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Title:
CEREBROSPINAL FLUID PURIFICATION SYSTEM
Document Type and Number:
WIPO Patent Application WO/2011/114260
Kind Code:
A1
Abstract:
Systems and methods the removal of toxins from the cerebrospinal fluid (CSF) are disclosed.

Inventors:
BEDNAR, Martin Michael (Pfizer Global Research and Development, Eastern Point RoadGroton, Connecticut, 06340, US)
MORRISON, Briggs William (Pfizer Inc. 235 East 42nd Street, New York, NY, 10017, US)
Application Number:
IB2011/050987
Publication Date:
September 22, 2011
Filing Date:
March 09, 2011
Export Citation:
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Assignee:
PFIZER INC. (235 East 42nd Street, New York, New York, 10017, US)
BEDNAR, Martin Michael (Pfizer Global Research and Development, Eastern Point RoadGroton, Connecticut, 06340, US)
MORRISON, Briggs William (Pfizer Inc. 235 East 42nd Street, New York, NY, 10017, US)
International Classes:
A61K35/12; A61K35/24; A61M1/00; A61P25/00; A61P25/16; A61P25/28
Attorney, Agent or Firm:
BENSON, Gregg C. et al. (Pfizer Inc, Eastern Point RoadGroton, Connecticut, 06340, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

1. A method for filtering cerebrospinal fluid (CSF) or interstitial fluid (ISF) in a patient, said method comprising: removing CSF/ISF from a first location in a CSF/ISF space of the patient; filtering the removed CSF/ISF; and shunting the filtered CSF/ISF to a second body cavity of said patient; wherein the removing and shunting steps are performed concurrently during the treatment.

2. A method of claim 1 , wherein said filtering is all performed within a closed system

3. A method of claim 1 wherein said first CSF space is a ventricle/cisterna magna of a patient's brain, and the second body cavity is the peritoneum of said patient.

4. A method as in claim 1 , wherein filtering the removed CSF comprises removing a targeted molecule, family of molecules or a diverse set of molecules or multiple biologic agents.

5. A method as in claim 1 , wherein filtering the removed CSF comprises one or more separation processes selected from the group consisting of biospecific affinity, immunoaffinity, cationic exchange, anionic exchange, hydrophobicity, size exclusion or other physicochemical properties.

6. A method as in claim 1 , wherein the filtering step is performed using a filtering unit implanted within and is part of the device/invention inserted within the patient's body. The shunt apparatus containing the filtering system may be wholly implanted within the body.

7. A method for filtering cerebrospinal fluid in a patient, said method comprising: introducing a catheter apparatus into a brain ventricle/cisterna magna; adjusting spacing between a pair of ports on the catheter apparatus so one port lies on one side of the ventricle and the other port drains into the peritoneal cavity or other body cavity/space; withdrawing CSF through one of said ports; filtering the withdrawn CSF; and draining the filtered CSF to the peritoneal cavity or other body cavity/space.

8. A system for filtering cerebrospinal fluid (CSF) in a patient, said system comprising: a catheter assembly having a first lumen with a distal port and a second lumen with a proximal port, said catheter being adapted to be introduced in a CSF space and said ports being spaced axially apart; a valve and/or pump connectable between the proximal and distal lumens to induce and regulate the flow of CSF there between; and a filtering component connectable or within the shunt portion of the device to filter the CSF flowing therebetween.

9. A system as in claim 7, further comprising a pump or valve with a flow rate adjustable generally between between 0.04 ml/min to 0.33 ml/min.

10. A system as in claim 7, wherein the filtering component is selected from the group consisting of biospecific affinity, immunoaffinity, cationic exchange, anionic exchange, hydrophobicity, size exclusion and any other physicochemical properties.

1 1. A system as in claim 7, wherein the system is fully implantable.

12. A method for ameliorating the symptoms of Alzheimer's Disease in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing beta-amyloid or tau/ptau proteins or another toxin or panel of toxins from the removed CSF; and draining the filtered CSF within the patient at a second location.

13. A method for ameliorating the symptoms of Parkinson's Disease in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing alpha-synuclein fibrils and oligomers or another toxin or panel of toxins from the removed CSF; and draining the filtered CSF to the patient at a second location.

14. A method for ameliorating the symptoms of Amyotrophic lateral sclerosis in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing nsoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, anti-GMI ganglioside antibodies or another toxin or panel of toxins from the removed CSF, thereby filtering the CSF; and draining the filtered CSF to the patient at a second location.

15. A method for ameliorating the symptoms of cerebral vasospasm in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing erythrocytes, hemoglobin, oxyhemoglobin, endothelin or another toxin or panel of toxins from the removed CSF, thereby filtering the CSF; and draining the filtered CSF to the patient at a second location.

16. A method for ameliorating the symptoms of encephalitis in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing tumor necrosis factor-alpha (TNFa), IgG or another toxin or panel of toxins from the removed CSF; and draining the filtered CSF to the patient at a second location.

17. A method for ameliorating the symptoms of Guillain Barre Syndrome in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing cells and inflammatory mediators such as C5a, TNF a, IL-2, I L-6, interferon-γ, IgG, endotoxins or another toxin or panel of toxins from the removed CSF; and draining the filtered CSF to the patient at a second location.

18. A method for ameliorating the symptoms of Multiple Sclerosis in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing T cells, B cells, anti-myelin antibodies, toxic or inflammatory mediators such as TNF-a, IL-2, I L-6, interferon-γ or another toxin or panel of toxins from the removed CSF; and draining the filtered CSF to the patient at a second location.

19. A method for ameliorating the symptoms of stroke in a patient, said method comprising: removing CSF from a first location in a CSF space of the patient; removing endothelin, enolase or another toxin or panel of toxins from the removed CSF, thereby filtering the CSF; and draining the filtered CSF to the patient at a second location.

20. A method as in any of claims 12 -19 wherein said patient is administered a therapeutically effective amount of a second active agent.

Description:
CEREBROSPINAL FLUID PURIFICATION SYSTEM

FIELD OF THE INVENTION

The invention pertains generally to medical devices, pharmacologic therapy and methods related to using both. More particularly, the present invention relates to devices, immunotherapies, systems, methods and kits for the removal of toxins from the cerebrospinal fluid (CSF). More specifically, the method and system can be used to treat disorders affecting the central nervous system (CNS) by modifying the chemical composition of CSF and thereby altering the brain exposure to toxic substances.

BACKGROUND OF THE INVENTION

Others have described devices for the handling and/or removal of cerebrospinal fluid (CSF) or brain interstitial fluid (ISF) to and from a patient.

For example, several patents disclose various methods for diverting or shunting CSF from the CSF compartment (ventricle, spinal column, citerna magna) to another portion of the body (e.g., abdomen, peritoneal cavity). See, e.g., US Patent Nos. 2,969,066; 3, 889, 687; 6,575,928 and 7, 1 18,549. Others have described administering therapeutic agents to the CSF compartment, but do not disclose removing the CSF. See, e.g., U.S. Patent Nos. 5,531 ,673; 6,056,725; 6,594,880; 6,682,508 and 6,689,756. Generally, the therapeutic agents are locally delivered to the brain but not to the greater cerebrospinal fluid space, which includes the brain and the spine. Others disclose removing CSF, but generally do not administer therapeutic agent or any other fluid. See, e.g. U.S. Patent Nos. 3,889,687; 5,683,357; 5,405,316 and 7,252,659. It is suggested that direct delivery of a therapeutic to the central compartment may result in greater efficacy that administration of a therapeutic systemically (Thakker, et al., Proc Natl Acad Sci U S A. 2009 Mar 17; 106(1 1 ): 4501-6. ). However, direct delivery of a therapeutic to the central compartment is likely to be a repetitive process, especially for the treatment a chronic neurodegenerative disease. The current invention abrogates this concern through the use of an indwelling catheter where the therapeutic is maintained within the catheter system. Thus, CSF containing noxious compounds coming in contact with the catheter that will facilitate the removal of these toxic mediators permanently and continuously without the need for repetitive invasive procedures within the central nervous system (CNS). Others disclose removal of CSF from the brain compartment through an "open" system, meaning that CSF is diverted outside the body and is either re-circulated to the brain ventricular system or is permanently removed from the body.

Devices exist having both input and output catheters for administering therapeutic agents or synthetic CSF and removing endogenous CSF, but the close spatial placement of the inflow and outflow catheters do not allow for flow of CSF throughout the cerebrospinal fluid space or full CSF exchange that provides access to the complete intracranial and intraspinal CSF volume. See, e.g., U.S. Patent Nos. 4,378,797; 4,904,237; 6,537,241 and 6,709,426. These devices also rely on either an "open" (CSF diverted outside the body) or "broken" (therapeutics need to be introduced into the device circuit from outside the body). The current application utilizes a novel approach whereby the device and therapeutic are in combination and abrogate the need for either an "open" or "broken" circuit that are associated with an ongoing risk of infection due to the nature of the system..

