WO2003015710A2

WO2003015710A2 - Combined drug and csf removal therapies and systems

Info

Publication number: WO2003015710A2
Application number: PCT/US2002/026435
Authority: WO
Inventors: Dawn Mcguire; Tom Saul; Denise F. Gottfried
Original assignee: Eunoe, Inc.
Priority date: 2001-08-21
Filing date: 2002-08-19
Publication date: 2003-02-27
Also published as: WO2003015710A3; AU2002313778A1

Abstract

Diseases and other conditions of the central nervous system are treated by concurrently or sequentially delivering a therapeutic agent to a cerebrospinal fluid (CSF) space and draining CSF from the CSF space. Systems (70) include one or more implantable catheters (52, 60, 66)for accessing the CSF space, typically in a ventricle or lumbar space, in one catheters for draining the CSF to another location, such as the peritoneal cavity. Implantable pumps (54) provided for delivering the therapeutic agent through the CSF space access catheter and implantable flow control mechanisms (64) are provided for controlling the rate and volume of CSF drainage from the CSF space.

Description

COMBINED DRUG AND CSF REMOVAL THERAPIES AND SYSTEMS

CROSS-REFERENCES TO RELATED APPLICATIONS

BACKGROUND OF THE INVENTION [01] 1. Field of the Invention. The present invention relates to methods and devices for the treatment of Alzheimer's disease (AD) and other diseases of the central nervous system associated with the accumulation of substances, such as proteins, peptides, and waste products. In particular, the present invention relates to methods and systems for the concurrent delivery of therapeutic compounds to the central nervous system (CNS) and removal of the compounds and/or other substances related to the compounds or disease from the CNS.

[02] Cerebrospinal fluid (CSF) is secreted by the choroid plexus and fills the four cerebral ventricles. CSF circulates from ventricular sites of secretion, around the spinal cord and over the convexity of the brain, where the CSF is absorbed into the superior sagittal sinus by way of specialized processes in the meninges (e.g., the arachnoid granulations). The CSF is continuous with brain interstitial (extracellular) fluid, and solutes, including macromolecules, are exchanged freely between CSF and interstitial fluid. This exchange is driven primarily by concentration gradients, osmotic pressures and, in the case of proteins, oncotic pressures, and bulk flow. [03] Once in the cerebral ventricles, molecules of all sizes can diffuse through a single, porous ependymal cell layer, and enter the continuous interstitial fluid network that bathes the brain. For example, micronutrients such as folate and thyroid hormone transport proteins (transthyretins) diffuse throughout the CNS after they are secreted into ventricular fluid by the choroid plexus. Conversely, waste products of cerebral metabolism are cleared from the brain down concentration, osmotic and oncotic gradients into ventricular fluid, and absorbed into the systemic circulation via the arachnoid granulations. [04] Several currently incurable neurodegenerative diseases are the result of failure of clearance of waste products, and in particular, clearance of certain proteins and/or peptides, herein referred to as proteins. The accumulation of such proteins, many of which are normally-occurring proteins, can result in their abnormal processing and/or in their aggregation. In some cases, soluble accumulations of these proteins are neurotoxic. In others, aggregation results in formation of insoluble fibrils or other three-dimensional structures (e.g., beta-pleated sheets) which are neurotoxic. Besides being directly neurotoxic, many protein aggregates implicated in neurodegenerative diseases of the CNS also stimulate a destructive immune response. Cytotoxic and pro-inflammatory secretions, particularly from macrophages and microglia, can cause further cell injury and neuronal cell death. Diseases for which abnormal protein aggregation appears to be a critical component of pathophysiology include, but are not limited to, Alzheimer's disease, Parkinson's disease, Progressive Supranuclear Palsy, Lewy-body dementia, Frontotemporal Dementia, Creutzfeld- Jacob disease and other "prion" diseases, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and the like.

[05] In such diseases, therapeutic agents designed to reduce or reverse protein aggregation or abnormal processing require two elements. First, they must be able to reach therapeutic, yet nontoxic concentrations in brain tissue. Second, any products resulting from the breaking up of abnormal protein aggregates must be cleared effectively from the CNS. Protein aggregation is concentration dependent. If protein breakdown products are not cleared from the brain interstitial fluid, re-aggregation is likely, and the net therapeutic effect of "disaggregation" will be lost. In other words, soluble products resulting from the action of therapeutic agents in the CNS diffuse down a concentration gradient into the CSF. If normal CSF circulation and turnover is impaired, as has been shown to be the case with normal aging; then the accumulation of the "macromolecular debris" will severely limit clearance of such products from brain interstitial fluid.

