
of 20 microliters per hour was limited to less than 5 cm of the
spinal cord relative to the infusion site.
[0005] In many situations and for many reasons, it would be
desirable to administer an agent at a low flow rate to a subject's
CSF; e.g. when using a chronically implanted infusion device, but
achieve broad distribution of the agent in the subject's CNS.
SUMMARY
[0006] The present disclosure presents results demonstrating that
agents may be broadly distributed in a subject's CSF when delivered
to the CSF at low flow rates, such as less than 1 ml per hour, less
than 0.5 ml per hour, over prolonged periods of time. Prior studies
at such low infusion rates concluded that CSF distribution is
limited. However, as disclosed herein, broad CSF distribution is
obtained with such low infusion rates. Further, broad distribution
is achieved at low flow rates regardless of whether the infused
molecule is a small molecule or a large molecule.
[0007] We demonstrate that a widespread distribution of small or
large molecules can be achieved in the CSF and also into the CNS
tissue upon administration of the molecules into the CSF at low
flow rates, particularly for a duration that allows the
establishment and maintenance of steady state levels in the CSF.
Steady state refers to the scenario wherein the amount of molecule
delivered into the CSF is equal to the amount of molecule cleared
from the CSF, such that roughly constant levels of the molecule are
maintained in the CSF at any given time. In this regard, the CSF
turnover/production rate of the subject is an important factor in
determining the time required to clear the administered molecule
from the CSF, and thereby, also the time required to achieve steady
state in the CSF.
[0008] In embodiments, a method for delivering a molecule to the
cerebrospinal fluid (CSF) of a subject is described. The method
includes administering a liquid formulation comprising the molecule
directly to the CSF, for example to the intrathecal space of the
subject at a flow rate of less than 500 microliters per hour. The
liquid formulation may be administered at any suitable flow rate,
such as less than 200 microliters per hour or between about 4
microliters per hour and about 100 microliters per hour, or between
about 2 microliters per hour and about 25 microliters per hour. The
molecule may have any suitable molecular weight, such as less than
5 kDa. (e.g., a small molecule), greater than 5 kDa (e.g., is not
small), between about 5 kDa and about 15 kDa (e.g., a mid-sized
biologic such as small peptides, antisense DNA, antisense RNA, and
short interfering (si)RNA), between about 15 kDa and about 200 kDa
(e.g., a large-sized biologic such as proteins and antibodies), or
greater than about 200 kDa (e.g., a very large protein/biologic
such as DNA, DNA-protein complexes, or virus, phage). The liquid
formulation may be administered to the CSF in any suitable manner,
such as via an implantable infusion device. In some embodiments,
the liquid formulation is introduced into the subject's CSF via a
catheter. The catheter may have a delivery region through which the
molecule is configured to exit, and the delivery region may be
positioned in a lumbar, thoracic, or cervical region of the
subject's spinal intrathecal space, the cerebral ventricles, the
subdural space (for example overlying the cerebral cortex), or any
other place where CSF may be safely accessed.
[0009] In embodiments, a method for delivering a molecule to CSF of
a brain of a subject is described. The method includes
administering a liquid formulation comprising the molecule to a
CSF-containing space of the subject at a flow rate of less than 500
microliters per hour. The liquid formulation may be administered at
any suitable flow rate, such as less than 200 microliters per hour
or between about 4 microliters per hour and about 100 microliters
per hour or between about 2 microliters per hour and about 25
microliters per hour. The molecule may have any suitable molecular
weight, such as less than 5 kDa, greater than 5 kDa, between about
5 kDa and about 15 kDa, between about 15 kDa and about 200 kDa, or
greater than about 200 kDa. The liquid formulation may be
administered to the CSF in any suitable manner, such as via an
implantable infusion device. In some embodiments, the liquid
formulation is introduced into the subject's intrathecal space via
a catheter. The catheter may have a delivery region through which
the molecule is configured to exit, and the delivery region may be
positioned in a lumbar, thoracic or cervical region of the
subject's spinal canal.
[0010] In embodiments, a method for broadly distributing a molecule
in the CSF of a subject. The method includes administering a liquid
formulation comprising the molecule to a CSF-containing space of
the subject at a flow rate of less than 500 microliters per
hour.
[0011] In embodiments, the present disclosure describes a method
for broadly distributing a molecule in the CSF of a subject. The
method includes administering a fluid composition comprising the
molecule to the subdural or epidural space of the subject at a flow
rate of less than 500 microliters per hour.
[0012] In embodiments, systems described herein include implantable
infusion devices configured, or programmed with instructions, to
carryout the methods described herein.
[0013] One or more embodiments described herein present one or more
advantages over existing devices, systems and methods for achieving
broad distribution of a molecule in a patient's CSF. For example,
achieving broad CSF distribution of a molecule at low flow rates
allows one to realize advantages associated with implantable
infusion devices, which are capable of delivering at flow rates of
less than 500 microliters per hour. Additionally, molecules can be
delivered to the brain via intrathecal administration at such low
flow rates, avoiding the need to penetrate brain tissue associated
with ICV or intraparenchymal (IPA) delivery. These and other
advantages will be evident to those of skill in the art upon
reading the disclosure presented herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a schematic drawing of a section of a brain and
portions of a spinal cord showing cerebrospinal fluid flow.
[0015] FIG. 2 is a schematic drawing of a side view of a
representative infusion device system.
[0016] FIG. 3 is a schematic drawing of a view of an infusion
device and associated catheter implanted in a patient.
[0017] FIG. 4 is a schematic drawing of a view of a section of a
patient showing an implanted infusion device and associated
catheter implanted.
[0018] FIG. 5 is a schematic drawing of a view showing an injection
port in the environment of a patient.
[0019] FIG. 6 shows MRI images of a rhesus monkey receiving
intrathecal administration of Gd-DTPA at the lumbar level (L2) at
various flow rates: (Panel A) prior to infusion of Gd-DTPA, (Panel
B) 0.1 ml/day, (Panel C) 0.4 ml/day, (Panel D) 1.2 ml/day and
(Panel E) 2.4 ml/day.
[0020] FIG. 7 shows MM images (axial views showing the brain Panels
A-B, and spinal cord Panels C-D) of a rhesus monkey receiving 70
mg/ml Gd-DTPA at a rate of 2.4 ml/day (100 microliters/hour)
intrathecally at L2 (Panels B, D). Panels A and C show the monkey
prior to administration of the Gd-DTPA.
[0021] FIG. 8 shows MRI images of rhesus monkeys receiving various
concentrations of Gd-DPTA intracerebroventricularly at various flow
rates: (A) prior to infusion of the Gd-DPTA; (B) 486 mg/ml at 0.048
ml/day; (C) 280 mg/ml at 0.1 ml/day; (D) 70 mg/ml at 0.4 ml/day;
(E) 35 mg/ml at 0.8 ml/day; (F) 22 mg/ml at 1.2 ml/day.