Furthermore, publications disclosing the exchange of CSF describe replacing endogenous CSF with synthetic CSF replacement fluid. See, e.g., U.S. Patent Publication No. 2003/0065309; and PCT Publication Nos. WO 01/154766 and WO 03/015710. It has been proposed to treat drug overdose or removal of tumor cells via a size-specific filter or CSF removal to clear debris before implantation of a ventriculo-peritoneal shunt shunt system. Such an apparatus is unnatural in that it requires flushing the entire system with an artificially produced solution rather than removing the toxins of interest from the patient's endogenous CSF, requires liters of instilled replacement fluid to be delivered on a regular basis, is neither targeted nor focused for removal of specific toxins of interest and is only practical in an acute setting where liters of fluid could be instilled. See, e.g. PCT Publication No. WO 01/54766. Thus, both the "open" or "broken" system and the introduction of synthetic CSF pose a risk of infection.

Various devices aimed at accessing the CSF or indirectly targeting the nervous system exist, however there exists no purification system that allows for the direct, targeted, logical and/or disease-specific permanent removal of one or more of target compounds from the body within a closed system or the use of a dual or multi-lumen catheter that influences or controls CSF flow, mixing and efficiency of toxin removal.

It is desirable to provide a method and system for processing and removal of one or more target compounds not only from the CSF of a patient, but, in the process, removing it from the body using a closed system that minimizes the chance for either infection as well as ensuring that the toxins cannot be re-circulated within the body resulting in further pathology (e.g., shunting of CSF to the peritoneal cavity where it may then be possible for these toxins to be re-circulated in the body). Also, by having the platform therapeutic within the body but confined to the device, this invention bypasses the concern of any toxic effect that can occur with single or repeated dosing of a therapeutic that is introduced into the body and thus the invention is viewed as having a considerable safety advantage. The invention does not directly expose the individual to any therapeutic and thus is proposed to have an excellent risk-benefit profile and therapeutic index. This invention has the capacity to respond to emerging data within the field and to add a specific therapeutic to the device that will target a new/novel observation. Furthermore, the system may be revised or changed as needed to resupply the necessary therapeutic within the device and/or remove accumulated toxins within the device. This may be done without accessing that part of the invention that is in-dwelling within the central compartment. Recently, a treatment for Alzheimer's disease was suggested which relied on removal of CSF by diversion of the fluid from the brain (ventricular system) to another portion of the patient's body (e.g. abdomen/peritoneal cavity) using a modified ventriculo-peritoneal shunt system. See, e.g., U.S. Patent Nos. 5,980,480 and 7,025,742. By continuously draining CSF at a low rate, the rationale was that the body's daily production of new CSF would dilute the concentration of contaminating substances remaining in the endogenous CSF and that the overall concentration of CSF/brain toxins would be reduced by changing the equilibrium through the removal of CSF. Such a system has several inherent limitations. The amount of a toxic species that is removed is not specifically targeted or focused for any particular toxin or group of toxins and it also does not prevent reabsorption of toxic species back into the systemic circulation and thereby back into the CSF and/or brain. See, e.g. U.S. Patent Nos. 5,980,480; 6,264,625; 6,689,085.

The present invention addresses this and other needs.

The present invention provides systems and methods for filtering cerebrospinal fluid (CSF) or interstitial fluid (ISF). Accordingly, in a first aspect, the invention provides a system for filtering cerebrospinal fluid (CSF) in a patient. In some embodiments, the systems comprise i) a catheter assembly having a first lumen with a distal port outside the central nervous system and a second lumen with a proximal port within the central nervous system said catheter being adapted to be introduced into a potential or actual central fluid space including but not limited to ventricles, and subarachnoid or interstitial spaces), and said ports being spaced axially apart; ii) a pump and/or valve connectable between the first and second lumens to regulate the flow of CSF there between; and iii) a filtering component connectable between the first and second lumens to filter the CSF flowing there between.

In some embodiments of the methods, the CSF shunt system may consist of: 1 ) a proximal catheter (inserted proximally into the cerebral ventricles, interstitial or subarachnoid spaces and linked distally to a second cavity). Many possible types and configurations are available, the mostly widely used of which are the straight and right angle ventricular catheters. This catheter may be multi-perforated or fenestrated in order to optimize CSF or interstitial fluid (ISF) flow through it. In other embodiments, the proximal tip is comprised of multiple slits or multiple holes.

2) a reservoir, which may be attached to or part of the valve (optional). When present, the reservoir may be used to assess the patency of the shunt and to access the CSF for injections and/or samples if needed or desired.

3) a unidirectional valve (or anti-reflux valve, i.e. one which prevents the flow of CSF towards the ventricles once the fluid has passed through the valve). Many types and configurations of these are available. The valve, whose function is to control the direction and rate of flow and is placed between the two catheters. The valves are designed to work at different pressures, depending on the patient, in order to provide optimal drainage of CSF and intracranial pressure. In one embodiment, the valve is programmable to allow for non-invasive adjustment of the opening pressure. In one embodiment the valve is comprised of a ruby ball and seat and stainless steel spring components in addition to the silicone exterior.

4) an anti-siphon device, which may be optionally attached to the valve. The anti-siphon device allows sudden increases in the differential pressure between the proximal and distal parts of the shunt to be corrected when subjects move from lying down to standing up.

5) a distal catheter (linked proximally to the valve and inserted distally into the peritoneal cavity or into the entrance to another fluid filled cavity with the body, e.g., the right atrium of the heart). Again, many types and configurations are available. The distal tip is usually open and may be multi- perforated in order to further facilitate the flow of CSF into the peritoneal (or cardiac) cavity. 6) connecting pieces such as tubes, which connect the catheter segments outlined above. The tubes are generally made of silicone but can be made of other types of materials.

7) a CSF filtering component. In one embodiment, the device has one or more filters, either for cells and/or for other biologic materials or debris. In another embodiment, the valve and filters are positioned between the proximal and distal catheters.

Systems are constructed from materials which have been shown to be well tolerated by the body, such as silicone, polysulphone and stainless steel or other alloys such as titanium as well as a ruby ball to be used for the valve component.

The catheter segments comprising both the proximal and the distal components are typically comprised of silicone. They may be impregnated with antibiotics such as rifampin and clindamycin/minocycline.

In one embodiment, the invention has one or more radio-opaque markers or MRI-sensitive markers to allow for non-invasive visualization of the device.

The shunt system is generally positioned under the skin with one end of the catheter placed within the ventricular system, ISF or subarachnoid space and is known as the ventricular or proximal end of the device. The other end is placed typically within the peritoneal cavity or alternatively within another fluid-filled space such as a second subarachnoid space, the spinal canal, or in the right atrium of the heart, and is called the distal end of the device. In one embodiment, the shunt may have tubes of additional length that can be coiled within the body to create a greater surface area for contact of the contaminated CSF with the device.

With respect to the embodiments of the systems, in some embodiments, the catheter assembly consists essentially of a single tubular member having an intake and an outlet lumen and port that allows for CSF/ISF to pass through and interact with the device. CSF/ISF can be sampled from the following CNS compartments: ventricle, cisterna magna, subarachnoid space, and interstitial space as well as the central canal and other spinal fluid spaces that surround the spinal cord and lumbar theca. The central fluid can be diverted to: all the above, as well as any cavity capable of accepting fluid, such as, but not limited to the peritoneal cavity, cardiac chambers, blood vessel, and urinary bladder.

In some embodiments, the first location or proximal port is in the cranial subarachnoid space. In some embodiments, the first location or proximal port is in one or more ventricles or the interstitial space of the cisterna magna. In some embodiments, the second location or distal port is in the sacral, lumbar, thoracic or cervical subarachnoid, interstitial or CSF space. In some embodiments, the second location or distal port is in the lumbar CSF space, for example at SI, L5, L4, L3, L2, LI or above or below. In some embodiments, the second location or distal port is in the peritoneal cavity.

In some embodiments, the first location or proximal port is in one or more ventricles. In some embodiments, the second location or distal port is in the peritoneal cavity. In some embodiments, the second location or distal port is in the right atrium of the heart.

In some embodiments, the first location or proximal port and the second location or distal port is in the ventricular space. For example, both the first location or proximal port and the second location or distal port can be on opposite sides of the ventricle, in another example, the first location or proximal port is in one ventricle and the second location or distal port is in another ventricle.