[06] Delivery of therapeutic agents to CNS target tissues is highly limited by the blood-brain barrier and blood-CSF barrier. These cellular barriers prevent most water soluble substances from entering the CNS from blood. Hence, therapeutic agents delivered by mouth, vein, or through skin or other membranes, lung, or muscle, cannot reach high enough concentrations in CNS to treat disease there unless inordinately high potential toxic doses are administered. Substances, including therapeutics delivered to the cerebral ventricles, can bypass the cellular barriers which prevent or limit entry into the CNS. [07] Intracerebro ventricular (ICV) administration of compounds is known. ICV administration has been used successfully to treat some acute or subacute diseases such as CNS infection and cancer. Implantation of an Ommaya reservoir occasionally has been used to deliver anti-infectives or chemo therapeutic drugs to the CNS. [08] The two hallmarks of Alzheimer's disease (AD) are: [09] 1. The accumulation of plaque-like deposits in several areas of brain consisting of small peptide components of amyloid, especially ABeta (1-42); and [10] 2. Accumulation of hyperphosphorylated Tau-protein-rich neurofibrillary

"tangles" which aggregate in helical arrays (or paired helical filaments). [11] Such accumulation is presently believed to result from a failure of the mechanisms governing clearance of these substances, failure of the mechanisms that inhibit aggregation of the substances, or failure of other clearance mechanisms resulting from altered cerebrospinal fluid (CSF) dynamics. Such alterations may include diminished CSF production, diminished CSF turnover, increased resistance to absorption of CSF, and altered CSF outflow patterns.

[12] There is strong evidence that the aggregated ABeta peptides and the helical arrays of Tau protein are toxic to nerve cells, and that this leads to the development and progression of AD. Both the "amyloidosis" and the "tauopathy" of AD cause the pathologic activation of microglia, resulting in elaboration of proinflammatory cytokines and chemokines. Such immunopathologic reactions, constantly stimulated by the degree of plaque and tangle burden in the brain, result in chronic inflammation and ongoing damage to brain.

[13] A number of drugs and biologies are under investigation that may either block

ABeta production (such as inhibitors of gamma secretase, beta secretase or aspartic proteases) or break up ABeta plaques (such as anti-aggregating monoclonal antibodies). Other drugs or biologies are being developed to block tangle-prone alterations (e.g., hyperphosphorylation) of Tau protein. Anti-inflammatory or antioxidant therapies are being developed to reduce the inflammation associated with the amyloidosis and tauopathy of AD. The stem cell or neuronal precursor cell therapies are being developed to enhance neuroregeneration in damaged brain. The success of these potential treatments will likely be limited by the difficulty in delivering them safely to the target tissue. For example, larger molecules cannot cross the blood brain barrier, while monoclonal antibodies are unstable when delivered orally, and penetrate the CNS poorly when given by vein. Doses of drugs or biologies that are large enough to reach therapeutic concentrations in the brain are often toxic when delivered systemically.

[14] 2. Description of the Background Art. Implantable pumps for delivering drugs to the brain for the treatment of Alzheimer's disease are described in U.S. Patent Nos. 5,846,220 and 6,056,725, and published U.S. Patent Application US2001/0023709A1. Implantable shunts for draining cerebrospinal fluid (CSF) to treat Alzheimer's disease are described in U.S. Patent Nos. 5,980,480; 6,264,625B1; and 6,383,159B1, assigned to the assignee of the present application, the full disclosures of which are incorporated herein by reference. Systems and methods for exchanging CSF for the treatment of drug overdoses and other conditions are described in published PCT Application No. WO 01/054,766, assigned to the assignee of the present application, the full disclosure of which is incorporated herein by reference. Other patents and published applications which describe methods and systems for draining or recirculating CSF include U.S. Patent Nos. 4,741,730; 5,385,541; 5,683,357; 6,132,415; published US. Patent Application No. US2001/0020159A1; and PCT Application WO 01/13984A2.