[0022] FIG. 9 shows MRI images of a rhesus monkeys receiving
various concentrations of Gd-albumin intrathecally at various flow
rates: (Panel A) prior to infusion of the Gd-albumin; (Panel B) 100
mg/ml at 0.1 ml/day; (Panel C) 100 mg/ml at 0.4 ml/day; (Panel D)
34 mg/ml at 1.2 ml/day; and (Panel E) 17 mg/ml at 2.4 ml/day.
[0023] FIG. 10 shows MRI images of a rhesus monkey receiving 100
mg/ml Gd-albumin intrathecally at various flow rates: (Panel A)
prior to infusion of Gd-albumin; (Panel B) 0.1 ml/day; (Panel C)
2.4 ml/day; Panel D is a view of a different slice of the brain of
the image presented in Panel C; and Panel E s a view of the
relatively caudal spinal region of the image presented in Panel
C.
[0024] FIG. 11 shows MM images of a rhesus monkey receiving various
concentrations of Gd-albumin intracerebroventricularly at various
flow rates: (Panel A) prior to infusion; (Panel B) 100 mg/ml at 0.1
ml/day at one day of infusion; (Panel C) 100 mg/ml at 0.4 ml/day at
one day of infusion; (Panel D) 100 mg/ml at 0.4 ml/day at three
days of infusion; (Panel E) 100 mg/ml at 0.8 ml/day at one day of
infusion; and (Panel F) 64 mg/ml at 1.2 ml/day at one day of
infusion.
[0025] The schematic drawings are not necessarily to scale. Like
numbers used in the figures refer to like components, steps and the
like. However, it will be understood that the use of a number to
refer to a component in a given figure is not intended to limit the
component in another figure labeled with the same number. In
addition, the use of different numbers to refer to components is
not intended to indicate that the different numbered components
cannot be the same or similar.
DETAILED DESCRIPTION
[0026] The following description illustrates various embodiments.
It is to be understood that other embodiments are contemplated and
may be made without departing from the scope or spirit of the
present invention. Thus, the following description is not to be
taken in a limiting sense.
[0027] All scientific and technical terms used in this application
have meanings commonly used in the art unless otherwise specified.
The definitions provided herein are to facilitate understanding of
certain terms used frequently herein and are not meant to limit the
scope of the present disclosure.
[0028] As used herein, the singular forms "a", "an", and "the"
encompass embodiments having plural referents, unless the content
clearly dictates otherwise.
[0029] As used herein, the term "or" is generally employed in its
sense including "and/or" unless the content clearly dictates
otherwise.
[0030] As used herein, "have", "having", "include", "including",
"comprise", "comprising" or the like are used in their open ended
sense, and generally mean "including, but not limited to".
[0031] As used herein, the terms "treat" or the like means
alleviating, slowing the progression, preventing, attenuating, or
curing the treated disease.
[0032] As used herein, "disease", "disorder", "condition" or the
like, as they relate to a subject's health, are used
interchangeably and have meanings ascribed to each and all of such
terms.
[0033] As used herein, "subject" means a mammal to which an agent
is administered for the purposes of treatment or investigation.
Mammals include mice, rats, cats, guinea pigs, hamsters, dogs,
sheep, monkeys, chimpanzees, and humans.
[0034] As used herein, a "liquid formulation of a molecule" is a
composition that contains the molecule and that is liquid at room
temperature and at 37.degree. C.
[0035] As used herein, an "interfering RNA molecule" is a
synthetic, double-stranded oligoribonucleotide that selectively
contributes to the degradation of endogenous or pathogenic target
RNA and reduces levels of the corresponding protein. Interfering
RNA molecules (iRNAs) typically have a molecular weight between
about 5 kDa and 15 kDa. WO 2011/008992 describes additional details
regarding iRNAs, which PCT publication is hereby incorporated
herein by reference in its entirety to the extent that it does not
conflict with the disclosure presented herein. In embodiments
described herein, a molecule in a liquid formulation is any
molecule other than an iRNA.
[0036] As used herein, an "iRNA configured to inhibit expression of
a Huntington protein" is an iRNA that, when introduced to or into a
cell, tissue, subject, or the like that expresses a Huntington
protein, results in decreased levels of the Huntington protein. WO
2011/008992 describes additional details regarding Huntington
proteins, which PCT publication is hereby incorporated herein by
reference in its entirety to the extent that it does not conflict
with the disclosure presented herein. In embodiments described
herein, a molecule in a liquid formulation is any molecule other
than an iRNA configured to inhibit expression of a Huntington
protein.
[0037] The present disclosure relates to achieving broad
distribution of molecules in CSF of a subject by delivering the
molecules in a liquid formulation at a flow rate of less than 1 ml
per hour, such as less than 500 microliters per hour and for a
duration that is up to or longer than that required to achieve
steady state (the latter may be approximated based on the known
turnover rate of CSF). Prior studies of such low infusion rates
concluded that CSF distribution is extremely limited. However, as
disclosed herein, broad CSF distribution is obtained with these low
infusion rates. Further, broad distribution is achieved at low flow
rates regardless of whether the infused molecule is a small
molecule or a large molecule.
[0038] According to various embodiments, a liquid formulation
containing a molecule of interest may be delivered directly to
cerebrospinal fluid 6 of a subject. Referring to FIG. 1,
cerebrospinal fluid (CSF) 6 exits the foramen of Magendie and
Luschka to flow around the brainstem and cerebellum. The arrows
within the subarachnoid space 3 in FIG. 2 indicate cerebrospinal
fluid 6 flow. The subarachnoid space 3 is a compartment within the
central nervous system that contains cerebrospinal fluid 6. The
cerebrospinal fluid 6 is produced in the ventricular system of the
brain and communicates freely with the subarachnoid space 3 via the
foramen of Magendie and Luschka. A liquid formulation including a
molecule of interest may be delivered to cerebrospinal fluid 6 of a
subject anywhere that the cerebrospinal fluid 6 is accessible. For
example, the composition may be administered intrathecally (e.g.,
at a lumbar, sacral, thoracic or cervical level or into the
cisterna magna), intracerebroventricularly, or the like. In some
embodiments, the fluid composition is administered subdurally, for
example by delivery of drug to the CSF over the cortical
convexities of the brain.
[0039] Any suitable molecule may be delivered. The results
presented in the Examples herein below illustrate that the molecule
may be of any suitable size. It is envisioned that a small molecule
(less than about 5 kDa) or large molecule (greater than about 5
kDa) may be administered to the CSF at low flow rates to achieve
broad CSF distribution. It is contemplated that various classes of
large molecules may be administered. For example, mid-sized
biologics such as polypeptides, larger-sized biologics such as
antibodies, and even larger sized biologics such as proteins may be
administered at low flow rates into the CSF to achieve broad
distribution. As used herein, "broad distribution" means that a
molecule is distributed generally throughout most, if not all, of
the region of interest. For example, if brain CSF is the region of
interest, then the molecule will be generally distributed
throughout the CSF compartments in and surrounding the brain. If
the CSF in general is the region of interest, a molecule delivered
to a specific location of the CSF is considered to be broadly
distributed in the CSF if, after delivery, the molecule is present
throughout the CSF.
