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  Pharmaceutical Patents  

 

Title:  Poly-Glu,Tyr for neuroprotective therapy
United States Patent: 
7,399,740
Issued: 
July 15, 2008

Inventors:
 Eisenbach-Schwartz; Michal (Rehovot, IL), Yoles; Ester (D.N. Nahal Sorek, IL), Hauben; Ehud (Hadera, IL)
Assignee:
  Yeda Research and Development Co. Ltd. (Rehovot, IL)
Appl. No.:
 10/807,414
Filed:
 March 24, 2004


 

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Abstract

Methods and compositions are provided for preventing or inhibiting neuronal degeneration, or for promoting nerve regeneration, in the central nervous system (CNS) or peripheral nervous system (PNS), or for protecting nerves from glutamate toxicity, which comprises administering to an individual in need thereof an effective amount of the copolymer poly-Glu,Tyr.

Description of the Invention

SUMMARY OF THE INVENTION

It has now been found by the present inventors that poly-Glu,Tyr can protect nerves from glutamate toxicity and from undergoing secondary degeneration following spinal cord contusion, and also following chronic elevation of intraocular pressure and cerebral ischemia. It was further found that active immunization with poly-Glu,Tyr attenuates neuronal degeneration induced by glutamate toxicity or by mechanical injury to the spinal cord.

The present invention thus relates to a method for preventing or inhibiting neuronal degeneration, or for promoting nerve regeneration, in the CNS or PNS, or for protecting nerves from glutamate toxicity, which comprises administering to an individual in need thereof an effective amount of poly-Glu,Tyr.

The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of poly-Glu,Tyr and methods for using such compositions to promote nerve regeneration or to prevent or inhibit neuronal degeneration in the CNS or PNS, or for protecting nerves from glutamate toxicity, in an amount which is effective to ameliorate the effects of an injury or disease of the NS.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms "poly-YE", "polyYE", "pYE", and "poly-Glu,Tyr" are each used interchangeably to denote a random copolymer comprising residues of L-glutamic acid and L-tyrosine. Any poly-Glu,Tyr presently available or to be discovered in the future is encompassed by the present invention, but most preferred is the random copolymer poly-Glu:Tyr 1:1, most preferably the sodium salt of poly-Glu:Tyr 1:1, mol wt 20,000-50,000, preferably 20,000-40,000 Da.

The compositions of the invention comprising poly-Glu,Tyr may be used to promote nerve regeneration or to prevent or inhibit secondary degeneration which may otherwise follow primary NS injury, e.g., closed head injuries and blunt trauma, such as those caused by participation in dangerous sports, penetrating trauma, such as gunshot wounds, hemorrhagic stroke, ischemic stroke, glaucoma, cerebral ischemia, or damages caused by surgery such as tumor excision. In addition, such compositions may be used to ameliorate the effects of disease that result in a degenerative process, e.g., degeneration occurring in either gray or white matter (or both) as a result of various diseases or disorders, including, without limitation: diabetic neuropathy, senile dementias, Alzheimer's disease, Parkinson's disease, facial nerve (Bell's) palsy, glaucoma, Huntington's chorea, amyotrophic lateral sclerosis (ALS), status epilepticus, non-arteritic optic neuropathy, intervertebral disc herniation, vitamin deficiency, prion diseases such as Creutzfeldt-Jakob disease, carpal tunnel syndrome, peripheral neuropathies associated with various diseases including, but not limited to, uremia, porphyria, hypoglycemia, Sjorgren Larsson syndrome, acute sensory neuropathy, chronic ataxic neuropathy, biliary cirrhosis, primary amyloidosis, obstructive lung diseases, acromegaly, malabsorption syndromes, polycythemia vera, IgA and IgG gammapathies, complications of various drugs (e.g., metronidazole) and toxins (e.g., alcohol or organophosphates), Charcot-Marie-Tooth disease, ataxia telangiectasia, Friedreich's ataxia, Guillain-Barre syndrome, amyloid polyneuropathies, adrenomyelo-neuropathy, Giant axonal neuropathy, Refsum's disease, Fabry's disease, lipoproteinemia, etc.