In some embodiments, the distance between the first location or proximal port and the second location or distal port is adjustable. For example, a pair of tubular members in a multilumen catheter can be axially adjusted relative to one another. In another embodiment, the system uses nano- or molecular or biologic motors to facilitate drainage of CSF/ISF. In some embodiments, the CSF is removed or withdrawn at a flow rate in the range from about 0.04 ml/min to about 0.33 ml/min, for example, from about 2.5 ml/hour to about 20 ml/hour, In some embodiments, the flow rate is maintained by a pump that has a flow rate adjustable between about 0.04 ml/min to about 0.33 ml/min, for example, from about 2.5 ml/hr to about 20 ml/hr. In some embodiments, fluid flow is regulated by a valve, which can either be set to allow flow within at a particular range of pressures or routinely interrogated and flexibly adjusted to the flow and pressure desired. In another embodiment, the pump comprises a peristaltic pump which is isolated from the CSF flow. In some embodiments, the pump is implantable with an Archimedes screw.

In some embodiments, the volume of CSF removed is below the volume that would induce a spinal headache or symptoms of overdrainage. In some embodiments, the volume of CSF removed from the patient never exceeds the rate of production.

In some embodiments, the distance between the first location and the second location is at least about 4 cm, for example, about 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90 or 100 cm. In some embodiments, the distance between the first location and the second location is separated by at least about 2 vertebrae.

In some embodiments, the filtering component is selected from the group consisting of biospecific affinity, biologic or immunoaffinity, cationic exchange, anionic exchange, hydrophobicity and size exclusion. For example, the filtering component can be a column or a cartridge placed with the hollow lumen of the catheter. In some embodiments, the catheter comprises the filtering component (e.g., bound to the inner surface of the catheter by covalent or non-covalent bonding).

With respect to size exclusion and filtration, the filtration component can be any type, e.g., membranous, nanoparticular, flat, tubular or capillary. In another embodiment, the system is coated with a biologic material that would capture any toxic agents. In another embodiment, a device that captures toxic agents ("capturing device ") is separate from but placed with the silicone shunt conduit. This capturing device may be a scaffold, cartridge or other device that allows for CSF sampling through it with the capture of undesirable toxic products. In another embodiment, the capture device is disposable and may be replaced as needed. In another embodiment, the capture device is part of the said shunt system and may be revised or replaced over time.

In some embodiments, the system is implantable.

Accordingly, in another aspect, the invention provides methods for filtering cerebrospinal fluid (CSF) in a patient. In some embodiments, the methods comprise: a) removing CSF from a first location in a CSF space of the patient; and b) filtering the CSF as it drains into a second location such as the peritoneal cavity, of the patient; wherein the removing and filtering steps are performed concurrently during at least a portion of a conditioning treatment.

In some embodiments, the filtering comprises removing a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. For example, the filtering can comprise one or more separation processes selected from the group consisting of biospecific affinity (e.g., antibodies, nucleic acids, receptors, enzymes), immunoaffinity, cationic exchange, anionic exchange, hydrophobicity and various size exclusion thresholds. In some embodiments, the filtering comprises removing 10% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 10% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 10% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 20% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 25% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 30% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 40% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 50% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 75% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 80% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF. In some embodiments, the filtering comprises removing 90% of a targeted molecule or number of related or distinct molecules (e.g., protein, peptide, oligopeptide) from the CSF.

In some embodiments, the filtering comprises removing pathological cells (e.g., B-cell, T-cells, macrophages, erythrocytes and other blood cells) and cellular debris.

In some embodiments, the filtering step is performed using a filtering unit implanted in the patient's body. In some embodiments, the methods comprise ameliorating the symptoms of Alzheimer's Disease in a patient by removing one or more toxin substances such as of beta-amyloid (any species or form) or tau (or any number of hyper phosphorylated tau isoforms) proteins from CSF employing the methods and systems described above and herein. In some embodiments, the methods comprise ameliorating the symptoms of Parkinson's Disease in a patient by removing at least one of alpha-synuclein proteins (including peptides or oligomers) or other toxic substances from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of Amyotrophic Lateral Sclerosis (ALS) in a patient by removing at least one of insoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, and anti-GMI ganglioside antibodies or other toxic substances from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of cerebral vasospasm in a patient by removing at least one of blood cells (e.g., erythrocytes), oxyhemoglobin and endothelin or other toxic substances from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of encephalitis in a patient by removing at least one of the causative bacterial or viral entity, tumor necrosis factor-alpha (TNFa) and IgG or other toxic substances from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of Guillain Barre Syndrome (GBS) in a patient by removing at least one of cells and inflammatory mediators including but not limited to C5a, TNF a, I L 2, IL-6, interferon-γ, IgG, and endotoxins from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of Multiple Sclerosis (MS) in a patient by removing at least one of T cells, B cells, anti-myelin antibodies and inflammatory mediators including but not limited to TNF a, IL 2, IL-6, interferon-γ from CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms of stroke in a patient by removing inflammatory mediators including but not limited to endothelin and enolase and cooling the CSF (and hence the CNS), employing the methods and systems described above and herein.

DEFINITIONS

The term "patient" refers to any mammal. The mammal can be a non- human mammal, a non-human primate or a human. In some embodiments, the mammal is a domestic animal (e.g., canine, feline, rodentia, etc.), an agricultural mammal (e.g., bovine, ovine, equine, porcine) or a laboratory mammal (rodentia, rattus, murine, lagomorpha, hamster) or a non- domesticated mammal.

The term "CSF space" refers to any volume of cerebrospinal fluid found in the cranial or spinal areas that is in contact with any component of the nervous system, and may or may not be within the tissue. Interstitial fluid may also be targeted for removal or toxic substances as described above.

The phrase "conditioning CSF" or "conditioned CSF" interchangeably refer to CSF wherein one or more target compounds have been partially, mostly or entirely removed.

The phrase "consisting essentially of" refers to the elements recited in the claim as well as insubstantial elements, and excludes elements that materially change the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 Ventricular-Peritoneal Shunt with Adsorbed or Impregnated

Biologic(s) to Scavenge CSF Toxin(s)

DETAILED DESCRIPTION

The present invention provides methods and systems for removing compounds from a patient's cerebrospinal fluid (CSF) or interstitial fluid (ISF) space. The removal of specific compounds can be tailored to the pathology of the specific disease. The removal may be targeted and specific, for example, through the use of specific size-exclusion thresholds, antibodies against specific toxins, and other chromatographic techniques or more general, targeting more than one compound or family of compounds or a diverse group of compounds (e.g., one or more species of Abeta and tau or one or more of its hyperphosphorylated forms to treat Alzheimer's disease) thought to be involved with the pathophysiology of a particular disease The invention finds use as a therapeutic platform for a variety of diseases affecting the CNS by accessing the CSF or ISF space or any other central space (including but not limited to the epidural, subdural, subarachnoid spaces).

The present invention offers a targeted, focused and logical treatment platform to treat a variety of debilitating and often devastating neurological diseases to which there are presently limited and ineffective treatment options. Exemplified disease conditions treatable by the present CSF processing systems and methods include, but are not limited to: Cerebral Vasospasm with or without subarachnoid hemorrhage, Guillain Barre Syndrome, Alzheimer's disease, mild cognitive impairment, prodromal Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple Sclerosis, Amyotrophic Lateral sclerosis, Spinal Cord Injury, Traumatic Brain Injury, Stroke, cancer affecting the brain or spinal cord, prion disease, encephalitis from various causes, meningitis from various causes, diseases secondary to enzymatic or metabolic imbalances, Biological Warfare, etc. The present invention potentially offers patients a method for reducing or ameliorating the signs and symptoms of a disease as well as a possible disease-modifying technology that addresses the known disease pathogenesis and effectively ameliorates the signs and symptoms of a number of neurological conditions. This device could also be used prophylactically in those individuals at great risk of developing a life- threatening disease. Cerebrospinal fluid (CSF) is primarily produced in the human CNS by vascular plexuses termed the choroid plexus in the lateral, third, and fourth ventricles of the brain. This normally clear fluid maintains a gradient between it, the interstitial fluid of the nervous system and the brain. Water and various substances are exchangeable to a variable degree between the CSF and the nervous system. Thus, many neurotransmitters, peptides and other neuroactive substances can be found within the CSF. The functional role of many of these peptides is not well understood and is under current research. The concentration of various neuroactive substances in the CSF or ISF is of great interest, because it represents an indirect view that corresponds closely to the extracellular fluid in the immediate vicinity of the neurons in the brain and spinal cord. Thus, CSF serves two main functions: 1 ) by coating the brain and spinal cord it provides a protective function, providing buoyancy and buffering and preventing traction on vessels and nerves upon impact to the skull or spinal column; 2) perhaps even more importantly, it contributes the maintenance of a constant composition of the neuronal environment. See, Blumenfeld, H. (2002). "Neuroanatomy through Clinical Cases." 951.