[0040] The molecule may be a therapeutic agent, a diagnostic agent,
or the like. In general, a therapeutic agent is an agent intended
to treat a disease, while a diagnostic agent is an agent intended
to aid in identifying a condition or disease of a subject, the
presence or absence of a molecule in a subject, or the like. For
example, the molecule may be any known or future developed small
molecule or biologic therapeutic agent. Examples of biologic
therapeutic agents that may be employed in accordance with the
teachings presented herein include antibodies or fragments thereof;
inhibitory RNA molecules such as antisense RNA, microRNA (miRNA),
small interfering RNA (siRNA), or the like; DNA; polypeptides;
proteins; viruses, vectors or the like. The molecules may be used
for therapeutic, diagnostic or investigatory purposes.
[0041] Generally, the molecules will be formulated into a liquid
formulation suitable for delivery to the CSF. The formulation may
include the molecule and a variety of other pharmaceutically
acceptable components. See Remington's Pharmaceutical Science (15th
ed., Mack Publishing Company, Easton, Pa. (1980)). The preferred
form may depend on the intended application. The formulations may
also include, depending on the formulation desired,
pharmaceutically-acceptable, non-toxic carriers or diluents, which
are defined as vehicles commonly used to formulate pharmaceutical
compositions for animal or human administration. In most cases, the
diluent is selected so as not to adversely affect the activity of
the molecule of interest. Examples of such diluents are distilled
water, physiological phosphate-buffered saline, artificial
cerebrospinal fluid, citrate buffered saline, Ringer's solutions,
dextrose solution, and Hank's solution.
[0042] Typically the liquid formulations are formed as injectable
compositions. Injectable compositions include solutions,
suspensions, dispersions, or the like. Injectable solutions,
suspensions, dispersions, or the like may be formulated according
to techniques well-known in the art (see, for example, Remington's
Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co.,
Easton, Pa.), using suitable dispersing or wetting and suspending
agents, such as sterile oils, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0043] Proper fluidity of solutions, suspensions or dispersions may
be maintained, for example, by the formation of liposomes, by the
maintenance of the desired particle size, in the case of
dispersion, or by the use of nontoxic surfactants.
[0044] The prevention of microorganisms can be accomplished by heat
sterilization or filter sterilization, whichever is compatible with
the molecule and formulation being used. Isotonic agents such as
sugars, buffers, or sodium chloride may be included. Solubility
enhancers may be added.
[0045] In various embodiments, the final formulation is adjusted to
have a pH between about 4 and about 9, between about 5 and about 7,
between about 5.5 and about 6.5, or about 6. The pH of the
composition may be adjusted with a pharmacologically acceptable
acid, base or buffer. Hydrochloric acid is an example of a suitable
acid, and sodium hydroxide is an example of a suitable base. The
hydrochloric acid or sodium hydroxide may be in any suitable form,
such as a 1N solution
[0046] In various embodiments, a resultant fluid composition
contains an amount of one or more molecules effective to treat a
disease to allow meaningful study of a subject to which the
composition is administered at a particular flow rate. The
effective amount of the molecule to be administered will vary
depending on the molecule itself and the disease to be treated. The
amount may also vary depending on the subject to which it is
administered and the location of administration (e.g., IT vs.
ICV).
[0047] The liquid formulation containing the molecule of interest
may be administered to the CSF in any suitable manner. In various
embodiments, a system including an infusion device is used to
deliver a liquid formulation containing a molecule of interest to
subject. The system may further include a catheter operably coupled
to the infusion device. The infusion device may include a drive
mechanism or pump, such as a piston pump, peristaltic pump,
positive pressure reservoir, or the like. Non-limiting examples of
infusion devices include osmotic pumps, fixed-rate pumps,
programmable pumps and the like. Each of the aforementioned pump
systems contains a reservoir for housing the fluid composition and
an outlet in fluid communication with the reservoir. The catheter
may be operably coupled to the outlet. The catheter includes one or
more delivery regions, through which the fluid may be delivered to
one or more target regions of the subject. The infusion device may
be implantable or may be placed outside the body via an
externalized catheter outside the body, external to the subject.
Alternatively an implanted port that is in direct communication
with a CSF compartment via a catheter can be accessed on an
intermittent basis and drug infused over the desired duration using
an external pump delivering the drug at an appropriate rate as
described herein.
[0048] The liquid formulation may be administered at any suitable
rate to the subject's CSF to achieve broad distribution. In many
embodiments, the composition is administered at a rate of less than
1 ml per hour, such as less than 500 microliters per hour. For
example, the composition may be administered at a rate of less than
200 microliters per hour or between about 4 microliters per hour
and 100 microliters per hour or between about 2 microliters per
hour and 25 microliters per hour. It will be understood flow rates
per hour may be converted to flow rates per minute, per second, per
day, etc. using appropriate conversion factors and that, when
properly converted, such flow rates are considered equivalent.
[0049] The infusion device may be configured to deliver the liquid
formulation at these rates. By way of example, the infusion device
may include electronics configured to control the rate at which the
liquid formulation may be delivered from the reservoir to the
outlet. In embodiments, the electronics are programmed with
instructions that cause the liquid formulation to be delivered at
the desired rates.
[0050] Based on the EXAMPLES provided below, it has been found that
for Rhesus monkeys a constant flow rate of greater than about 0.1
ml/day of an agent into the CSF over a period of 1 through 3 days
was sufficient to cause wide distribution in the CSF. For example,
flow rates of between 0.4 ml/day and 2.4 ml/day over a period of 1
through 3 days were effective in broadly distributing agents
throughout the CSF. Further, flow rates in the range of 0.048
ml/day and 0.1 mL/day also distributed the test articles in the CSF
given sufficient time for infusion to allow for test article levels
in the CSF to reach steady state. For example, the steady state
distribution of Gd-DTPA infused intracerebroventricularly at 0.1
mL/day demonstrated a complete CSF coverage, and that infused at
0.048 mL/day was evident in the CSF compartments in and around the
brain, but not the spinal cord. Therefore, in addition to
demonstrating that prolonged infusion at low flow rates can
distribute the infused molecules widely into the CSF compartments,
we also show the significance of selecting an appropriate flow rate
for the desired extent of CSF distribution of the infused
molecule.
[0051] We found that the molecular weight of an infused molecule
also contributes towards its distribution within the CSF of Rhesus
monkeys. In this case, steady state CSF levels of the infused
molecule are subject to the size of the test article. For example,
the test article of molecular weight .about.600 Da, Gd-DTPA,
distributed broadly throughout the CSF in and around the brain and
spinal cord, when infused intracerebroventricularly at a flow rate
of 0.1 mL/day for a period of 6 hours. Relative to the 600 Da
Gd-DTPA, the distribution of 74,000 Da Gd-albumin was largely
confined to the CSF in and around the brain, and not in the spinal
cord. Consequently, flow rates for prolonged infusion of test
articles can be selected based on the molecule's size to achieve
the desired CSF coverage at steady state.