In light of the findings with respect to the glutamate protective aspect of the present invention, other clinical conditions that may be treated in accordance with the present invention include epilepsy, amnesia, anxiety, hyperalgesia, psychosis, seizures, abnormally elevated intraocular pressure, oxidative stress, and opiate tolerance and dependence. In addition, the glutamate protective aspect of the present invention, i.e., treating injury or disease caused or exacerbated by glutamate toxicity, can include post-operative treatments such as for tumor removal from the CNS and other forms of surgery on the CNS.

In view of the fact that poly-Glu,Tyr immunization has been surprisingly found useful in protecting against glutamate toxicity, it is expected that poly-Glu,Tyr treatment in accordance with the present invention will be effective in the treatment of the above listed conditions not only in a late phase when myelin is being affected, but also in the early stages in which the neurons are being attacked by factors which cause an elevation in glutamate levels to toxic levels. Thus, the present invention is useful for any indication, i.e., chronic or acute neurodegeneration, which is caused or exacerbated by an elevation in glutamate levels, including the early stages of ischemic stroke, Alzheimer's disease, etc.

The present invention provides a method for preventing or inhibiting neuronal degeneration, or for promoting nerve regeneration, in the central nervous system (CNS) or peripheral nervous system (PNS), or for protecting nerves from glutamate toxicity, which comprises administering to an individual in need thereof an amount of poly-Glu,Tyr effective to prevent or inhibit neuronal degeneration, or to promote nerve regeneration, in the CNS or PNS, or to protect nerves from glutamate toxicity.

In one embodiment, the compositions of the invention comprising poly-Glu,Tyr are used in a method to promote nerve regeneration or to prevent or inhibit secondary degeneration which may otherwise follow primary CNS injury.

In one preferred embodiment, the present invention relates to a method for reducing neuronal degeneration caused by the neurodegenerative effects of an injury, disease, disorder or condition in the CNS or PNS of the individual in need, which comprises administering poly-Glu,Tyr in an amount effective to reduce the neurodegeneration caused by said injury, disease, disorder or condition.

In a preferred embodiment, the individual in need is one suffering from secondary neuronal degeneration resulting from an injury that has caused primary neuronal damage.

Thus, in a preferred embodiment, the method of the present invention comprises administering poly-Glu,Tyr to an individual in need for treating neurodegenerative effects caused by a primary injury, in an amount effective to reduce neuronal degeneration caused by said primary injury. The primary injury includes spinal cord injury, closed head injury, blunt trauma such as those caused by participation in dangerous sports, penetrating trauma such as gunshot wounds, hemorrhagic stroke, ischemic stroke, cerebral ischemia, optic nerve injury, myocardial infarction and injury caused by surgery such as tumor excision.

In one more preferred embodiment, the injury is myocardial infarction. In another more preferred embodiment, the injury is spinal cord injury. I a still more preferred embodiment, the injury is ischemic stroke.

In another preferred embodiment, the method of present invention comprises administering poly-Glu,Tyr to an individual in need for treating neurodegenerative effects caused by a condition, disorder or disease associated with the eye, such as non-arteritic optic neuropathy, age-related macular degeneration, a retinal disorder or a disease associated with elevated intraocular pressure, e.g. glaucoma, in an amount effective to reduce neuronal degeneration caused by said condition, disorder or disease associated with the eye. In a most preferred embodiment of the invention, poly-Glu,Tyr is administered for preventing or reducing optic nerve degeneration in glaucoma patients.

In another preferred embodiment, the present invention provides a method for treating an injury, disease, disorder or condition caused or exacerbated by glutamate toxicity, which comprises administering poly-Glu,Tyr to the individual in need in an amount effective to ameliorate the neurodegeneration caused or exacerbated by glutamate toxicity.