BRIEF SUMMARY OF THE INVENTION [15] The present invention provides methods and systems for treating diseases of the central nervous system (CNS). In particular, the present invention is intended to treat patients suffering from conditions, which are treatable by administering a therapeutic agent to a patient's cerebrospinal fluid wherein the activity or efficacy of the therapeutic agent is enhanced by removing CSF from the patient concurrently or sequentially with the administration of the therapeutic agent. Delivery of the therapeutic agent directly to the CSF achieves one level of enhancement by bypassing the blood-brain barrier which can inhibit therapeutic agents delivered by other routes. The removal of CSF concurrently or sequentially with the delivery of the therapeutic agent can further enhance the activity of the therapeutic agent in one or more ways. First, the removal of CSF can remove and lower the concentration of an endogenous substance responsible for the condition being treated. Second, the removal of CSF can lower the concentration of harmful byproducts of the treatment, including metabolites of the therapeutic agent, toxic products generated by the action of the therapeutic agent on the endogenous pathogenic agent, and breakdown products of the endogenous substance which may reform or reaggregate if left in the CSF. The latter mechanism is typified by the treatment of patients suffering from Alzheimer's disease by therapeutic agents which breakdown the ABeta plaque. In those instances, the breakdown products of the ABeta plaque can reform into the plaque if not removed from the CSF. Third, removal of CSF can help control the concentration and/or circulation of the therapeutic agent in the CSF, e.g., lowering concentrations of potentially toxic agents introduced at high concentrations and enhancing the circulation of agents introduced at particular points in the CSF space, as defined below. [16] Methods according to the present invention are thus suitable for treating patients suffering from conditions treatable by administering a therapeutic agent to a patient's cerebrospinal fluid. The methods comprise delivering the therapeutic agent to the patient's CSF and concurrently or sequentially removing CSF from a CSF space of the patient. Delivering the therapeutic agent may comprise passing the drug through an implanted conduit to an administration site in the patient's CSF space, typically the lateral ventricles, a lumbar region, other central nervous system cisternal spaces, or the like. In particular, passing the agent through the implanted conduit may comprise pumping the agent from an implanted reservoir connected to the conduit, injecting the agent to an implanted port connected to the implanted conduit, or the like.

[17] Removing CSF from the patient's CSF space typically comprises draining

CSF through a conduit implanted at a removal site in the CSF space, typically the lateral ventricles, a lumbar region, other central nervous system cisternal spaces, or the like. The removal site may be the same as or different than the administration site, as described in more detail below. The implanted conduit may lead to an internal or external drainage site, typically to an internal drainage site, such as the peritoneal cavity, right atrium, pleural cavity, bladder, or the like.

[18] The use of such implanted conduits will usually provide for a continuous, low- flow drainage of the CSF from the CSF space, typically being in the range from 15 ml to 1500 ml in each one-day period, preferably being in the range from 40ml to 300 ml in each one-day period, and more preferably being in the range from 60 ml to 100 ml in each one-day period. The methods of the present invention, however, are not limited to continuous removal of CSF, and may instead comprise a periodic removal which may be coordinated or synchronized to occur concurrently with or shortly after the administration of the therapeutic agent, particularly when it is desired to remove substances produced by the administration of the therapeutic agent.

[19] The therapeutic agents utilized in the methods of the present invention may be selected to have a wide variety of therapeutic activities. In a first instance, therapeutic agents may be selected to lyse or breakdown toxic CSF substances to produce breakdown products in the CSF. Removal of the CSF will thus lower the concentrations of both the toxic CSF substance and the breakdown products of the toxic CSF substance, which breakdown products may themselves be toxic, may be otherwise deleterious, or may be subject to reaggregation or reformation of the toxic CSF substance which has been lysed. For example, in patients suffering from Alzheimer's disease, the therapeutic agent may be selected to lyse the ABeta plaque, or the precursors to ABeta plaque, such as anti-aggregating enzymes and antibodies which break down plaque. Such therapeutic agents include neprilysin, insulin degrading enzyme, endothelin converting enzyme, angiotensin converting enzyme, or pharmacologies which activate these proteolytic enzmes which lyse the ABeta plaque, or the like. Removal of the breakdown products of the ABeta plaque or its precursors can thus reduce the opportunity for the breakdown products to reform into the ABeta plaque or its precursors.

[20] In other instances, the methods of the present invention may be utilized with therapeutic agents, which are themselves potentially toxic, particularly at elevated concentrations or when present in the CSF for prolonged periods. By removing CSF concurrently or sequentially with the administration of such therapeutic agents, the residence time of those agents in the CSF can be controlled to permit efficacy while preventing or inhibiting any deleterious effects from the therapeutic agents themselves. For example, caspase 3 inhibitors, such as lithium, which reduce apoptotic cell death in several neurodegenerative diseases, may be administered. The residence time and concentration of the agent may then be moderated by the rate of CSF drainage.