[0052] Further, we also demonstrate the significance of selecting
an appropriate infusion site to achieve the desired distribution of
the infused molecule. For example, ICV infusion at 0.4 mL/day
resulted in a narrower distribution of Gd-albumin (74,000 Da) in
the CSF over a period of 3 days, whereas intrathecal lumbar
infusion at the same flow rate widely distributed the same molecule
throughout the CSF within 1 day. Differences in CSF distribution
upon ICV versus IT infusion were also evident with Gd-DTPA (600
Da), wherein ICV infusion at 0.1 mL/day flow rate provided complete
CSF coverage for the molecule, while IT infusion confined the
molecule in the IT space.
[0053] Collectively, our data reflect the importance of selecting a
combination of factors, including the time to allow the infused
test article to reach steady state, infusion target site, infusion
flow rate, and the molecular weight of the molecule in order to
achieve the predetermined distribution of the molecule in the CNS.
Due to differences in CSF volume and turnover between monkey and
humans some scaling may be desirable for achieving similar
distribution of an agent in humans. Table 1 below provides some
parameters of SCF in Rhesus monkeys and humans and provides some
insights as to how scaling may be achieved.
TABLE-US-00001 TABLE 1 CSF parameters of Rhesus monkey and human
CSF turnover/hr Avg. CSF volume Avg. turnover rate Monkey 16% 13 ml
2.1 ml/hr Human 16% 125 ml 20 ml/hr
[0054] As shown in Table 1, the volume of the CSF of an average
adult human is about 10 times greater than the volume of a mature
Rhesus monkey. Accordingly, scaling in terms of flow rate may be
increased about 10 fold in humans relative to Rhesus monkeys. That
is, flow rates of greater than about 1 ml/day may be useful in
broadly distributing an agent administered to CSF of a human. For
example, flow rates of about 2 ml/day, 3 ml/day, 4 ml/day, 5
ml/day, 10 ml/day, 20 ml/day, or the like, or greater may be
suitable for achieving broad distribution in humans. Such a scaling
factor is supported by the fact that many humans receiving
intrathecal morphine or baclofen at constant rates of 0.5 ml/day do
not appear to suffer from any supraspinal side effects, suggesting
that the drugs do not reach the brain in appreciable
concentrations.
[0055] Alternatively, as the CSF turnover rate is similar between
Rhesus monkeys and humans (see Table 1), it is possible that
scaling on this basis (approximately 1:1) can achieve similar
distribution in monkeys and humans--particularly if CSF turnover is
a significant factor for movement of an agent throughout the CSF.
However, to achieve a similar effect in humans and rhesus monkeys a
10 fold higher concentration of agent may be desired due to the
difference in CSF volume, assuming similar distribution with
similar flow rates.
[0056] Likely, appropriate scaling is somewhere between the two
scenarios described above. For example, suitable flow rates of
between 1 and 10 times higher in humans than in monkeys with
corresponding concentrations of between 10 and 1 times higher in
humans than in monkeys may result similar effects in humans with
similar distribution between the two species.
[0057] Appropriate scaling between other species may be determined
in a manner similar to that outlined above with regard to Rhesus
monkeys and humans.
[0058] In any case, it may be desirable to limit the volume of
therapeutic or diagnostic composition administered to the CSF of a
subject to avoid adverse effects such as hydrocephalus or the like.
For example, it may be desirable to limit the volume of therapeutic
or diagnostic composition delivered per day to about 25% or less,
about 20% or less, about 15% or less, or about 10% or less, about
5% or less, or about 2% or less of the CSF volume of the subject to
which the composition is delivered. By way of example, 25% of the
CSF volume of a typical adult human is about 30 ml, and 10% of the
CSF volume is about 12.5 ml.
[0059] To achieve a suitable flow rate to achieve broad
distribution while conserving on the amount or volume delivered, a
therapeutic or diagnostic composition may be delivered to a
subject's CSF in pulsatile or episodic manner, as a controlled and
programmed therapy rather than at a constant rate. For example, a
therapeutic agent may be administered at a sufficiently high flow
rate and duration to achieve desired distribution within the CNS,
and then the flow rate would be reduced to a very low level for a
prolonged period of time (days to weeks) to conserve drug and also
maintain patency of the catheter. This pattern may be repeated on a
chronic basis. It will be understood that nearly any other
pulsatile dosage regimen may be employed and that the regimens
discussed above are merely examples.
[0060] In some embodiments, between about 10 ml and 100 ml of a
therapeutic or diagnostic composition is delivered to the CSF of a
subject per month; e.g., about 20 ml/month or about 40 ml/month. A
desired pulsatile delivery regimen may thus be calculated based on
this desired volume. By way of example, if a flow rate of 2.4 ml
per day is suitable to achieve desired CSF distribution and if it
is desired to deliver 20 ml or less per month, the composition may
be delivered at a rate of about 0.0017/min for one minute, every
four minutes (or 15 times an hour). This would result in delivery
of about 0.0255 ml/hour, 0.612 ml/day, or about 18.36 ml/month
(assuming 30 days in a month). The rate, duration, and frequency of
delivery may be modified as desired to achieve desired distribution
and desired delivery volumes.
[0061] Preferably, the rate, duration, and frequency of delivery
are determined such that an appropriate steady state concentration
of therapeutic or diagnostic agent is achieved at desired CSF
location. For example, if a therapeutic agent is delivered at an
intrathecal location with the intention of having an effect at the
brain, it would be desirable for steady state concentrations of the
therapeutic agent in the CSF at, for example, the ventricles to be
sufficiently high to be effective for treating a disease state. It
will be understood that the CSF turnover rate and the tendency for
the agent to diffuse out of the CSF may be accounted for in
determining appropriate rates, durations, and frequencies of
delivery, as well as concentrations of therapeutic agent.