In healthy adults, CSF is produced at a rate of about 0.3 ml/min, 18 ml/hour, or about 432 ml/day. However, the total volume found in the ventricles, subarachnoid space and spinal canal is about 150 ml. Thus, the total volume of CSF is replaced several (approximately three) times each day. The CSF then spreads over the entire surface of the brain and spinal cord, providing a constant balance of extracellular fluid to individual neurons throughout the CNS. The CSF is primarily drained from the CNS by small protrusions called arachnoid granulations, which are particularly prominent along the major venous drainage sites such as the superior sagittal sinus. Fluid passes from the subarachnoid space to the venous sinuses by a hydrostatic gradient. See, Blumenfeld, H. (2002). "Neuroanatomy through Clinical Cases." In most organs, small-molecular weight substances pass through the capillary wall with relative ease, and their concentration is therefore similar in the plasma as in the interstitial (extracellular) fluid. The composition of the interstitial fluid of the CNS differs from most other organs because of the selective properties of brain capillaries, known as the blood-brain barrier (BBB). This barrier is comprised of extensive tight junctions between endothelial cells, preventing the passage of a number of substances from the peripheral plasma. Similar to the BBB, the epithelium of the choroid plexus represents an additional barrier between blood and CSF, known as the blood- CSF barrier. Neurons depend on the precise control of ions and compounds in their extracellular environment for their normal functioning. Many substances that enter the brain do so via receptor mediated and/or active transport systems although there is a passive gradient between the central and peripheral body compartments for some substances. See, Blumenfeld, H. (2002). "Neuroanatomy through Clinical Cases." 951.

Diseases affecting the nervous system are among the most devastating and debilitating medical conditions. Increasingly we understand the pathophysiology of a variety of endogenous and exogenous pathogens that can be found within the CSF and ISF that produce a direct or indirect deleterious effect on the CNS. This represents an opportunity for prevention, intervention or amelioration of the disease process. Furthermore, the system can be tailored to the individual disease process in a logical, targeted and focused manner.

It is now understood that a number of "endogenous pathogens" (cells, prions and neurotoxic molecules released from the brain into the CSF) and "exogenous pathogens" (cells, bacteria and viral pathogens and neurotoxic molecules from the peripheral circulation which enter the CSF) can perturb the normal environment of the CNS and are thought to play a key role in a number of diseases affecting the nervous system. See, Caughey, B. and P. T. Lansbury (2003). Annu Rev Neurosci 26: 267-98. Many neurodegenerative disorders are characterized by aggregates of protein fibrils and neurotoxic oligomeric (mis-folded) species as well as infiltrations of endogenous or exogenous pathological inflammatory cell types (e.g., B-cells, T-cells, macrophages) that are implicated in progressive brain degeneration. See, Caughey, B. and P. T. Lansbury (2003). Annu RevNeurosci 26: 267-98; and Taylor, J. P., J. Hardy, et al. (2002). Science 296(5575): 1991-5. See, Table 1 and Figure 5. Despite differences in the molecular composition of these protein fibrils and other toxic mediators as well as differences in the brain regions and cell types affected in each disorder, a similar mechanism of treatment from a medical device point of view can be used - i.e. filtering of the CSF and/or ISF to remove toxicities.

The CSF/ISF purification system described in the present invention serves as a broad platform technology for the treatment of a number of diseases affecting the nervous system. Several examples along with detailed rationale are provided below for a number of neurologic diseases to which there are presently limited or ineffective therapies.

It would be desirable to provide improved and alternative methods, systems, kits for the processing, purification and/or modification of CSF for a variety of purposes. The current invention possesses numerous benefits and advantages over previously described methods and uses the CSF/ISF as a conduit to gain access to toxic substances located within the central compartment. First, the removal of agents based on size (such as red blood cells, and their breakdown products in cerebral vasospasm, T- and B-cells in MS, auto-antibodies in GBS or other large molecules such as proteins, protein aggregates and nucleic acids). With the recent advances in nanotechnology and ultrafiltration, it is now possible to remove agents on the nanometer scale as well as those on the micrometer scale, offering nearly a 1000x improvement in targeted filtration than previous systems. Prior filtration methods based on size were limited to 0.2 micron filters allowing the majority of smaller toxic molecules to pass directly through the filter and back to the patient.

Second, with the recent advances in immunotherapy, the current invention applies ex-vivo immunotherapy targeted at removal of pathogenic molecules from the CSF or ISF that directly affect the CNS. Antibodies and other immunotherapies provide an unprecedented level of specificity for molecules that are too small and without size separation from physiologic molecules to remove by present-day size filters. In vivo immunotherapy applications have been met with a number of serious complications including encephalitis, vasogenic edema and death as described above. By securing the antibody to an immunoaffinity column, for example using a streptavidin- biotin system (strongest chemical bond known), CSF/ISF is processed over the antibody cartridge and sequestration of toxic substances can be achieved without any reasonable risk of systemic antibody delivery and the potential for attendant complications such as encephalitis, vasogenic edema or death. The antibodies or other therapeutic, could alternatively be affixed to the inner lumen of the catheter tubing either along the entire length of the system or for some pre-specified length. In either instance, there would be the possibility of replacing or re-charging the part of the invention that is capturing the toxic substances. The use of biologic separation (including Abeta and Tau/pTau proteins in AD, alpha-synuclein in PD, etc.) can be beneficially applied to a number of diseases by altering the neuro-immune axis using a platform ex- vivo immunotherapy approach.

The present invention allows for the processing of large volumes of CSF in a short amount of time with minimal or no impact on the endogenous intracranial/intraspinal pressure and volume.

The purification schema can be tailored to a specific disease or group of diseases based on a number of features, including size, affinity, biochemical/physicochemical properties and/or temperature, but more specifically purification schema based on diffusion, size-exclusion, ex- vivo immunotherapy using immobilized antibodies or antibody fragments, hydrophobic/hydrophilic, anionic/cationic, high/low binding affinity, chelators, anti-bacterial, anti-viral, anti-DNA/RNA, protein/amino acid, carbohydrate, enzymatic, magnetic or nanoparticle-based systems. The system allows for passive flow but may also include a mechanism of active pumping with transient or continuous flow. Furthermore, a number of measures (including, but not limited to, pressure sensor, velocity detector, bubble detector, pH, temperature, osmotic equilibrium, blood pressure, transmembrane pressure sensor) to ensure both control of CSF/ISF removal as well as patient safety are included. Pressure sensors to continuously record/maintain/adjust intracranial and/or intraspinal pressures are also available. Programmable control of intake, output and overflow exhaust valves are additional contemplated features. The system is adjustable to a broad range of biologic parameters and flows. Alarms and automatic on/off settings are further included to provide a signal for immediate attention and interrogation of the system. This part of the invention could be located at any portion of the system, although this is most typically envisioned near the proximal end of the system over the calvarium. A given volume of CSF/ISF removed from the patient's brain at any one time is typically less than that which produces symptoms associated with spinal headache or overdrainage.

A portion of the purification system can be incorporated into the catheter itself by fashioning it with a membrane, filter or cartridge that allows for the passive or active filtration of the endogenous CSF.

In some embodiments, the catheter includes radio-opaque markers for the accurate localization and confirmation of catheter tip location in the cranial or spinal CSF spaces as well as other key components of the invention (e.g., placement within the peritoneal cavity). The radio-opaque markers can then be visualized using simple X-ray or computerized tomography. A variety of other methods can be utilized to confirm accurate catheter deployment and placement. This includes the use of an endoscope to directly visualize placement of the cranial or spinal catheter. This method may especially be useful in those patients with small cranial ventricles containing CSF or in those patients with spinal stenosis or scoliosis, where lumbar access is challenging.

One of the major concerns of any implanted device is the risk for infection. The risk of infection in the CSF is serious and includes meningitis, encephalitis and even death. A number of safety measures can be incorporated into the present invention to minimize the possible risk of patient infection. First, the proximal end of the catheter can be tunneled a variable distance away from the entry site to minimize the risk of organisms tracking back in from the skin surface entry site. The rate of infection can be further reduced by having a completely contained and completely implanted system. Second, meticulous care on a daily basis to clean access site(s) of catheter if the invention is externalized in the case of temporary CSF/ISF drainage. Third, immediately before catheter placement as well as during the time the catheter remains indwelling during CSF processing and immediately after removal, antibiotics can be administered to the patient to further reduce the risk of infection. Fourth, the catheter system itself can be impregnated with a specific antibiotic of choice. Fifth, a specific metal and/or flexible catheter material can be used to produce a transiently charged surface or otherwise minimize/prohibit the ability of bacteria or other organisms to adhere to its surface. This has been shown to deter bacterial ingrowth and the incidence of catheter infections in general, can be incorporated. Sixth, an antibiotic of choice can be delivered into the CSF a certain time before, during or after CSF processing to further eliminate the risk of bacterial seeding or infection. Finally, an antibiotic cuff at one or more places along the catheter system can be placed to further reduce any risk of infection.