According to this embodiment, the disease, disorder or condition caused or exacerbated by glutamate toxicity may be a neurodegenerative disease such as a senile dementia of both Alzheimer's type and non-Alzheimer's type, Parkinson's disease, facial nerve (Bell's) palsy, glaucoma, Huntington's chorea, a motor neurone disease such as amyotrophic lateral sclerosis (ALS), Alper's disease, Batten disease, Cockayne syndrome, Lewy body disease, Guillain-Barre syndrome, and a prion disease such as Creutzfeldt-Jakob disease.

Thus, poly-Glu,Tyr may be used to ameliorate the effects of disease or disorder that result in a degenerative process, e.g. degeneration occurring in either gray or white matter (or both) as a result of the chronic neurodegenerative diseases recited in the previous paragraph or as a result of further diseases, disorders and conditions. For example, in a patient suffering from Huntington's disease, poly-Glu,Tyr is administered in an amount therapeutically effective to reduce disease progression and/or to protect the patient from neurodegeneration and/or from glutamate toxicity. In a patient suffering from a motor neurone disease, poly-Glu,Tyr is administered in an amount effective to reduce disease progression, and/or to protect the patient from motor nerve degeneration and/or from glutamate toxicity. In a particular embodiment, the motor neurone disease is amyotrophic lateral sclerosis (ALS) and poly-Glu,Tyr may be administered to the ALS patient as sole therapy or in combined therapy with Riluzole. In a patient suffering from Alzheimer's disease, poly-Glu,Tyr is administered in an amount therapeutically effective to reduce disease progression and/or to protect the patient from neurodegeneration and/or from glutamate toxicity and/or to reduce memory loss associated with the disease.

In another embodiment of the invention, poly-Glu,Tyr may be used for the treatment of a peripheral neuropathy. Peripheral neuropathy, a general term referring to disorders of the PNS, can be associated with poor nutrition, a number of diseases, and pressure or trauma. Known etiologies include complications of other diseases, mainly diabetes. Nearly 60% of all people with diabetes suffer from peripheral neuropathy. Peripheral neuropathy can be classified by where it occurs in the body: nerve damage that occurs in one area of the body is called mononeuropathy, and in many areas, polyneuropathy. It can also be categorized by cause such as diabetic neuropathy and nutritional neuropathy. When a cause cannot be identified, the condition is called idiopathic neuropathy.

According to the present invention, poly-Glu,Tyr may be used for the treatment of peripheral neuropathies, both mononeuropathies and polyneuropathies, caused by or associated with many diseases, disorders and conditions.

Examples of peripheral neuropathies that may be treated with poly-Glu,Tyr according to the invention include, but are not limited to, adrenomyeloneuropathy, alcoholic neuropathy (associated with chronic alcoholism), amyloid neuropathy or polyneuropathy (caused by amyloidosis), axonal neuropathy, chronic sensory ataxic neuropathy associated with Sjogren's syndrome, diabetic neuropathy, an entrapment neuropathy or nerve compression syndrome such as carpal tunnel syndrome or a nerve root compression that may follow cervical or lumbar intervertebral disc herniation, giant axonal neuropathy, hepatic neuropathy (associated with viral hepatitis, liver cirrhosis, or biliary cirrhosis), ischemic neuropathy, nutritional polyneuropathy (due to nutritional deficits such as vitamin, e.g. vitamin B6, B12 deficiency, malabsorption syndromes and alcoholism), porphyric polyneuropathy (a severe form associated with various types of porphyria), toxic neuropathy (caused by toxins such as organophosphates), uremic polyneuropathy (caused by the uremia of chronic renal failure), a neuropathy associated with a disease or disorder such as acromegaly, ataxia telangiectasia, Charcot-Marie-Tooth disease, chronic obstructive pulmonary diseases, Fabry's disease, Friedreich ataxia, Guillain-Barre syndrome (an acute inflammatory polyneuropathy), hypoglycemia, IgG or IgA monoclonal gammopathy (non-malignant or associated with multiple myeloma or with osteosclerotic myeloma), lipoproteinemia, polycythemia vera, Refsum's syndrome, Reye's syndrome, Sjogren-Larsson syndrome, or a polyneuropathy associated with various drugs (e.g., nitrofurantoin and metronidazole), or a polyneuropathy associated with hypoglycemia, with infections such as HIV infection, or with cancer (radiation treatments, chemotherapy or the cancer can be the cause of the nerve damage).