[0062] To assist in obtaining such dosage regimens, an infusion
system may be employed. An example of an infusion system that may
be employed is shown in FIG. 2. The system includes an infusion
device 30 having a reservoir 12 for housing a fluid composition and
a pump 40 operably coupled to the reservoir 12. The system further
includes a catheter 38 having a proximal end 35 coupled to the
infusion device 30 and a distal end 39 configured to be implanted
in a target location of a subject. Between the proximal end 35 and
distal end 39 or at the distal end 39, the catheter 38 has one or
more delivery regions (not shown), such as openings, through which
the fluid composition may be delivered. The infusion device 30 may
have a port 34 into which a hypodermic needle can be inserted to
inject the composition into the reservoir 12. The infusion device
30 may have a catheter port 37, to which the proximal end 35 of
catheter 38 may be coupled. The catheter port 37 may be operably
coupled to reservoir 12. The infusion device 30 may be operated to
discharge a predetermined dosage of the pumped fluid into a target
region of a subject at a predetermined rate. The infusion device 30
may contain a microprocessor 42 or similar electronics that can be
programmed to control the amount and rate of fluid delivery. The
programming may be accomplished with an external programmer/control
unit via telemetry. With the use of a programmable infusion device
30, dosage regimens may be programmed and tailored for a particular
subject. Additionally, different dosages can be programmed for
different combinations of fluid compositions. Those skilled in the
art will recognize that a programmable infusion device 30 allows
for starting conservatively with lower doses and adjusting to a
more aggressive dosing scheme, if warranted, based on safety and
efficacy factors when used for therapeutic purposes.
[0063] FIG. 3 illustrates an example of an infusion system
configured for intrathecal delivery of a composition containing a
molecule of interest. As shown in FIG. 3, a system or device 30 may
be implanted below the skin of a patient. Preferably the device 30
is implanted in a location where the implantation interferes as
little as practicable with activity of the subject in which it is
implanted. One suitable location for implanting the device 30 is
subcutaneously in the lower abdomen. In various embodiments,
catheter 38 is positioned so that the distal end 39 of catheter 38
is located in the subarachnoid space 3 of the spinal cord such that
a delivery region (not shown) of catheter is also located within
the subarachnoid space 3.
[0064] In many embodiments, a composition containing a molecule is
administered intrathecally at a low flow rate to achieve
distribution of the molecule in the brain. Intrathecal
administration provides several advantages to administration
directly to the brain or ICV administration. Primarily, intrathecal
administration allows one to avoid placement of a catheter or
cannula through parenchymal tissue of the brain to reach a desired
location or the cerebral ventricle. Accordingly, the subject to
which the molecule is delivered is spared a great deal of risk and
discomfort with IT delivery relative to ICV delivery. Further, the
time involved with surgical procedures for delivering a molecule
intrathecally is significantly less than delivering the molecule
intracerebroventricularly.
[0065] However, in some embodiments, a composition containing a
molecule of interest is delivered intraparenchymally or
intracerebroventricularly. For example, for ICV delivery, a
catheter may be operably coupled to the infusion device and a
delivery region of the catheter may be placed in the ventricle.
[0066] One suitable system for administering a therapeutic agent to
the brain is discussed in U.S. Pat. No. 5,711,316 (Elsberry).
Referring to FIG. 4, a system or infusion device 10 may be
implanted below the skin of a subject. The device 10 may have a
port 14 into which a hypodermic needle can be inserted through the
skin to inject a quantity of a composition comprising the molecule
of interest. The composition is delivered from device 10 through a
catheter port 20 into a catheter 22. Catheter 22 is positioned to
deliver the agent to a cerebral ventricle 115 in the brain (B).
Device 10 may take the form of the like-numbered device shown in
U.S. Pat. No. 4,692,147 (Duggan), assigned to Medtronic, Inc.,
Minneapolis, Minn., take the form of a SynchroMed II infusion
device (Medtronic, Inc.), or take the form of any currently
available or future developed infusion device. In the depicted
embodiment, the distal end of catheter 22 terminates in a
cylindrical hollow tube 22A having a distal end implanted in the
ventricle 115 by conventional stereotactic surgical techniques.
Tube 22A is surgically implanted through a hole in the skull 123
and catheter 22 is implanted between the skull and the scalp 125 as
shown in FIG. 4. Catheter 22 may be coupled to implanted device 10
in the manner shown or in any other suitable manner.
[0067] Referring to FIG. 5, a molecule of interest may be delivered
to a subject's CSF via an injection port 10 implanted
subcutaneously in the scalp of a patient 1, e.g. as described in
U.S. Pat. No. 5,954,687 or otherwise known in the art. A guide
catheter 10 may be used to guide an infusion catheter through port
10 to a target location. Of course, an infusion catheter may be
directly be inserted through port 10 to the target location. Such
ports 10 may also be employed to deliver the molecule
intrathecally.
[0068] Any other known or developed implantable or external
infusion device or port may be employed.
[0069] A brief summary of various aspects of methods, systems and
devices described herein are presented below:
[0070] A 1.sup.st aspect is a method for delivering a therapeutic
or diagnostic molecule to cerebrospinal fluid (CSF) of a brain of a
subject that includes administering a liquid formulation comprising
the molecule to an CSF-containing intrathecal space of the subject
at a flow rate of less than 500 microliters per hour, wherein the
liquid formulation is administered for a period of time sufficient
to reach a steady state concentration in CSF of the brain, and
wherein the molecular weight of the molecule is less than 5 kDa,
between 15 kDa and 200 kDa, greater than 200 kDa, or a polypeptide
or antisense DNA having a molecular weight of between 5 kDa and 15
kDa.
[0071] A 2.sup.nd aspect is a method of aspect 1, wherein the
liquid formulation is administered at a flow rate of less than 200
microliters per hour.
[0072] A 3rd aspect is a method of aspect 1, wherein the liquid
formulation is administered at a flow rate of between about 4
microliters per hour and about 100 microliters per hour.
[0073] A 4.sup.th aspect is a method of aspect 1, wherein the
liquid formulation is administered at a flow rate of between about
2 microliters per hour and about 25 microliters per hour.
[0074] A 5.sup.th aspect is a method according to any of aspects
1-4, wherein the liquid formulation is delivered via a catheter
having a delivery region placed in the CSF-containing space.
[0075] A 6.sup.th aspect is a method of aspect 5, wherein the
CSF-containing space is selected from the group consisting of
lumbar intrathecal space, thoracic intrathecal space, and cervical
intrathecal space.
[0076] A 7.sup.th aspect is a method according to any of aspects
1-6, wherein the molecule is a therapeutic molecule and wherein the
steady state concentration is a therapeutically effective
concentration.
[0077] An 8.sup.th aspect is a method according to aspect 7,
further comprising administering the liquid formulation at a second
slower rate for a period of time sufficient to reduce the
concentration of the molecule in the CSF.
[0078] A 9.sup.th aspect is a method according to aspect 8, wherein
the liquid formulation is administered via a catheter, and wherein
the second slower rate is sufficient to keep the catheter
patent.
[0079] A 10.sup.th aspect is a method for broadly distributing a
therapeutic or diagnostic molecule in cerebrospinal fluid (CSF) of
a subject including administering a liquid formulation comprising
the molecule to the CSF at a flow rate of less than 500 microliters
per hour, wherein the liquid formulation is administered for a
period of time sufficient to reach a steady state concentration in
the CSF, and wherein the molecular weight of the molecule is less
than 5 kDa, between 15 kDa and 200 kDa, greater than 200 kDa, or a
polypeptide or antisense DNA having a molecular weight of between 5
kDa and 15 kDa.