[21] In still a further instance, the methods of the present invention provide an enhancement or synergy of the independent actions of the therapeutic agent and the CSF removal. By both treating the toxic substances in CSF with the therapeutic agent and removing the toxic substances by draining the CSF, the combined therapeutic action of the two treatment modalities can be more effective than either modality alone. For example, the administration of an anti -ABeta antibody in order to clear cerebral amyloid into the peripheral circulation would be synergistic with CSF drainage since the residence times of both the antibody and the solubilized ABeta in the CSF would be minimized; thus limiting the inflammatory response to the antibody and the deleterious effects of the solubilized ABeta. Such a treatment offers benefit in a number of diseases associated with primary or secondary ABeta accumulations, such as Alzheimer's disease, frontotemporal dementias, and hereditary cerebral hemorrage with amyloidosis of the Dutch type. Treatments using antibodies to tau and tau mutations associated with various tauopathies, including, frontotemporal dementias and progressive supranuclear palsy would benefit similarly. In still other cases, Beta synuclein or local dopaminergic system inhibitors may be administered to interfere with alpha synuclein aggregation in such diseases as Parkinson's and Lewy body dementia. [22] In yet another instance, the methods of the present invention will allow for control or modulation of the concentration of the therapeutic agent, particularly potentially toxic agents, such as secretases, immune system inhibitors, vasopeptidases and the like. Particular agents include alpha secretase and gamma secretase inhibitors, which block the normal pathways of amyloid formation. Such a treatment would have benefit in diseases associated with amyloidosis as indicated above. Other such agents include imunomodulators, immunosupressants, and anti-inflammatory agents whose residence times should be controlled in order to to preserve normal, functional brain immunity. [23] Systems according to the present invention will provide for concurrent or sequential delivery of the therapeutic agent to a patient's CSF space and drainage of CSF from the CSF space. Systems will comprise a first conduit having an end which implantable in the patient's CSF space, a second conduit having an end which is implantable outside of the CSF space, and means for delivering the therapeutic agent to the CSF space through the first conduit and for removing CSF from the CSF space through the second conduit. Usually, the means for draining will further comprise a chamber containing the therapeutic agent which is connected to the first conduit and the means for removing CSF will comprise a flow control valve attachable between the first and second conduits. In this way, the methods of the present invention for delivering therapeutic agents to the CSF and draining CSF from the CSF space may be conveniently performed. [24] In a first alternative, systems according to the present invention may comprise a first conduit having an end implantable in a patient's CSF space, a second conduit having an end implantable in the CSF space, and a third conduit having an end implantable outside of the CSF space. Systems will include means for delivering a therapeutic agent to the CSF space through the first conduit, removing CSF through the second conduit, and disposing of the removed CSF through the third conduit. Such systems which have two conduits implantable in the CSF space are advantageous since they permit the concurrent delivery of the therapeutic agent and removal of the CSF. Moreover, the first and second conduits may be implanted within different regions of the CSF space to assure that the drug will have a minimum residence time within the CSF space and/or to induce preferred flow patterns of the therapeutic agent from the location in the CSF space where the first conduit is implanted to the location where the second conduit is implanted. Such systems may further comprise chambers containing the therapeutic agent connectable to the second conduit, flow mechanisms disposed between the chambers in the first conduit, flow control mechanisms disposed between the second and third conduits, and the like. [25] In a second alternative, systems according to the present invention for treating

Alzheimer's disease in a patient may comprise a therapeutic agent which breaks down the ABeta plaque or fibrillar ABeta to produce breakdown products in the patient's cerebrospinal fluid. Such systems further comprise means for removing CSF to lower the concentration of the ABeta breakdown products to, for example, reduce the likelihood that such breakdown products may reform into the ABeta plaque or precursors of the ABeta plaque. Suitable therapeutic agents include neprilysin, and vasopeptidases such as insulin degrading enzyme, endothelin converting enzyme, angiotensin converting enzyme, or pharmacologies which activate these proteolytic enzymes which lyse the ABeta plaque, and the like. The CSF removal means will typically comprise implantable shunts, usually comprising shunts which are able to drain from 15 ml to 1500 ml of CSF in a day, usually from 40 ml to 300 ml of CSF in a day, and preferably from 60 ml to 100 ml of CSF in a day. Such shunts will have one end implanted at a location in the patient's CSF space and another end implanted in the peritoneal cavity. Optionally, the shunts will include means for delivering the therapeutic agent to a desired location in the patient's CSF space.