As mentioned before, other clinical conditions that may be treated in accordance with the present invention include epilepsy, amnesia, anxiety, hyperalgesia, psychosis, seizures, abnormally elevated intraocular pressure, oxidative stress, and opiate tolerance and dependence.

Thus, in another preferred embodiment of the invention, poly-Glu,Tyr is used for the treatment of a psychosis or psychiatric disorder selected from the group consisting of an anxiety disorder, a mood disorder, schizophrenia or a schizophrenia-related disorder, drug use and drug dependence and withdrawal, and a memory loss or cognitive disorder.

The psychosis or psychiatric disorder that can be treated according to the invention is selected from: (i) anxiety disorders, that include phobic disorders, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), acute stress disorder and generalized anxiety disorder; (ii) mood disorders, that include depression, dysthymic disorder, bipolar disorders and cyclothymic disorder; (iii) schizophrenia and related disorders such as brief psychotic disorder, schizophreniform disorder, schizoaffective disorder and delusional disorder; (iv) dependence on or withdrawal from a drug of abuse such as alcoholism, opiate dependence, cocaine dependence, amphetamine dependence, hallucinogen dependence, and phencyclidine use; and (v) memory loss disorders such as amnesia or memory loss associated with Alzheimer's type dementia or with non-Alzheimer's type dementia, e.g. multi-infarct dementia or memory loss associated with Parkinson's disease, Huntington's disease, Creutzfeld-Jakob disease, head trauma, HIV infection, hypothyroidism and vitamin B12 deficiency, and cognitive deficits in children or in adults associated with psychosis, drug-induced psychosis, stroke, and sexual dysfunction. The cognitive problems may be related to thinking, reasoning, problem solving, visual perception and auditory processing problems, including difficulties in spatial cognition and orientation, e.g. object localization, spatial memory, awareness of position and place. In this aspect, poly-Glu,Tyr may also be useful for improving memory (both short term and long term) and learning ability.

In one preferred embodiment, poly-Glu,Tyr is used for treatment of schizophrenia; in another embodiment, for treatment of depression; and in another embodiment, for improving memory in patients suffering from memory loss associated with a disease or disorder as defined in (v) in the previous paragraph.

In another preferred embodiment of the invention, poly-Glu,Tyr may be used for treatment of individuals exposed to neurotoxins, e.g. nerve gases such as organophosphate nerve gases, for example, sarin.

In another preferred embodiment of the invention, poly-Glu,Tyr may be used in post-operative treatments such as for tumor removal from the CNS and other forms of surgery on the CNS, that may be caused or exacerbated by glutamate toxicity.

Acute and/or chronic injuries to the adult CNS in the brain, spinal cord and the visual system lead to the irreversible loss of function resulting from the loss of neurons and the very scarce neurogenesis in the adult CNS. The injury is often compounded by the inability of nerve cells within the CNS to regenerate damaged axons, eventually inducing degeneration of the entire neuron. In addition, regardless of the initial cause of the primary injury, the dying cells cause accumulation of neural toxic molecules at the site of the injury. Due to failure to cope with the accumulating toxic molecules, neurons and glial cells adjacent to the site of the primary injury die, leading to additional progressive neuronal loss--a phenomenon known as secondary degeneration. The volume of tissue destroyed by secondary degeneration is usually larger than that caused by the initial injury. The use of a neuroprotective agent that can mitigate the adversities associated with secondary neurodegeneration could preserve nerve function. Towards minimizing neuronal loss (neuroprotection), several approaches have been adopted in the past, with the most common approach targeting the risk factors in an attempt to neutralize or inhibit their actions. Unfortunately, these therapeutic strategies showed marginal efficacy in human subjects and with concomitant severe side effects. The failure of agents with discrete singular mechanism of action argues for a multi-pronged approach.