Another concern of any catheter system is the risk of kinking or physical obstruction. Incorporating certain shape memory materials in catheters for use in the CSF space and for the length of the system can be an added strategy of preventing kinking, maintaining shape, and allowing for maximum access of the CSF space. Nickel titanium is a shape memory alloy also commonly referred to as Nitinol. Above its transformation temperature, it is superelastic and able to withstand a large amount of deformation. Below its transformation temperature, it displays a shape memory effect. When it is deformed, it will remain in that shape until heated above its transformation temperature, at which time it will return to its original shape. Nitinol is typically composed of 55% nickel by weight and making small changes in the composition can change the transition temperature of the alloy significantly which makes it suitable for many applications in medicine. In some embodiments, the catheter incorporates nickel titanium in its manufacturing. Such a catheter would allow for the easy entry of the catheter via the cranial or spinal access routes due to superelastic nature of Nitinol, while once in the CSF space the catheter would be return to its prior structure due to its shape memory. Nitinol's physical function resembles biological muscle; when activated it contracts. The contraction movement may be applied to any task requiring physical movement with low to moderate cycling speeds. The small size, light weight, ease of use and silent operation allow it to even replace small motors or solenoids. Such a catheter system that is internally adjustable and tailored to access varying areas of the cranial or spinal CSF space while minimizing the risk of kinking and catheter obstruction would be an additional feature in the present invention.

The present systems allow for a number of different CSF outflow connections for the processing of CSF between any point in the CSF system such that total outflow is relatively equal during at least most of the time it is operational. The spatial location of the inflow and outflow ports are sufficiently distant to allow for CSF flow throughout a major portion or the entire CSF space. The custom cranial or spinal catheters can be introduced via a number of routes, including but not limited to: single ventricular insertion, dual ventricular insertion, cisterna magna, single level spinal insertion, dual/multi- level spinal insertion and ventriculo-spinal. In some embodiments, a first catheter is inserted into a brain ventricle or into the cervical spine, and a second catheter is inserted into the lumbar spine. In addition, any of the above systems could be fashioned to exchange CSF from any two points within the subarachnoid space. One example is a ventricular catheter with entry/exit sites communicating with the subarachnoid space overlying the adjacent brain parenchyma. The epidural, subdural and interstitial spaces may also be accessed.

The present systems allow for the active movement of a wide range of CSF volumes over time, and do not require the removal of CSF from the human body. Due to the varying entry and exit sites in the custom catheter, the system allows for the production of active, in addition to the normally passive, CSF flow. The active movement of CSF can be generated in a number of ways including but not limited to motorized pumps for active CSF withdrawal. Furthermore, the pump system can have a variety of mechanisms which facilitate the requirement that inflow and outflow are relatively equal. Examples of suitable pumps include, but are not limited to, rotatory, syringe- driven, volumetric, peristaltic, piston, pneumatic, bellows, electromagnetic, magnetostrictive, hydraulic, nano- and biologic/molecular. The pumps can be a single apparatus with bi-directional functionality or two unidirectional pumps that are in communication with one another. There are several pumping mechanisms available to reach the desired endpoint of creating active, in addition to the normally passive, flow of CSF. The pump can be external or internal to the patient's body. Internal or implantable pumps are known in the art (e.g., an Archimedes screw pump). The rate of CSF flow could also be pre-determined through the use of a one-way valve that opens above a certain desired ICP and would not open if the ICP were below that value. These valves would also include an anti-siphon device so that there was not a difference in flow based on body position (e.g., supine versus standing). In some embodiments, the systems provide a customizable filtering system based on the specific disease process being addressed. Removal of specific compounds or other biological material can be targeted based on size-exclusion, specific antibodies, hydrophobic-hydrophilic interactions, anionic-cationic exchangers, compounds with high-low binding affinity, antibacterial, anti-viral, anti-DNA/RNA, protein size or secondary, tertiary or quaternary structure, immunotherapy-based, immuno-modulatory, enzymatic digestion, etc. In addition to the variety of neurochemical filtration approaches, other filtration systems based on electromechanical basis including, but not limited to, radiofrequency, electromagnetic, acoustic wave, piezoelectric, electrostatic, nano-, molecular/biologic forces, atomic force and ultrasonic filtration can be employed. Other features can be added to the filter system including a differential centrifugal force to aid in the rapid separation of items of interest, e.g. ultrafiltrate, proteins, cells, etc.

In some embodiments, a cartridge-based schema can be employed for rapid changing or combinations of the aforementioned purification-based schema. For example, a system combining size, antibody and charge based approaches is envisioned with single or multiple cartridges for the purification, such that when the time came for replacement of the purification filter, antibody, etc., it could be done in an easy to use, rapid exchange system. The filtering system or chromatographic cartridges (e.g., biospecific interaction, ionic exchangers, size exclusion) can be external or internal to a patient's body. In some embodiments, the filtering cartridges or filters are contained within one or more lumens of the single or multilumen catheters. In some embodiments, the lumen of the catheters, or sections thereof, are coated (e.g., by covalent or non-covalent binding) with chromatographic moieties (e.g., biospecific capture moieties, including antibodies and nucleic acids, cationic or anionic exchangers, hydrophobic moieties, and the like).

In some embodiments, the systems include sensors or reservoirs for the intermittent or continuous monitoring, sampling and/or quantification of CSF levels of specific compounds or parameters of interest. For instance, in cerebral vasospasm, one could serially sample and quantify levels of red blood cells, hemogolobin, endothelin, or other molecules or biologic substances and have an indication of how much the system has cleared the CSF. Similarly in Alzheimer's, one could measure levels of Αβ, Tau/pTau or other molecules and have an indication of production or removal of specific items of interest. Sensors may be utilized to record/maintain/adjust levels of specific compounds in the CSF noninvasively. The reservoirs could also be placed both proximal and distal to the site of toxin removal in order to asses the efficiency of removal.

The shunt typically consists of two catheter tubes that are interconnected by a pressure control valve. In one embodiment, the valve is both one-way (unidirectional) and has an anti-siphon device. The proximal catheter, referred to as the ventricular catheter, has one end inserted through a hole that is drilled in the skull through which the catheter is placed into a ventricle (or cisterna magna) of the brain. The other end of the ventricular catheter is connected to the pressure control valve, which is typically implanted under the scalp. The second catheter, known as the drainage catheter, has one end connected to the pressure control valve, and the other end of the drainage catheter empties into a lower body cavity, usually the peritoneal cavity.

The pressure control valve is designed to open at a predetermined pressure to allow drainage of CSF from the ventricle of the brain to the peritoneal cavity, where it is re-absorbed by the body. This maintains the CSF pressure in the brain within a set range of values. The pressure control valve can be of a number of different designs. Some pressure control valves use flexible elastomeric membranes to flex open under pressure, while others use ball and spring designs or other means to open in order to control CSF pressure. In one embodiment, the valve can be interrogated by an external device that will allow the user to change the pressure range over which the valve is functional and hence control the rate of CSF flow. To reduce risk of infection, the valves are designed to allow CSF flow only out of the brain, and not back into the brain.

An additional effect occurs when CSF flows through the shunt, not because of a positive pressure in the brain, but due to the negative (suction) pressure created because the lower end of the drainage catheter is typically at a lower level then the end of the ventricular catheter in the brain, or because the egress pressure is less than the intracranial pressure. This effect is commonly known as the siphoning effect and causes CSF to drain even when the CSF pressure in the brain is within normal or set parameters. The siphoning effect varies with the position of the patient, being the most extreme siphoning effect occurs when the patient is upright, while there is virtually no siphon effect when the patient is lying down. In all situations, however, the siphoning effect is extremely undesirable and must be eliminated or kept to an absolute minimum.

To control unwanted siphoning, the filtering systems are equipped with a second valve (a siphon control valve) placed in line with the pressure control valve in order to prevent or reduce siphoning. In another embodiment, the anti-siphon device could be part of the pressure control valve. The basic principle is generally one or more flexible walls of a chamber surrounding a port through which the fluid must flow to drain. The flexible walls are designed to collapse onto and occlude the port when negative pressure is experienced. This provides additional flow resistance to counteract the effect of the negative pressure, while still allowing drainage under positive pressure from the brain.

CSF is removed from the cranial or spinal CSF space passed through a disease- specific filtering system and returned to a different location in the patient, now considerably reduced or absent of the toxic substances that had been targeted for removal. CSF is removed using a combination of natural passive flow but potentially augmenting it with a pumping mechanism to produce an active CSF flow dynamics. The locations of the catheter may vary but include single, multi-lumen or a combination of catheters placed via single ventricular insertion, dual ventricular insertion, cisterna magna, subarachnoid, epidural, subdural, interstitail, single level spinal insertion, dual/multi-level spinal insertion and ventriculo-spinal.