BRIEF DESCRIPTION OF THE DRAWINGS [26] Fig. 1 is an illustration of the CSF space including the brain and the spinal column. [27] Fig. 2 is a block diagram of a system constructed in accordance with the principles of the present invention for removing CSF from the CSF space and delivering a therapeutic agent to the CSF space using a common conduit.

[28] Fig. 3 is a block diagram illustrating a system similar to that shown in Fig. 2 comprising a ventricular catheter for draining CSF and delivering a therapeutic agent to a ventricle of the brain and a peritoneal catheter for draining the removed CSF to the peritoneal cavity.

[29] Fig. 4 is block diagram illustrating a third system constructed in accordance with the principles of the present invention and including a ventricular catheter for delivering a therapeutic agent using a pump, a lumbar catheter for removing CSF from the lumbar region of the CSF space, and a peritoneal catheter for draining the removed CSF to the peritoneal cavity.

[30] Fig. 5 illustrates a system similar to that shown in Fig. 4 and further including a synchronization mechanism to coordinate the delivery of a therapeutic agent to the CSF space with removal of CSF from the CSF space. DETAILED DESCRIPTION OF THE INVENTION [31] The present invention provides methods and systems for treating diseases and conditions of the central nervous system (CNS) which rely on the concurrent or successive delivery of a therapeutic agent and removal of cerebrospinal fluid (CSF) from a CSF space, as defined below. The methods and systems are particularly intended for the treatment of Alzheimer's disease and other conditions which are caused by or otherwise related to the retention and/or excessive accumulation of toxic and other substances in the CSF. In addition to Alzheimer's disease, the present invention will be useful for treating other conditions resulting from the accumulation of toxic substances and resulting lesions in the patient's brain, such as Down's Syndrome, hereditary cerebral hemorrhage with amyloidosis of the

Dutch-Type (HCHWA-D), and the like. Other treatable conditions relating to the presence or excessive accumulation of potentially harmful substances include epilepsy, Parkinson's disease, Progressive Supranuclear Palsy, Lewy-body dementia, Frontotemporal Dementia, Creutzfeld- Jacob disease and other "prion" diseases, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and the like.

[32] Devices and methods of the present invention are particularly intended for treating conditions in patients having "normal" intracranial pressures, i.e. intracranial pressures below 200 mm H O when the patient is reclining and above -170 mm H₂O when the patient is upright (where the pressures are measured relative to the ambient). In contrast, patients suffering from hydrocephalus will have constant or periodic elevated intracranial pressures above 200 mm H O (when reclining), often attaining levels two or three times the normal level if untreated. The devices and methods of the present invention are generally not intended for the treatment of patients having chronically elevated intracranial pressures in general and patients suffering from hydrocephalus in particular. [33] The brain and spinal cord are bathed in cerebrospinal fluid (CSF) and encased within the cranium and vertebral column inside a thin membrane known as the meninges (Fig. 1). The space within the meninges M, which is the three-membrane complex enveloping the brain and spinal cord, consists of the subarachnoid space (SAS), including the ventricles (including the lateral ventricle (LV), third ventricle (3V), and fourth ventricle (4V)), the vertebral column, and the brain interstitial spaces. The total space within the meninges M is referred to herein as the "CSF space." The volume of the brain intracranial spaces is on average about 1700 ml. The volume of the brain is approximately 1400 ml, and the volume of the intracranial blood is approximately 150 ml. The remaining 150 ml is filled with CSF (this volume will typically vary within 60 ml to 290 ml). The CSF circulates within the CSF space. CSF is formed principally by the choroid plexis, which secrete about 80% of the total volume of the CSF. The sources of the remainder are the vasculature of the subependymal regions, and the pia matter. The total volume of the CSF is normally renewed several times per day, so that about 500 ml are produced every 24 hours (equivalent to about 20 ml/hr or 0.35 ml/min) in healthy adults. The production rate varies in the old and the young, declining in the elderly.

[34] The cerebrospinal fluid is absorbed through the arachnoid villi, located principally over the superior surfaces of the cerebral hemispheres. Some villi also exist at the base of the brain and along the roots of the spinal nerves. The absorptive processes include bulk transport of large molecules and as well as diffusion across porous membranes of small molecules. The production and absorption of CSF are well described in the medical literature. See, e.g., Adams et al. (1989) "Principles of Neurology," pp. 501-502. [35] While CSF is naturally absorbed and removed from circulation, as just described, it is presently believed that certain toxic or other substances may be present in the CSF, such as those associated with Alzheimer's disease, and may accumulate or persist to an extent which can cause Alzheimer's disease or other disorders. Such substances are either produced in excess, removed at a rate slower than their production rate, or not properly circulated so that they accumulate or stagnate and increase in toxicity and/or reach a threshold concentration in which they become toxic in the brain or elsewhere within CSF space.