Injury to the CNS triggers the immediate death of injured neurons, and this is inevitably followed by a series of destructive processes, collectively termed secondary degeneration (Yoles and Schwartz, 1998), which result in the gradually spreading degeneration and death of initially undamaged adjacent neural cells. The processes of secondary degeneration are mediated mainly by destructive self-compounds that emanate from the directly damaged neurons and render the extracellular environment hostile to recovery. Until very recently, the prevailing view was that the CNS, being an immune-privileged site, cannot benefit from immune intervention and that all immune activity is detrimental. Studies by our group showed, however, that one way in which the hostility of the environment at the damaged site can be circumvented is by eliciting a systemic defensive activity that homes to the lesion site and helps the innate arm of the immune system to fight off the toxicity. This assistance is provided by the spontaneous recruitment of T cells specific to CNS-related self-antigens (Hauben et al., 2000b). The autoimmune T cells home to the site of the lesion and become activated there by encountering their specific antigens, which are presented to them by antigen-presenting cells (e.g. activated microglia). Thus, contrary to the prevailing belief that the immune system is always harmful to the CNS, our work suggested that the CNS withstands injurious post-injury conditions by eliciting a protective autoimmunity (Moalem et al., 1999).

Further studies by our group showed that adult rats or mice deficient in mature T cells, or deprived (as a result of immunization at birth with spinal cord homogenate) of T cells specific to self-antigens residing in the site of damage, are unable to withstand injurious conditions in the CNS (Kipnis et al., 2001; Schori et al., 2002). The T cells that participate in protection were found to possess a phenotype characteristic of Th1 cells (Kipnis et al., 2002b). These and related results led us to formulate the concept of "protective autoimmunity" as a physiological mechanism of protection against destructive self-compounds (Schwartz and Kipnis, 2001; Yoles et al., 2001). When stressed, the CNS signals to the immune system to help regulate self-compounds that have exceeded their normal physiological levels and become toxic. This recruited immune activity is in the form of autoimmune T cells directed against abundant antigens residing in the site of stress. This discovery not only challenges the way we view immune activity in the brain and thus the meaning of immune "privilege", but also changes the way we view autoimmunity: Instead of seeing autoimmunity as a "mistake" in which the body attacks its own tissues, it can be seen as the body's way of defending itself against self-enemies.

One of the self-enemies that has received a great deal of attention in the last two decades is glutamate, an amino acid pivotal for the functioning of the CNS. Yet when glutamate exceeds its normal physiological levels it is a major cause of neuronal toxicity and death. Unregulated levels of glutamate have been associated with psychogenic and neurodegenerative disorders. After it was discovered that autoimmunity helps regulate glutamate toxicity as well as other local CNS threats, it became clear that it might be possible to develop therapeutic approaches to psychogenic and neurodegenerative diseases by regulating this beneficial autoimmune response. This boosting takes the form of therapeutic vaccination using self- or self-like peptides which promote autoimmune protection without inducing autoimmune disease. Thus, our group showed that this physiological response can be boosted by injection (passive transfer) of activated autoimmune T cells (Moalem et al., 1999; Kipnis et al., 2002b; Hauben et al., 2000a) or by active vaccination with self- or self-related antigens (Hauben et al., 2001a, 2001b; Kipnis et al., 2000; Schori et al., 2001a).

Moreover, the spontaneous protective response was found to be suppressed by the constitutive presence of naturally occurring regulatory T cells (Treg) cells. Thus, nude mice replenished with splenocytes deprived of Treg are better able to withstand injurious conditions in the CNS than their matched wild-type controls or nude mice replenished with a population consisting of the full complement of spleen cells (Kipnis et al., 2002a; Schwartz and Kipnis, 2002).

The naturally occurring CD4.sup.+CD25.sup.+ cells, which comprise about 10% of the total CD4.sup.+ population, are the so-called (natural) regulatory T cells (Treg). Treg cells display suppressive functions in vitro or in vivo, and were originally called suppressor T cells. Treg cells express the transmembrane protein called CD25, the a chain of the IL-2 receptor (Sakaguchi et al., 1995). CD4.sup.+CD25.sup.+ T cells are potent suppressors of the activation of both CD4.sup.+ and CD8.sup.+ T cells in vitro and also potent suppressors of a large number of animal models of autoimmunity, including gastritis, thyroiditis, inflammatory bowel disease and insulin-dependent diabetes mellitus. Both suppressor cytokines, such as interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-.beta., and a cell-contact-dependent mechanism, may have a role in the suppression of the disease in vivo (Shevach, 2002).