The flow rates may be varied and are limited by the pressure differential placed on the catheter walls, but generally can be in the range of 0.04 ml/min to approximately 0.33 ml/min, for example, about 2.5 to 20 ml/hr.

The CSF is then filtered using a variety of mechanisms as described above and generally include size and other physicochemical properties, biospecific, and/or temperature-mediated mechanisms. In performing the filtering step, the removed CSF is contacted with one or more substrates comprising selection agents.

The methods provide a customizable filtering schema based on the specific disease process being addressed and the target compounds to be removed from the CSF. Depending on the one or more target compounds to be removed (e.g., proteins, oligomeric peptides, amino acids, nucleic acids, bacteria, small molecules, etc.), the CSF can be contacted with one or more substrates comprising size-exclusion filtration, hydrophobic-hydrophilic interactions, anionic-cationic exchangers, compounds with high-low binding affinity, anti-bacterial, antiviral, biospecific interactions including nucleic acid hybridization and immunoaffinity (e.g., antibodies or non-antibody binding proteins), enzymatic digestion, or a combination thereof. Antibodies can be whole immunoglobulin molecules or fragments thereof (e.g., FAb, single chain variable regions (scFv), variable regions). Non-antibody binding molecules, for example, based on A-domain scaffolding, also find use. In addition to the variety of chromatographic approaches, filtration systems based on electromechanical bases also find use, including radiofrequency, electromagnetic, acoustic wave, piezoelectric, electrostatic, nano-, molecular/biologic forces, atomic force and ultrasonic filtration can be employed. The CSF may also be subject to differential centrifugal force to aid in the rapid separation of items of interest, e.g. ultrafiltrate, proteins, cells, etc.

In some embodiments, the CSF is contacted with multiple substrates, e.g., combining size, biospecific and charge-based selection criteria. The conditioning step can be performed external or internal to a patient's body. In some embodiments, the conditioning substrates are contained within one or more lumens of the multilumen catheters. In some embodiments, the lumen of the catheters, or sections thereof, is coated (e.g., by covalent or non- covalent binding) with chromatographic moieties (e.g., biospecific capture moieties, including antibodies and nucleic acids, cationic or anionic exchangers, hydrophobic moieties, and the like).

The concept of ex-vivo immunotherapy (i.e., immunoaffinity) using the CSF is itself a broadly applicable and novel component of the present invention. A number of conditions affecting the nervous system are now better understood and a common feature is a disruption in the neuroimmune axis or weak points in the blood brain barrier allowing B-cells, T-cells and the humoral and cell-mediated immune responses or the overproduction or underutilized clearance of toxic substances made within the brain and/or spinal cord. In each instance, the normal neuronal (and perhaps glial) architecture is victim to a broad range of toxic substances, neuro- inflammatory components and reactive oxidative stress proteins. The present invention allows for targeted removal of these toxic substances, inflammatory cells and proteins and elimination and/or neutralization of oxidative stress proteins.

With regards to immunotherapy, present day active and passive immunotherapy treatments carry significant risk of vasogenic edema, encephalitis or generalized neuronal inflammation as well as other adverse events. By harnessing the immunotherapy components in an immobilized immunoaffinity approach, one can bring the CSF to the antibody and prevent any risk of mounting a generalized immune response against oneself or any other adverse event as the therapeutic remains within the device and does not enter the body to any significant extent.. Furthermore, this eliminates the risk of a number of potential safety issues, including the generation of autoantibodies against systemically delivered immunotherapies, which could have devastating effects and high mortality in a subset of patients. Cartridge- based schema would allow for further rapid replacement of the conditioning approach. This approach can also minimize the number of interactions where the subject needs to return for follow-up care and/or additional therapeutic intervention.

The methods contemplate the possible periodic re-use or re-charging of the filtration/processing component of the system. For instance, in the ex- vivo immunotherapy approach, a specific eluent can be used to release the captured oligomers or proteins and regenerate the active antigen binding sites on the antibodies. Furthermore, this eluted compound represents a purified human protein which can then be used as a "neuropharmaceutical" agent. For example, in Alzheimer's disease, purified Αβ or Tau/pTau components may then be released and used for a variety of other commercial or research studies involving the structure-activity function and relationship of disease-specific compounds in human disease. Also, the ability to automatically or periodically collect CSF or specific subcomponents without resorting to a lumbar puncture and store/freeze creating a CSF bank for specific disease processes is contemplated.

Methods of Ameliorating Disease Conditions

i. Alzheimer's Disease (AD)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulations of amyloid plaques and neurofibrillary tangles. Amyloid plaque formation is thought to be partly due to failure of clearance of beta-amyloid protein (Αβ). APP (amyloid precursor protein) generates various forms of amyloid Αβ through enzymatic processing. See, Blennow, K., M. J. de Leon, et al. (2006). Lancet 368(9533): 387-403. Diffusible oligomers of Αβ (from plaques) are neurotoxic, inhibit long term potentiation, cause membrane damage, alter membrane fluidity, and act as pore-forming toxins. See, Caughey, B. and P. T. Lansbury (2003). Annu RevNeurosci 26: 267-98; and Glabe, C. G. (2006). Neurobiol Aging 27(4): 570-5. In AD, tau and ptau proteins also aggregate, resulting in degeneration of neuronal axons and dendrites and producing neurofibrillary tangles. Tau protein accumulation leads to cellular oxidative stress, which may be a causal factor in tau-induced neurodegeneration. See, Dias-Santagata, D., T. A. Fulga, et al. (2007). J Clin Invest 1 17(1 ): 236-45. Specifically, highly reactive oxygen species oxidize lipids, proteins, and DNA, leading to tissue damage and cell death. These markers for oxidized lipids and proteins accumulate in regions that are particularly affected in neurodegenerative diseases. Markers of oxidative damage have been detected in brain tissue from patients with AD and other neurodegenerative disorders. See, Koo, E. H., P. T. Lansbury, Jr., et al. (1999). Proc Natl Acad Sd USA 96(18): 9989-90. Free radical injury also appears to be a fundamental pathophysiologic mediator of tissue injury in human disease, including acute ischemic stroke, amyotrophic lateral sclerosis, Parkinson's disease, and AD. See, Taylor, J. P., J. Hardy, et al. (2002). Science 296(5575): 1991-5. Current therapies for AD are only marginally effective, as they may not slow rate of neurodegeneration, and have significant side-effects. Some strategies currently being investigated (e.g., immunotherapy) have an unclear risk-benefit ratio at best. Except for the placement of the current invention, there are very few additional risks that are envisioned.

In contrast, CSF processing of amyloid and tau/ptau proteins and neutralization of reactive oxidative species among others is both a symptomatic and disease-modifying treatment through its ability to reduce, limit, and prevent plaque and tangle formation as well as counteract neuro- inflammation. It has the ability to address the disease process from multiple different perspectives based on our present day understanding of disease pathogenesis. It may also be safer due to lower risk of liver and other end- organ damage as well as brain inflammation compared to current pharmacologic and immunotherapeutic regimens, respectively, as the therapeutic is never in direct contact with any body organ or solid tissue.

Accordingly, the present methods provide for ameliorating or reducing the symptoms of Alzheimer's disease by reducing or eliminating the presence of beta-amyloid and/or tau/pTau proteins (and/or any other toxic biological entity) in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of pathological proteins, including Αβ and tau/ptau, and inflammatory mediators (e.g., cytokines, including TNF-a, IL-I, IL-2, IL-6, I L- 12, interferon- γ, etc.) from the CSF, and shunting the filtered CSF to another body compartment. In some embodiments, the Αβ or tau/ptau proteins and/or inflammatory mediators are removed from the CSF using an immunoaffinity/size exclusion column; a filtering cartridge or both. In some embodiments, the Αβ or tau/ptau proteins and/or inflammatory mediators are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters. Depending on any given individual's diagnosis, this invention can be individualized to specifically treat their abnormality. This is another feature as not everyone with a specific disease has the same profile of abnormalities. Further embodiments for treating Alzheimer's disease are as discussed above and herein.

In another embodiment, other diseases manifesting either overexpression or altered processing of APP, such as Down's syndrome (DS) and cerebral amyloid angiopathy may also be treated with this device.