[36] The present invention will employ known and as-yet-to-be-developed therapeutic agents and drugs intended for the treatment of diseases and conditions of the CNS, including those listed above. Usually, the therapeutic agents will be directed at a toxic or other substance present in the CSF space, including the CSF and brain parenchyma (target tissue), which is responsible in some way for the condition to be treated. In addition to the toxic or other responsible substance, the therapeutic agents could be neuronal precursors, stem cells, embryoid bodies, catalysts, growth factors, enzymes, and other substances. Such therapeutics may, in themselves, result in production of toxic or otherwise deleterious contribution to the condition to be treated. In such cases, CSF drainage according to the present invention will benefit by learing such products. For example, in the case of

Alzheimer's disease, the therapeutic agents could be directed at any of the proteins or other factors which lead to the formation of the ABeta plaque or other materials responsible for the condition. The disaggregation produces soluble ABeta proteins which, if not cleared, are toxic to selective brain cell populations.or soluble ABeta proteins, if not cleared, are toxic to selective brain cell populations.

[37] In a first particular example, the therapeutic agent is an enzyme or monoclonal antibody which is directed against ABeta plaque, breaking up the plaque to produce breakdown products. As described below, in this instance, the therapeutic agent acts directly on one of the substances directly responsible for the condition, while the removal of CSF removes both endogenous precursors to the ABeta plaque as well as the breakdown products of the plaque, which are subject to reaggregation if not removed. [38] The therapeutic agents may be of any conventional form, including small molecule drugs, typically having a molecular weight below 2 kilodaltons, large molecule drugs, biological agents such as proteins, nucleic acids, embryonic and other stem cells or progenitor cells, other therapeutic cellular products, and the like. The therapeutic agents may be incorporated into conventional forms for delivery, typically being present in a liquid carrier at a concentration selected to permit delivery of a desired dosage using the methods and systems described below. While the concentrations and volumes of the therapeutic agents delivered will vary greatly depending on the nature of the particular agent, the concentrations will often be in the range from 1 mM to 1 pM, with total dosage delivered in any one-day period being in the range from 1 mM to 1 nM. [39] The therapeutic agents may be delivered continuously or discontinuously. That is, the therapeutic agents may be delivered to the CSF space as infrequently as once per day, once per week, or even less often, typically using an injection port or programmable delivery system having only a limited amount of agent to be delivered, but may also be delivered on a substantially continuous basis, typically using a pump having a replenishable reservoir for holding the therapeutic agent. [40] In most instances, CSF removal from the CSF space will be performed continuously or semi-continuously. CSF removal will typically be accomplished using implanted catheters or cannulas having at least one port or access point implanted within the CSF space, typically, in a ventricle or in the lumbar space, and at least one other port or drainage point implanted at a disposal site in the body, typically the peritoneal cavity. Controlled, typically low, drainage rates are preferred, usually being in the range from 15 ml/day to 1500 ml/day, typically from 40 ml/day to 300 ml/day, preferably from 60 ml/day to 100 ml/day. A variety of catheter systems suitable for achieving such drainage rates are described in patents and pending patent applications of the assignee herein. See, for example, U.S. Patent Nos. 5,980,480; 6,264,625B1; and 6,383,159B1; as well as co-pending application nos. 10/ ; (Attorney Docket No. 18050-001000), the full disclosures of which are incorporated herein by reference.

[41] Preferably, the systems of the present invention will combine and integrate the capabilities for both delivering the therapeutic agent to the CSF space and draining CSF from the CSF space. In particularly preferred configurations, the systems will be able to coordinate and synchronize the delivery of therapeutic agent with the removal of CSF, e.g., by draining CSF in a coordinated fashion with delivering the therapeutic agent, typically during and/or immediately after the delivery of the therapeutic agent. The combined systems may combine one or more component which act to both deliver therapeutic agent and drain CSF. For example, the systems may combine a single ventricular catheter for delivering the therapeutic agent to the CSF and removing CSF from the CSF space. The catheter may have a single lumen, in which case therapeutic agent delivery and CSF removal would have to be performed successively. Alternatively, the ventricular catheter could have two or more lumens, enabling concurrent therapeutic agent delivery and CSF removal. The systems will also often include a single "flow controlling" component or module which acts to both control the drainage of CSF from the CSF space and to deliver the therapeutic agent to the CSF space. In the latter case, the flow control module will typically also include a reservoir for holding the drug, a percutaneously accessible port for replenishing the reservoir or directly injecting the therapeutic agent, as well as the components for controlling the drainage volumes and rates.