As described above, recent evidence provided by the present inventors indicates that autoimmunity, that has long been viewed as a destructive process, is the body's endogenous response to CNS injury and its purpose is in fact beneficial. This neuroprotective autoimmunity was shown by the inventors to be inhibited by naturally occurring CD4.sup.+CD25.sup.+ cells, that suppressed an endogenous T-cell mediated neuroprotective mechanism to achieve maximal activation of autoimmunity and, therefore, to withstand injury to the CNS (Kipnis et al., 2002a).

Thus, it can be summarized that the peripheral immune response to injury is part of a natural repair mechanism of the human body. This spontaneous T cell-mediated neuroprotective immune response can be enhanced by accumulation of activated T cells at the site of injury. This may be achieved either by active immunization of the individual with a nervous tissue-specific antigen, e.g. MBP, a MBP peptide, or an altered MBP peptide, or by passive immunization with MBP-activated T cells as shown previously by the inventors (Moalem et al., 1999; Hauben et al., 2001a; WO 99/060021; WO 02/055010), or by circumventing the tissue specificity using weak antigens like Copolymer 1 or poly-Glu,Tyr, or by down-regulating the suppressive effect of the Treg cells.

It has further been unexpectedly found in accordance with the present invention that poly-Glu,Tyr down-regulates the suppressive activity of the Treg cells on the autoimmune Teff cells.

Thus, administration of poly-Glu,Tyr according to the invention follows a fundamentally different approach to nerve preservation and restoration, taking advantage of natural physiological mechanisms of protection and self-healing via the immune system. As described above, activation of the autoimmune response is part of a physiological repair mechanism following CNS damage. However, this response is restricted in the CNS by naturally-occurring Treg cells. An appropriately controlled boost to the immune response by administering poly-Glu,Tyr that down-regulates the suppressive activity of Treg on the autoreactive effector T cells, protects CNS cells from further degeneration and enhances functional recovery. This is accomplished by causing the effector T cells, which recognize their antigen at the lesion site, to home there, and activate the resident cells to eliminate self-destructive compounds that cause nerve degeneration and to secrete growth factors that may induce axonal elongation, synaptogenesis and neurogenesis.

According to the present invention, poly-Glu,Tyr is shown to down-regulate the suppressive activity of Treg cells on the Teff cells, and thus to boost the spontaneous protective activity of T cells at the site of injury or disease.

In another aspect, the present invention relates to a method for down-regulation of the suppressive activity of CD4.sup.+CD25.sup.+ regulatory T cells (Treg) on CD4.sup.+CD25.sup.- effector T cells (Teff), modulation of the immune response, modulation of the autoimmune response, protection from glutamate toxicity, or a combination thereof, in an individual suffering from a neurological, neurodegenerative or psychiatric injury, condition, disorder or disease, which comprises administering to said individual in need an amount of the copolymer poly-Glu,Tyr effective for the treatment of said neurological, neurodegenerative or psychiatric injury, condition, disorder or disease.

In still another aspect, the present invention relates to a method for conferring neuroprotection to an individual suffering from a neurological, neurodegenerative or psychiatric injury, disease, disorder or condition, which comprises administering poly-Glu,Tyr to the individual in need in an amount effective to ameliorate the neurodegeneration associated with said neurological, neurodegenerative or psychiatric injury, disease, disorder or condition.

It is envisaged by the present invention that poly-Glu,Tyr affords neuroprotective activity and broad therapeutic benefits to all injuries, diseases, disorders and conditions in the CNS and PNS defined in the present specification and in the claims, irrespective of their etiology and/or associated risk factors.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Methods of administration of compositions containing poly-Glu,Tyr include, but are not limited to, parenteral, e.g., intravenous, intraperitoneal, intramuscular, subcutaneous, mucosal (e.g., oral, intranasal, buccal, vaginal, rectal, intraocular), intrathecal, topical and intradermal routes. Administration can be systemic or local. Most preferably, poly-Glu,Tyr is administered subcutaneously or topically, e.g. as eye drops.