In another embodiment, other dementias (e.g., fronto-temporal, Lewy body, dementia with PD, ALS or Huntington's disease, vascular, etc ..) may also be treated with this device.

ii. Parkinson's Disease (PD) Parkinson's disease (PD) is caused by a loss of dopamine-containing pigmented neurons in the substantia nigra. Free radical injury and formation of alpha-synuclein fibrils and oligomers (i.e., peptides) are involved in pathogenesis of PD. See, Steece-Collier, K., E. Maries, et al. (2002). Proc Natl Acad Sci USA 99(22): 13972-4. Current treatments (dopamine replacement therapy with L-dopa, Catechol-O-methyl transferase (COMT) inhibitors, amantadine and anticholinergic medications for symptomatic relief, surgery with deep brain stimulation) do not have a long-lasting effect, do not address the cause of disease and can have debilitation side-effects including dyskinesias. See, Dunnett, S. B. and A. Bjorklund (1999). Nature 399(6738 Suppl): A32-9; Dawson, T. M. and V. L. Dawson (2003). Science 302(5646): 819-22; and DeKosky, S. T. and K. Marek (2003). Science 302(5646): 830-4. There is a need for treatment that halts degeneration by removing such substances as free radicals and neurotoxic species. See, Shoulson, I. (1998). Science 282(5391 ): 1072-4. CSF filtration fulfills that unmet medical need and can represent a disease-modifying mechanism for new PD treatments.

Accordingly, the present methods provide for ameliorating or reducing the symptoms of Parkinson's disease by reducing or eliminating the presence of alpha-synuclein fibrils and/or oligomers in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one toxic substance such as alpha- synuclein proteins or inflammatory mediators from the CSF, and shunting the filtered CSF to a second body compartment. In some embodiments, the alpha- synuclein fibrils and oligomers are removed from the CSF using an immunoaffinity column or a size exclusion column, or both. In some embodiments, the alpha-synuclein fibrils and oligomers are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters. Further embodiments for treating Alzheimer's disease are as discussed above and herein. Further embodiments for treating Parkinson's disease are as discussed above and herein.

iii. Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS)/Lou Gehrig's Disease is a rapidly progressive, invariably fatal motor neuron disease that attacks the nerve cells responsible for controlling voluntary muscles. See, Rowland, L. P. (1995). Proc Natl Acad Sci USA 92(5): 1251 -3. Both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. ALS patients had higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die when they are exposed over long periods to excessive amounts of glutamate. See, Rowland, L. P. (1995). Proc Natl Acad Sci U S A 92(5) : 1251-3. Increased levels of neurofilament protein were found in CSF of ALS patients as well as increased levels of antibodies against GMI- gangliosides, AGMI-gangliosides and sulfatides in 20%, 15%, 8% of CSF of ALS patients, respectively. See, Valentine, J. S. and P. J. Hart (2003). Proc Natl Acad Sci USA 100(7): 3617- 22; and Band, L, I. Bertini, et al. (2007). Proc Natl Acad Sci USA 104(27): 1 1263-7. Thus, toxic antibodies may be implicated in ALS by impairing the function of motor neurons, interfering with the transmission of signals between the brain and muscle. Free radical injury is also likely to be involved in ALS. A marker of oxidative stress and lipid peroxidation, 4-hydroxynonenal (HNE), was elevated in the CSF of patients with sporadic ALS. Current clinical treatments for ALS (Riluzole) that reduce the amount of glutamate released do not reverse the damage already done to motor neurons and cause side-effects such as hepatotoxicity. In ALS, CSF purification would reduce excessively high glutamate levels in CSF and reduce oxidative species, thus prolonging the lifespan of motor neurons w/o serious side effects such as liver damage, and it would remove autoimmune antibodies and reactive oxidative species from CSF. Accordingly, the present methods provide for ameliorating or reducing the symptoms of Amyotrophic lateral sclerosis (ALS) by reducing or eliminating the presence of one or more of insoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, and anti-GMI ganglioside antibodies in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of the toxic substances such as insoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, and anti-GMI ganglioside antibodies or other inflammatory mediators from the CSF, and shunting the filtered CSF to another body compartment. In some embodiments, the insoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, anti-GMI ganglioside antibodies or other inflammatory or toxic mediators are removed from the CSF using one or more immunoaffinity columns, a size exclusion column, an anionic exchange column, a cationic exchange column, and a Protein A or Protein G column. In other embodiments, the insoluble superoxide dismutase-1 (SODI), glutamate, neurofilament protein, anti-GMI ganglioside antibodies or other inflammatory or toxic mediators are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters.

Further embodiments for treating Amyotrophic lateral sclerosis (ALS) are as discussed above and herein,

iv. Cerebral Vasospasm

Cerebral vasospasm is a time-dependent narrowing of cerebral vessel caliber, typically due to blood in the subarachnoid space (post cerebral aneurysm rupture, subarachnoid hemorrhage (SAH), craniocerebral trauma, bacterial meningitis, after surgery in the sellar/parasellar region, etc.). See, Macdonald, R. L, R. M. Pluta, et al. (2007). Nat CHn Pract Neurol 3(5): 256- 63. Hemolysis appears necessary for vasospasm to develop and oxyhemoglobin is believed to be one of the many vasoactive substance released. Elevated levels of oxyhemoglobin are maintained in the CSF over the duration of vasospasm, in contrast, most other vasoactive agents released after clot lysis are rapidly cleared from the CSF. See, Macdonald, R. L, R. M. Pluta, et al. (2007). Nat CHn Pract Neurol 3(5): 256-63. In subarachnoid patients with vasospasm, endothelin in the CSF remained at or increased above levels measured before surgery. The increase coincided with the appearance of vasospasm as documented by transcranial doppler and clinical symptoms. In SAH patients who did not develop vasospasm, the concentration of endothelin in the CSF decreased with time. See, Macdonald, R. L, R. M. Pluta, et al. (2007). Nat CHn Pract Neurol 3(5): 256-63. Current therapies (calcium channel blockers, hypervolemic, hypertensive therapy and hemodilution (HHH therapy)) may not be very effective in preventing vasospasm and have their own risk of significant adverse events. CSF filtration is more likely to be therapeutic by early and direct removal of blood clot, red blood cells, platelets and the downstream cascades involving various toxic substances such as oxyhemoglobin and endothelin that lead to vasospasm.

Accordingly, the present methods provide for ameliorating or reducing the signs and symptoms of cerebral vasospasm by reducing or eliminating the presence of one or more of blood cells (e.g., erythrocytes), hemoglobin, oxyhemoglobin, endothelin or other inflammatory or toxic mediators in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of the toxic substances such as blood cells, hemoglobin, oxyhemoglobin, endothelin or inflammatory or toxic mediators from the CSF, and shunting the filtered CSF to a second body compartment. In some embodiments, the oxyhemoglobin and endothelin are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anionic exchange column, and a cationic exchange column. In other embodiments, the oxyhemoglobin and endothelin are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters. Further embodiments for treating cerebral vasospasm are as discussed above and herein,

v. Encephalitis

Encephalitis is inflammation of the brain due to multiple causes: HSV (herpes simplex virus), Lyme disease, syphilis, bacterial infection, etc. Infants younger than 1 year and adults older than 55 are at greatest risk of death from encephalitis. See, Vernino, S., M. Geschwind, et al. (2007). Neurologist 13(3): 140-7. Current therapies (corticosteroids to reduce brain swelling and NSAIDs to decrease fever) do not target the cause of encephalitis. Levels of sTNF-R (reflects biologic activity of TNF-alpha, a major inflammatory mediator) were significantly higher in the CSF and serum of children with acute encephalitis than in those of control subjects. See, Vernino, S., M. Geschwind, et al. (2007). Neurologist 13(3): 140-7. Levels of IgG were increased in herpes simplex encephalitis. See, Vernino, S., M. Geschwind, et al. (2007). Neurologist 13(3): 140-7. CSF processing could restore levels of TNF-alpha and IgG to physiologic levels, reduce inflammation and aid in removal of viruses, parasites, prions, fungi and bacteria. Further applications include treating victims of biologic warfare (anthrax, botulinum, ricin, saxitoxin, etc.) by directly removing the toxin of interest from attacking the CNS.

Accordingly, the present methods provide for ameliorating or reducing the symptoms of encephalitis by reducing or eliminating the presence of one or more toxic mediators such as tumor necrosis factor-alpha (TNFa) and IgG in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of TNFa and IgG or other inflammatory mediators from the CSF or other toxic mediators, and shunting the filtered CSF to a second body compartment. In some embodiments, the TNFa and IgG are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anionic exchange column, a cationic exchange column and a Protein A or Protein G column. In other embodiments, the TNFa and IgG are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters.

Further embodiments for treating encephalitis are as discussed above and herein.

vi. Guillain Barre Syndrome (GBS)

Guillain Barre Syndrome (GBS) is divided into the two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). See, Parkhill, J., B. W. Wren, et al. (2000). Nature 403(6770): 665-8; and Yuki, N., K. Susuki, et al. (2004). Proc Natl Acad Sd USA 101 (31 ): 1 1404-9. In Europe and North America, GBS is usually caused by AIDP with prominent lymphocytic infiltration of the peripheral nerves and macrophage invasion of myelin sheath and Schwann cells. Activated complement found in cerebrospinal fluid of Guillain-Barre and multiple sclerosis (MS) patients may contribute to demyelination. See, Parkhill, J., B. W. Wren, et al. (2000). Nature 403(6770): 665-8; and Yuki, N., K. Susuki, et al. (2004). Proc Natl Acad Sci USA 101 (31 ): 1 1404-9. Treatment of GBS is subdivided into symptomatic management of severely paralyzed patients requiring intensive care and ventilatory support, and specific disease therapy to lessen the nerve damage.