[42] Referring now to Fig. 2, systems 10 constructed in accordance with the principles of the present invention will provide at least one access point or "input space" 12 within the CSF space and at least one other access point or "output space" 14 at a body location outside of the CSF space. The input space 12 will provide both delivery of the therapeutic agent and drainage of the CSF from the CSF space, where delivery of the therapeutic agent is controlled by a fluid input device 16, such as a pump, injection port, or the like, and drainage of the CSF to the output space is modulated by a fluid control device 18. Particular fluid input devices are described in the medical and patent literature. For example, suitable pumps are described in U.S. Patent No. 5,846,220, the full disclosure of which is incorporated herein by reference. Suitable injection ports are described, for example, in U.S. Patent Nos. 5,053,031; 5,057,084; and 6,258,079, the full disclosures of which are incorporated herein by reference. Suitable fluid control devices for controlling drainage of the CSF are described in the patents and pending applications of the assignee of the present application, as listed above. The fluid input device 16 and fluid control device 18 may be connected to the input space 12 and output space 14 using suitable connection conduits, such as ventricular catheters and peritoneal catheters, as also described in the patents and pending applications of the assignee of the present application, as listed above. [43] A first exemplary system 30 incorporating the principles of the present invention is illustrated in Fig. 3. A ventricular catheter 32 is implanted at one end in the patient's ventricle and connected at its other end to an antechamber 34 and fluid control device 36. The antechamber 34 comprises a reservoir which is filled or fillable with the desired therapeutic agent which can be delivered to the ventricle through the ventricular catheter, using either a common lumen which also provides for drainage or a separate lumen specifically intended for the delivery of the agent. The therapeutic agent will typically be delivered using a pump in the fluid control device 36 which may be powered by a motor, by patient motion, patient muscular contraction, or the like. The ventricular catheter 32 also provides for drainage of CSF from the ventricle, where the drainage rate and timing are controlled by the fluid control device 36. The CSF drains to the peritoneal cavity through a separate peritoneal catheter 38. Particular examples of suitable fluid control devices 36 are provided in the patents and pending applications of the assignee of the present application, listed above.

[44] System 50 shown in Fig. 4 differs from systems 10 and 30 in that it includes separate subsystems for delivering the therapeutic agent and for draining CSF. The therapeutic agent is delivered to the CSF space, typically to ventricle 12 through a ventricular catheter 52 by a fluid pump 54 connected to a reservoir 56. The reservoir 56 will typically be replenishable but in some instances could include only a single dosage or limited number of dosages of the therapeutic agent. System 50 includes a separate lumbar catheter 60 for draining CSF from a lumbar space 62 to a fluid control device 64. The peritoneal catheter 66 is provided to drain the CSF from the fluid control device 64 to the peritoneal cavity 14, as with prior systems.

[45] Separate delivery of the therapeutic agent to ventricle 12 and drainage of CSF from the lumbar space 62 provides potential advantages. For example, in the case of potentially toxic drugs, higher concentrations of the drug can be delivered to the ventricle with the drug then flowing to the lumbar space where it is removed. In some instances, relatively high removal rates of the CSF could be employed for relatively short times to permit relatively high concentrations of such toxic agents. Alternatively, the rate at which the CSF is drained from the lumbar space can be controlled to provide a desired drug residence time in the ventricles, the spinal cord area, and the like. [46] System 70 in Fig. 5 is similar to system 50, but further includes a synchronization mechanism 72 which coordinates the fluid pump 54 and fluid control device 64. The synchronization mechanism may perform a variety of functions, but will typically at least coordinate the timing and/or relative flow rates provided by the fluid pump 54 and fluid control device 64. For example, in many instances it will be desirable to deliver the therapeutic agent on a predetermined schedule and dosage level. The synchronization mechanism 72 may both control the fluid pump 54 to provide the desired delivery schedule and dosages, and may further control the fluid control device 64 to drain the CSF in a coordinated manner. As described above, for potentially toxic therapeutic agents, it may desirable to initiate or increase the removal of CSF at or immediately following the delivery of the therapeutic agent. Conversely, for therapeutic agents requiring long residence times, it may be desirable to decrease or stop the CSF drainage at or following the delivery of the therapeutic agent. In still other instances, it may be desirable to provide relatively high drainage rates immediately prior to drug delivery in order to advantageously affect the formal kinetics of the drug in some way. Such synchronized systems 70 according to the present invention can provide for a wide variety of dosage in CSF removal protocols. [47] While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a patient suffering from a condition treatable by administering a therapeutic agent to a patient's cerebrospinal fluid, said method comprising: delivering the therapeutic agent to the patient's CSF; and concurrently or sequentially removing CSF from a CSF space of the patient.