As shown hereinafter in Section III of the Examples, poly-Glu,Tyr can be administered as eye drops both for treatment of an injury, disease or disorder associated with the eye, particularly glaucoma, and of any other CNS or PNS injury, disease or disorder, because the effect of poly-Glu,Tyr administered as eye drops is systemic.

Thus, in one preferred embodiment, the invention provides pharmaceutical compositions in the form of eye drops comprising poly-Glu,Tyr and a pharmaceutically acceptable carrier.

The compositions may be formulated for subcutaneous and parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen free water, before use. Where the composition is administered by injection, an ampoule of sterile water or saline for injection can be provided so that the ingredients may be mixed prior to administration.

Pharmaceutical compositions comprising poly-Glu,Tyr may be also administered with an adjuvant in the usual manner for immunization, but preferably no adjuvant is added to the composition.

The present invention also provides a pharmaceutical kit comprising a package housing a container containing poly-Glu,Tyr, and instructions for using poly-Glu,Tyr in the treatment of an injury, condition, disease or disorder as described in the specification in order to prevent or inhibit neuronal degeneration caused by said injury, condition, disease or disorder, or to protect from glutamate toxicity.

As will be evident to those skilled in the art, the therapeutic dose of poly-Glu,Tyr to be administered to the individual in need will be determined by the physician and will depend on the injury, condition, disorder or disease to be treated, on the individual's age and health condition, on other physical parameters (e.g., gender, weight, etc.) of the individual, as well as on various other factors, e.g., whether the individual is taking other drugs. In general, the dose will be from 0.1 to 100, preferably 10-50, more preferably, 15-30, and most preferably, 20 mg poly-Glu,Tyr per person.

According to the invention, poly-Glu,Tyr may be administered as a single dose or may be repeated, preferably at 4 weeks intervals, and then at successively longer intervals, once every two months, once every three months, once every six months, etc. The course of treatment may last several months, several years or occasionally also through the life-time of the individual, depending on the condition or disease which is being treated. In the case of a CNS injury, the treatment may range between several days to months or even years, until the condition has stabilized and there is no or only a limited risk of development of secondary degeneration. In chronic human disease such as glaucoma, Alzheimer's disease or Parkinson's disease, the therapeutic treatment in accordance with the invention may be for life.

It is envisaged by the present invention that poly-Glu,Tyr will be used as sole therapy or that it is used in conjunction with a drug commonly used for the treatment of the injury, disease, disorder or condition being treated. For example, for the treatment of ALS, the treatment may include administration of poly-Glu,Tyr together with Riluzole; for the treatment of glaucoma, the treatment may include administration of poly-Glu,Tyr together with a drug that decreases the intraocular pressure; for the treatment of ischemic stroke, the treatment may include administration of poly-Glu,Tyr together with an anti-clot drug; or before exposure to organophosphate nerve gases, the individual may receive the usual antidote treatment (e.g., atropine) followed by an anti-convulsant after exposure, e.g. midazolam.

The present invention further provides an article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, said pharmaceutical composition comprising poly-Glu,Tyr; and said packaging material includes a label that indicates that poly-Glu,Tyr is therapeutically effective for conferring neuroprotection to an individual suffering from a neurological, neurodegenerative or psychiatric injury, disease, disorder or condition, wherein said neurological, neurodegenerative or psychiatric injury, disease, disorder or condition is as described hereinbefore in the specification.
 

Claim 1 of 11 Claims

1. A method for down-regulating the suppressive activity of CD4.sup.+CD25.sup.+ T.sub.reg cells at the site of a lesion in the central or peripheral nervous system, comprising administering to a subject in need, an amount of poly-Glu,Tyr effective to down-regulate the suppressive activity of CD4.sup.+CD25.sup.+ T.sub.reg cells at the lesion site.

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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