Accordingly, the present methods provide for ameliorating or reducing the symptoms of Guillain Barre Syndrome (GBS) by reducing or eliminating the presence of one or more of cells and inflammatory mediators selected from the group that includes C5a, TNF-a, IL-2, IL-6, interferon-γ, IgG, and endotoxins in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of cells and inflammatory or toxic mediators selected from the group that includes C5a, TNF-a, IL-2, IL-6, interferon-γ, IgG, and endotoxins from the CSF, and shunting the filtered CSF to a second body compartment. In some embodiments, the cells and inflammatory or toxic mediators selected from the group such as C5a, TNF-a, IL-2, IL-6, interferon-γ, IgG, and endotoxins are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anionic exchange column, a cationic exchange column and a Protein A or Protein G column. In some embodiments, the cells and inflammatory or toxic mediators selected from the group which includes C5a, TNF-a, IL-2, IL-6, interferon-γ, IgG, and endotoxins are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters.

Further embodiments for treating Guillain Barre Syndrome are as discussed above and herein.

vii. Multiple Sclerosis (MS)

Multiple sclerosis (MS) is the most common demyelinating disease in humans and has an unknown etiology. However, it is widely accepted to be an autoimmune disease mediated by autoreactive T lymphocytes with specificity for myelin antigens. See, Noseworthy, J. H. (1999). Nature 399(6738 SuppI): A40-7. The pathologic hallmark of the disease is the MS plaque, an area of white matter demyelination usually accompanied by inflammatory infiltrate composed of T lymphocytes, some B cells and plasma cells, activated macrophages or microglial cells. IgG and complement are localized primarily at the periphery of plaques. B lymphocyte clones accumulate in the CSF of MS patients and patients with other neurological disorders. Anti- myelin-oligodendrocyte glycoprotein antibodies were detected in CSF from seven of the patients with MS, compared to two with other neurological diseases and one with tension headache. See, Hohlfeld, R. and H. Wekerle (2004). Proc Natl Acad Sd USA 101 SuppI 2: 14599-606. Elevated numbers of CD4+ T helper cells can be found in the CSF during early exacerabations. Osteopontin is increased in patients' plasma before and during relapses and was found to induce worsening autoimmune relapses and severe progression of myelinating diseases. See, Hohlfeld, R. and H. Wekerle (2004). Proc Natl Acad Sd USA 101 SuppI 2: 14599-606. Current therapies include global immunosuppression mediated by steroids, monoclonal antibody targeting the cellular adhesion molecule a4-integrin (anti-VLA4), interferon beta therapy, monoclonal antibody treatments and peptide fragments similar to myelin proteins. Although some of these therapies represent medical advances, they are associated with very significant AEs, including progressive, multifocal leukoencephalopathy (PML). CSF purification would have the advantage of removing deleterious cell populations or mediators, and alleviating the effects of MS exacerbations by actions such as: 1 ) removal of autoreactive CD4+ and CD8+, 2) reduction in the levels of pro-inflammatory cytokines and 3) reduction in the production of autoreactive antibodies by B cells. Depletion of these autoreactive cell populations also can reduce the recurrence of MS exacerbations, limit permanent damage caused by the inflammation seen in an exacerbation, and prevent lesions that mark progression of the disease. By restricting this depletion to the CSF, the present systems and methods addresses these issues without many of the complications associated with steroid treatment, systemic immunosuppression or the adverse events with other biological therapeutics (e.g., PML)..

Accordingly, the present methods provide for ameliorating or reducing the symptoms of multiple sclerosis (MS) by reducing or eliminating the presence of one or more toxic substances such as T cells, B cells, anti-myelin antibodies and inflammatory mediators selected from the group consisting of TNF-a, IL-2, IL-6, interferon-γ in the CSF using the systems described herein. The methods comprise removing CSF from a patient, as described herein; removing at least one of T cells, B cells, anti-myelin antibodies and inflammatory mediators selected from the group of toxic mediators which includes TNF-a, IL-2, IL-6, interferon-γ from the CSF, and returning the endogenous CSF to the patient (within a closed system), wherein the removing and returning steps are performed concurrently during at least a portion of the treatment. In some embodiments, the T cells, B cells, anti- myelin antibodies and inflammatory mediators selected from the group consisting of TNF-a, IL-2, IL-6, interferon-γ are removed from the CSF using one or more of an immunoaffmity column, a size exclusion column, an anionic exchange column, a cationic exchange column and a Protein A or Protein G column. In some embodiments, the T cells, B cells, anti-myelin antibodies and inflammatory mediators selected from the group which includes TNF-a, IL-2, IL-6, interferon-γ are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters.

Further embodiments for treating multiple sclerosis (MS) are as discussed above and herein.

viii. Stroke

Stroke occurs when a blood clot blocks an artery or a blood vessel ruptures, interrupting blood flow to an area of the brain; brain cells then begin to die and brain damage occurs. Free radical injury is one of the toxic mediators implicated in pathogenesis of stroke damage. CSF enolase was raised in patients with transient ischemic attacks and patients with complete strokes. See, McCulloch, J. and D. Dewar (2001 ). Proc Natl Acad Sd USA 98(20): 10989-91. A high cerebrospinal fluid enolase was always associated with a poor prognosis. Endothelin 1 (ET-I), a highly potent endogenous vasoactive peptide, exerts a sustained vasoconstrictive effect on cerebral vessels. See, Mascia, L, L. Fedorko, et al. (2001 ). Stroke 32(5): 1 185-90; and Kessler, I. M., Y. G. Pacheco, et al. (2005). SurgNeurol 64 SuppI 1 : SI :2- 5; discussion Sl:5. Elevation of ET-I in plasma has been reported 1 to 3 days after ischemic stroke. Mean CSF concentration of ET-I in the CSF of stroke patients was 16.06±4.9 pg/mL, compared with 5.51 =1 =1.47 pg/mL in the control group (P<.001 ). See, Mascia, L., L. Fedorko, et al. (2001 ). Stroke 32(5): 1 185-90; and Kessler, I. M., Y. G. Pacheco, et al. (2005). Surg Neurol 64 SuppI 1 : S 1 :2-5; discussion S 1 :5. Current stroke management is only marginally effective for most patients and includes symptomatic treatment (surgery, hospital care, and rehabilitation) or carries a risk of brain hemorrhage (cerebral angioplasty and use of tissue plasminogen activator (tPA) to dissolve acute clot in vessel) and must be initiated with an ~ 4.5 hour window of time. Similarly, traumatic brain injury (TBI) or spinal cord injury (SCI) occurs when sudden trauma affects the brain or spinal cord following both low and high velocity insults to the brain and/or spinal cord, including falls, motor vehicle accidents, assaults etc. Current treatment of TBI and SCI focuses on increasing independence in everyday life and rehabilitation (i.e. individual therapy). Moderate hypothermia is thought to limit deleterious metabolic processes that can exacerbate injury. CSF processing would allow for the removal of toxic and neuroinflammatory components such as enolase, ET-I, free radicals or hemoglobin and its breakdown products.

Accordingly, the present methods provide for ameliorating or reducing the symptoms of stroke, traumatic brain injury (TBI), spinal cord injury (SCI) by reducing or eliminating the presence of one or more toxic mediators such as endothelin, enolase, hemoglobin or other inflammatory mediators in the CSF using the systems described herein. The methods comprise removing CSF from a patient's brain; removing at least one of endothelin and enolase from the CSF, and shunting the filtered CSF to a second body compartment. In some embodiments, the endothelin and enolase or other inflammatory mediators are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anionic exchange column, a cationic exchange column and a Protein A or Protein G column. In some embodiments, the endothelin, enolase, hemoglobin or other inflammatory mediators are removed from the CSF by antibodies or other therapeutics affixed to the inner lumen of the tubing connecting the catheters.

Further embodiments for treating stroke are as discussed above and herein.

The above described system can also optionally be used in combination with other therapeutic- symptomatic, neuroprotective or neurorecovery active agents. Such an active agent may be, for example, an atypical antipsychotic, a cholinesterase inhibitor, NMDA receptor antagonist or latrepirdine. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone; such NMDA receptor antagonists include but are not limited to memantine; and such cholinesterase inhibitors include but are not limited to donepezil, galantamine and rivastigmine.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.