2. A method as in claim 1, wherein delivering comprises passing the agent through an implanted conduit to a target site in the CSF space.

3. A method as in claim 2, wherein the target site is selected from the group consisting of the lateral ventricles, a lumbar region, or other ventricular or cisternal spaces.

4. A method as in claim 2, wherein passing comprises pumping from an implanted reservoir.

5. A method as in claim 2, wherein passing comprises injecting to an implanted port connected to the implanted conduit.

6. A method as in claim 1, wherein removing comprises draining CSF through a conduit implanted at a target site in the CSF space.

7. A method as in claim 6, wherein the target site is selected from the group consisting of the lateral ventricles a lumbar region, or other ventricular or cisternal spaces.

8. A method as in claim 7, wherein the CSF drains to a site selected from the group consisting of the peritoneal cavity, right atrium, pleural cavity, bladder.

9. A method as in claim 6, wherein draining comprises draining from 15 ml to 1 00 ml in each one day period.

10. A method as in claim 1, wherein the therapeutic agent lyses a toxic CSF substance to produce breakdown products, wherein removing the CSF removes the breakdown products.

11. A method as in claim 10, wherein the patient suffers from Alzheimer's disease and therapeutic agent is selected from the group consisting of anti-aggregating enzymes which lyse ABeta plaque and or fibrillar ABeta, and antibodies which break down plaque.

12. A method as in claim 1 , wherein the therapeutic agent is toxic at elevated concentrations in the CSF, and removing the CSF removes the agent to control the concentration of the agent.

13. A method as in claim 12, wherein the agent is selected from the group consisting of secretases, immune system inhibitors, and vasopeptidases.

14. A method as in claim 1, wherein the combined therapeutic actions of the therapeutic agent and the therapeutic action of the CSF removal are more effective than the therapeutic action of the therapeutic agent or the CSF removal alone.

15. A system comprising: a first conduit having an end which is implantable in a patient's CSF space; a second conduit having an end which is implantable outside the CSF space; and means for delivering therapeutic agent to the CSF space through the first conduit and removing cerebrospinal fluid (CSF) through the first conduit and disposing of the removed CSF through the second conduit.

16. A system as in claim 15, wherein the means for delivering comprises a chamber containing the therapeutic agent which is connected to the first conduit.

17. A system as in claim 15, wherein the means for removing comprises a flow control valve attachable between the first and second conduits.

18. A system as in claim 17, wherein the first conduit has a first end implantable in a ventricle, a lumbar space, or other ventricular or cisternal spaces.

19. A system as in claim 18, wherein the second conduit has a first end implantable in a peritoneal cavity.

20. A system comprising: a first conduit having an end which is implantable in a patient's CSF space; a second conduit having an end which is implantable within the CSF space; a third conduit having an end which is implantable outside the CSF space; and means for delivering a therapeutic agent to the CSF space through the first conduit, removing cerebrospinal fluid (CSF) through the second conduit, and disposing of the removed CSF through the third conduit.

21. A system as in claim 22, wherein the means for delivering comprises a chamber containing the therapeutic agent which is connectable to the second conduit.

22. A system as in claim 23, wherein the means for delivering comprises a flow control mechanism attachable between the chamber and first conduit.

23. A system as in claim 22, wherein the first conduit has a first end implantable in a ventricle or a lumbar space.

24. A system as in claim 19, wherein the means for removing comprises a flow control mechanism attachable between the second and third conduits.

25. A system as in claim 21, wherein the flow control mechanisms are synchronized.

26. A system as in claim 24, wherein the first conduit has a first end implantable in a ventricle, a lumbar space, or other ventricular or cisternal spaces.

27. A system as in claim 26, wherein the third conduit has an end implantable in a peritoneal cavity.