[0080] An 11th aspect is a method of aspect 10, wherein the liquid
formulation is administered at a flow rate of less than 200
microliters per hour.
[0081] A 12.sup.th aspect is a method of aspect 10, wherein the
liquid formulation is administered at a flow rate of between about
4 microliters per hour and about 100 microliters per hour.
[0082] A 13.sup.th aspect is a method of aspect 10, wherein the
liquid formulation is administered at a flow rate of between about
2 microliters per hour and about 25 microliters per hour.
[0083] A 14.sup.th aspect is a method of any of aspects 10-13,
wherein the liquid formulation is delivered via a catheter having a
delivery region placed in the CSF.
[0084] A 15.sup.th aspect is a method according to aspect 14,
wherein the delivery region is positioned in a CSF location
selected from the group consisting of lumbar intrathecal space,
thoracic intrathecal space, cervical intrathecal space, cisterna
magna, subdural space, subarachnoid space, and the
intracerebroventricular space.
[0085] A 16.sup.th aspect is a method according to any of aspects
10-15, wherein the molecule is a therapeutic molecule and wherein
the steady state concentration is a therapeutically effective
concentration.
[0086] A 17.sup.th aspect is a method according to aspect 16,
further comprising administering the liquid formulation at a second
slower rate for a period of time sufficient to reduce the
concentration of the molecule in the CSF.
[0087] An 18.sup.th aspect is a method according to aspect 17,
wherein the liquid formulation is administered via a catheter, and
wherein the second slower rate is sufficient to keep the catheter
patent.
[0088] A 19.sup.th aspect is a system comprising: (i) a liquid
formulation comprising a therapeutic or diagnostic molecule,
wherein the molecular weight of the molecule is less than 5 kDa,
between 15 kDa and 200 kDa, greater than 200 kDa, or a polypeptide
or antisense DNA having a molecular weight of between 5 kDa and 15
kDa; and (ii) a programmable implantable infusion device having (a)
a reservoir configured to house the liquid formulation, (b) an
outlet in fluid communication with the reservoir, (c) a drive
mechanism configured to control the rate at which the liquid
formulation is delivered to the outlet from the reservoir; (d)
electronics operably coupled to the drive mechanism, wherein the
electronics are programmed with instructions that cause the liquid
formulation to be delivered from the reservoir to the outlet at a
flow rate of less than 500 microliters per hour for a period of
time sufficient to reach a steady state concentration in a
subject's cerebrospinal fluid (CSF) if the liquid formulation is
administered to a CSF-containing compartment of the subject.
[0089] A 20.sup.th aspect is a system of aspect 19, wherein
instructions cause the liquid formulation to be administered at a
flow rate of less than 200 microliters per hour.
[0090] A 21.sup.st aspect is a system of aspect 19, wherein
instructions cause the liquid formulation to be administered at a
flow rate of between about 4 microliters per hour and about 100
microliters per hour.
[0091] A 22.sup.nd aspect is a system of aspect 19, wherein
instructions cause the liquid formulation to be administered at a
flow rate of between about 2 microliters per hour and about 25
microliters per hour.
[0092] A 23.sup.rd aspect is a system of any of aspects 19-22,
further comprising a catheter operably couplable to the outlet for
delivering the liquid formulation to a target location of subject's
CSF.
[0093] A 24.sup.th aspect is a system comprising: (i) a liquid
formulation comprising a therapeutic or diagnostic molecule,
wherein the molecular weight of the molecule is less than 5 kDa,
between 15 kDa and 200 kDa, greater than 200 kDa, or a polypeptide
or antisense DNA having a molecular weight of between 5 kDa and 15
kDa; and (ii) a programmable implantable infusion device having (a)
a reservoir configured to house the liquid formulation, (b) an
outlet in fluid communication with the reservoir, (c) a drive
mechanism configured to control the rate at which the liquid
formulation is delivered to the outlet from the reservoir; (d)
electronics operably coupled to the drive mechanism, wherein the
electronics are configured to cause the liquid formulation to be
delivered from the reservoir to the outlet at a flow rate of less
than 500 microliters per hour for a period of time sufficient to
reach a steady state concentration in a subject's cerebrospinal
fluid (CSF) if the liquid formulation is administered to a
CSF-containing compartment of the subject.
[0094] A 25.sup.th aspect is a system according to aspect 24,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of less than 200
microliters per hour.
[0095] A 26.sup.th aspect is a system according to aspect 24,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of between about 4
microliters per hour and about 100 microliters per hour.
[0096] A 27.sup.th aspect is a system according to aspect 24,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of between about 2
microliters per hour and about 25 microliters per hour.
[0097] A 28.sup.th aspect is a system according to any of aspects
24-27, further comprising a catheter operably couplable to the
outlet for delivering the liquid formulation to a target location
of subject's CSF.
[0098] A 29.sup.th aspect is a method for delivering a therapeutic
or diagnostic molecule to the brain of a subject, comprising
administering a liquid formulation comprising the molecule to an
intrathecal space of the subject at a flow rate of less than 500
microliters per hour.
[0099] A 30.sup.th aspect is a method of aspect 29, wherein the
liquid formulation is administered at a flow rate of less than 200
microliters per hour.
[0100] A 31.sup.st aspect is a method of aspect 29, wherein the
liquid formulation is administered at a flow rate of between about
4 microliters per hour and about 100 microliters per hour.
[0101] A 32.sup.nd aspect is a method according to any of aspects
29-31, wherein administering the liquid formulation comprises
delivering the liquid formulation from an implantable infusion
device or an external infusion device.
[0102] A 33.sup.rd aspect is a method according to any of aspects
29-32, wherein the molecule has a molecular weight of less than 5
kDa.
[0103] A 34.sup.th aspect is a method according to any of aspects
29-32, wherein the molecule has a molecular weight of greater than
5 kDa.
[0104] A 35.sup.th aspect is a method according to any of aspects
29-32, wherein the molecule has a molecular weight of between about
5 kDa and about 15 kDa.
[0105] A 36.sup.th aspect is a method according to any of aspects
29-32, wherein the molecule has a molecular weight of between about
15 kDa and about 200 kDa.
[0106] A 37.sup.th aspect is a method according to any of aspects
29-32, wherein the molecule has a molecular weight of greater than
about 200 kDa.
[0107] A 38.sup.th aspect is a method according to any of aspects
29-37, wherein the liquid formulation is delivered via a catheter,
wherein the catheter has a delivery region, and wherein the deliver
region is placed in the subject's lumbar intrathecal space,
thoracic intrathecal space, or cervical intrathecal space.
[0108] A 39.sup.th aspect is a method according to any of aspects
29-38, wherein the molecule is a therapeutic molecule and is
delivered at a rate, frequency, duration, location and
concentration suitable to achieve a therapeutically effective
steady state concentration.
[0109] A 40.sup.th aspect is a method according to any of aspects
29-39, with the proviso that the molecule is not an interfering RNA
molecule.
[0110] A 41.sup.st aspect is a method according to any of aspects
29-39, with the proviso that the molecule is not a inhibitory RNA
molecule configured to inhibit expression of a Huntington
protein.
[0111] A 42.sup.nd aspect is a method for broadly distributing a
therapeutic or diagnostic molecule in cerebral spinal fluid of a
subject, comprising administering a liquid formulation comprising
the molecule to the cerebrospinal fluid of the subject at a flow
rate of less than 500 microliters per hour.
[0112] A 43.sup.rd aspect is a method according to aspect 42,
wherein the liquid formulation is administered at a flow rate of
less than 200 microliters per hour.
[0113] A 44.sup.th aspect is a method according to aspect 42,
wherein the liquid formulation is administered at a flow rate of
between about 4 microliters per hour and about 100 microliters per
hour.
[0114] A 45.sup.th aspect is a method according to any of aspects
42-44, wherein administering the liquid formulation comprises
delivering the liquid formulation from an implantable infusion
device or an external infusion device.
[0115] A 46.sup.th aspect is a method according to any of aspects
42-45, wherein the molecule has a molecular weight of less than 5
kDa.
[0116] A 47.sup.th aspect is a method according to any of aspects
42-45, wherein the molecule has a molecular weight of greater than
5 kDa.
[0117] A 48.sup.th aspect is a method according to any of aspects
42-45, wherein the molecule has a molecular weight of between about
5 kDa and about 15 kDa.
[0118] A 49.sup.th aspect is a method according to any of aspects
42-45, wherein the molecule has a molecular weight of between about
15 kDa and about 200 kDa.
[0119] A 50.sup.th aspect is a method according to any of aspects
42-45, wherein the molecule has a molecular weight of greater than
about 200 kDa.
[0120] A 51.sup.st aspect is a method according to any of aspects
42-50, wherein the molecule is delivered via a catheter having a
delivery region, wherein the delivery region is placed in the
subject's intrathecal space.
[0121] A 52.sup.nd aspect is a method according to any of aspects
42-51, wherein the molecule is a therapeutic molecule and is
delivered at a rate, frequency, duration, location and
concentration suitable to achieve a therapeutically effective
steady state concentration.
[0122] A 53.sup.rd aspect is a method according to any of aspects
42-52, with the proviso that the molecule is not an interfering RNA
molecule.
[0123] A 54.sup.th aspect is a method according to any of aspects
42-52, with the proviso that the molecule is not a inhibitory RNA
molecule configured to inhibit expression of a Huntington
protein.
[0124] A 55.sup.th aspect is a system comprising: (i) a liquid
formulation comprising a therapeutic or diagnostic molecule, with
the proviso that the molecule is not an interfering RNA molecule or
that the molecule is not a inhibitory RNA molecule configured to
inhibit expression of a Huntington protein; and (ii) a programmable
implantable infusion device having (a) a reservoir configured to
house the liquid formulation, (b) an outlet in fluid communication
with the reservoir, (c) a drive mechanism configured to control the
rate at which the liquid formulation is delivered to the outlet
from the reservoir; (d) electronics operably coupled to the drive
mechanism, wherein the electronics are programmed with instructions
that cause the liquid formulation to be delivered from the
reservoir to the outlet at a flow rate of less than 500 microliters
per hour for a period of time sufficient to reach a steady state
concentration in a subject's cerebrospinal fluid (CSF) if the
liquid formulation is administered to a CSF-containing compartment
of the subject.
[0125] A 56.sup.th aspect is a system according to aspect 55,
wherein instructions cause the liquid formulation to be
administered at a flow rate of less than 200 microliters per
hour.
[0126] A 57.sup.th aspect is a system according to aspect 55,
wherein instructions cause the liquid formulation to be
administered at a flow rate of between about 4 microliters per hour
and about 100 microliters per hour.
[0127] A 58.sup.th aspect is a system according to aspect 55,
wherein instructions cause the liquid formulation to be
administered at a flow rate of between about 2 microliters per hour
and about 25 microliters per hour.
[0128] A 59.sup.th aspect is a system according to any of aspects
55-58, further comprising a catheter operably couplable to the
outlet for delivering the liquid formulation to a target location
of subject's CSF.
[0129] A 60.sup.th aspect is a system comprising: (i) a liquid
formulation comprising a therapeutic or diagnostic molecule, with
the proviso that the molecule is not a inhibitory RNA molecule or
that the molecule is not a inhibitory RNA molecule configured to
inhibit expression of a Huntington protein; and (ii) a programmable
implantable infusion device having (a) a reservoir configured to
house the liquid formulation, (b) an outlet in fluid communication
with the reservoir, (c) a drive mechanism configured to control the
rate at which the liquid formulation is delivered to the outlet
from the reservoir; (d) electronics operably coupled to the drive
mechanism, wherein the electronics are configured to cause the
liquid formulation to be delivered from the reservoir to the outlet
at a flow rate of less than 500 microliters per hour for a period
of time sufficient to reach a steady state concentration in a
subject's cerebrospinal fluid (CSF) if the liquid formulation is
administered to a CSF-containing compartment of the subject.
[0130] A 61.sup.st aspect is a system according to aspect 60,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of less than 200
microliters per hour.
[0131] A 62.sup.nd aspect is a system according to aspect 60,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of between about 4
microliters per hour and about 100 microliters per hour.
[0132] A 63.sup.rd aspect is a system according to aspect 60,
wherein the electronics are configured to cause the liquid
formulation to be administered at a flow rate of between about 2
microliters per hour and about 25 microliters per hour.
[0133] A 64.sup.th aspect is a system according to any of aspects
60-63, further comprising a catheter operably couplable to the
outlet for delivering the liquid formulation to a target location
of subject's CSF.
[0134] In the following, non-limiting examples of the methods
described herein are presented.
EXAMPLES
[0135] CADD ambulatory infusion pumps were used to deliver
gadolinium (Gd) labeled diethylene triamine pentaacetic acid (DTPA)
or Gd-labeled albumin to rhesus monkeys, either intrathecally or
intracerebroventricularly. Distribution of the Gd-labeled agents
was tracked in-life via magnetic resonance imaging (MRI).
[0136] The Gd-DPTA has a molecular weight of about 600 Daltons and
serves as a proxy for small molecule agents. The Gd-albumin had a
molecular weight of about 74 kDa and serves as a proxy for
mid-sized biologics.
[0137] For the Gd-DTPA studies, various concentrations of the
Gd-DTPA were administered. The Gd-DTPA was administered
intrathecally at L2 or intracerebroventricularly via a lateral
ventricle at a variety of flow rates. Within a given monkey various
flow rates were tested, followed by a washout period with phosphate
buffered saline (PBS). An example study design that was used is
presented below in Table 2:
TABLE-US-00002 TABLE 2 Flow rates and agents used for intrathecal
Gd-DTPA Study Day 1 4 7 12 15 20 23 28 31 36 Test PBS Gd- PBS Gd-
PBS Gd- PBS Gd- PBS Gd- Article DTPA DTPA DPTA DTPA DPTA Flow 0.096
0.096 0.096 0.384 0.096 1.2 0.096 2.4 0.096 0.096 Rate (ml/day)
[0138] At lower concentrations (e.g., 17.5 mg/ml, 5.8 mg/ml, and
2.9 mg/ml), Gd-DTPA infused at 0.4 mL/day was not appreciably
detectable by MRI. However at 70 mg/ml concentration, Gd-DTPA was
detectable and was observed to be broadly distributed throughout
the CSF. While not detectable at lower concentrations, it is
believed that the distribution of the lower concentration agent was
similar to that observed at the 70 mg/ml concentration at similar
flow rates. FIG. 6 shows MM images obtained from monkeys receiving
Gd-DTPA at 0.1 ml/day (B), 0.4 ml/day (C), 1.2 mL/day (D), and 2.4
ml/day (E). FIG. 6A is an MRI image of the same monkey prior to
infusion of Gd-DTPA. As shown in FIG. 6, broad distribution was
observed at all flow rates of about 0.4 ml/day or greater. At the
2.4 ml/day (100 microliters per hour) flow rate the amount of
Gd-DTPA delivered was the greatest, and thus the signal was most
intense.
[0139] As shown in FIG. 7B, which is an axial view of the monkey
receiving 70 mg/ml Gd-DTPA at a rate of 2.4 ml/day (100
microliters/hour) intrathecally at L2, the Gd-DTPA appears to be
taken up by the parenchymal tissue of the brain of the monkey (FIG.
7A is an axial view of the monkey's brain prior to infusion of
Gd-DTPA). These results suggest not only that the agent is broadly
distributed in the CSF at low flow rates but also that it is able
to be taken up by the brain tissue. As discussed below with regard
to FIG. 10, which shows images of various MRI slices of monkeys to
which Gd-albumin were delivered, a similar broad CNS tissue
distribution of Gd-DPTA was observed (data not shown).
[0140] Interestingly, FIG. 7D, which is an axial view including the
spinal cord of the same monkey shown in FIGS. 7A-B, shows that the
Gd-DTPA has distributed in a circumferential manner around the
intrathecal space under steady state conditions (FIG. 7C shows the
same monkey prior to administration of the Gd-DTPA). Such
circumferential distribution has not been reported by others, and
it was thought that an agent administered intrathecally would
remain in a column.
[0141] Referring now to FIGS. 8A-F, MM images of a rhesus monkey
receiving various concentrations of Gd-DPTA
intracerebroventricularly at various flow rates are shown. FIG. 8A
is an MRI image of a monkey receiving PBS prior to infusion of the
Gd-DPTA. FIG. 8B is an MM image of a monkey receiving 486 mg/ml at
0.048 ml/day. FIG. 8C is an MRI image of a monkey receiving 280
mg/ml at 0.1 ml/day. FIG. 8D is an MRI image of a monkey receiving
70 mg/ml at 0.4 ml/day. FIG. 8E is an MRI image of a monkey
receiving 35 mg/ml at 0.8 ml/day. FIG. 8F is an MM image of a
monkey receiving 22 mg/ml at 1.2 ml/day. As shown in the figure,
the Gd-DTPA is broadly distributed in the CSF, including in the
intrathecal space at flow rates of about 0.05 ml/day or greater.
Accordingly, broad distribution appears to be achievable at low
flow rates, regardless of the CSF site of administration.
[0142] For the Gd-albumin studies, various concentrations of the
Gd-albumin were administered intrathecally at L2 at various flow
rates. FIGS. 9A-E are MRI images of rhesus monkeys receiving
intrathecal Gd-albumin. FIG. 9A shows a rhesus monkeys receiving
intrathecal PBS prior to infusion of the Gd-albumin. FIG. 9B shows
a rhesus monkey receiving intrathecal 100 mg/ml Gd-albumin at 0.1
ml/day. FIG. 9C shows a rhesus monkey receiving intrathecal 100
mg/ml Gd-albumin at 0.4 ml/day. FIG. 9D shows a rhesus monkey
receiving intrathecal 34 mg/ml Gd-albumin at 1.2 ml/day. FIG. 9E
shows a rhesus monkey receiving intrathecal 17 mg/ml Gd-albumin at
2.4 ml/day. As shown, a sufficiently strong signal was observed at
all concentrations, with greater distribution observed with higher
infusion rates. However, even at low rates of infusion distribution
was seen throughout the spinal intrathecal space (see 9B, 0.1
ml/day) and within the CSF surrounding the brain (see 9C, 0.4
ml/day).
[0143] FIG. 10 shows various MRI slices revealing that Gd-albumin
was detectable throughout the CSF-containing compartments of the
monkey. FIG. 10A is an MRI image prior to infusion of Gd-albumin;
FIG. 10B is an image of the monkey while receiving 100 mg/ml at 0.1
ml/day; FIG. 10C is an image of the monkey while receiving 100
mg/ml at 2.4 ml/day; FIG. 10D is a higher magnification view of the
brain of the image presented in FIG. 10C; and FIG. 10E is a higher
magnification view of the spinal region of the image presented in
FIG. 10C.
[0144] Referring now to FIGS. 11A-F, MRI images of a rhesus monkey
receiving various concentrations of Gd-albumin
intracerebroventricularly at various flow rates are shown. FIG. 11A
is an MM image of a monkey receiving PBS prior to infusion of the
Gd-albumin. FIG. 11B is an MM image of a monkey receiving 100 mg/ml
at 0.1 ml/day at one day of infusion. FIG. 11C is an MRI image of a
monkey receiving 100 mg/ml at 0.4 ml/day at one day of infusion.
FIG. 11D is an MRI image of a monkey receiving 100 mg/ml at 0.4
ml/day at three days of infusion. FIG. 11E is an MRI image of a
monkey receiving 100 mg/ml at 0.8 ml/day at one day of infusion.
FIG. 11F is an MRI image of a monkey receiving 64 mg/ml at 1.2
ml/day at one day of infusion. As shown in FIG. 11D, broader
distribution is observed after three days of infusion relative to
one day of infusion (compare to FIG. 11C). Similar increased
distribution was observed at three days relative to one day at
other infusion rates (data not shown). At infusion rates of about
0.4 ml/day and greater, distribution in the spinal intrathecal
space was observed.
[0145] Like the small molecules (Gd-DTPA), large molecules
(Gd-albumin) are also broadly distributed following infusion into
the CSF at low flow rates.
[0146] Thus, embodiments of the METHODS FOR DISTRIBUTING AGENTS TO
AREAS OF BRAIN are disclosed. One skilled in the art will
appreciate that the present invention can be practiced with
embodiments other than those disclosed. The disclosed embodiments
are presented for purposes of illustration and not limitation, and
the present invention is limited only by the claims that
follow.
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