EP0729361A1 - Procede de traitement de troubles neurologiques - Google Patents

Procede de traitement de troubles neurologiques

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Publication number
EP0729361A1
EP0729361A1 EP95901254A EP95901254A EP0729361A1 EP 0729361 A1 EP0729361 A1 EP 0729361A1 EP 95901254 A EP95901254 A EP 95901254A EP 95901254 A EP95901254 A EP 95901254A EP 0729361 A1 EP0729361 A1 EP 0729361A1
Authority
EP
European Patent Office
Prior art keywords
igf
igfbp
complex
insulin
growth factor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95901254A
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German (de)
English (en)
Other versions
EP0729361A4 (fr
Inventor
Christopher A. Maack
Debra Brown
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Celtrix Pharmaceuticals Inc
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Celtrix Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Celtrix Pharmaceuticals Inc filed Critical Celtrix Pharmaceuticals Inc
Publication of EP0729361A1 publication Critical patent/EP0729361A1/fr
Publication of EP0729361A4 publication Critical patent/EP0729361A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • IGFBP-3 may be synthesized by recombinant organisms as discussed in Sommer, A. S., et. al. , In Modern Concepts of Insulin- Like Growth Factors (E. M. Spencer, ed. , Elsevier, New York) 715-728 (1991) . This recombinant IGFBP-3 binds IGF-I in a 1:1 molar ratio. The topical administration of the IGF-I/IGFBP-3 complex to rat and pig wounds was significantly more effective than IGF-I alone. Sommer et.
  • Patent Cooperation Treaty Publication No. WO 92/19256 published on November 12, 1992 and applied for by Kabi Pharmacia AB, discloses a method for inducing nerve regeneration by treating subjects suffering from neuropathy or degenerative neural disorders with IGF-II or IGF-II + IGF-I. The use of any IGF binding protein in these treatments is not disclosed.
  • IGF-II mRNA is somewhat elevated in the choroid plexus, cerebellum and medulla- pons, and somewhat reduced in midbrain and corpus striatum.
  • IGF-II mRNA is synthesized by cultured embryonic astroglial but not neuronal cells. Both mRNAs are highest at embryonic day 8-14 in rat brain, and decline from this peak to the adult level by the time of birth.
  • IGF-I and IGF-II have also been detected in cerebrospinal fluid (CSF) and by immunohistochemistry in human, rat and cat brain. IGF-II immunoreactivity in the brain is higher than that of IGF-I.
  • CSF cerebrospinal fluid
  • IGF-II immunoreactivity in the brain is higher than that of IGF-I.
  • Adult and fetal human brain contain both the normal form of IGF-I and a truncated form of IGF-I missing three N-terminal amino acids.
  • IGF-I peptide is also secreted by cultured rat glioma cells. IGF-II immunoreactivity is highest in the anterior pituitary, dorsomedial hypothalamus and supraoptic nucleus of the brain.
  • IGF-II Intraleukin-II peptides
  • IGF-II Intraleukin-II peptides
  • IGF-I genes in neural tissue is under complex hormonal control.
  • basic fibroblast growth factor bFGF
  • dexamethasone and retinoic acid which inhibit the growth of rat glioma cells, reduce the accumulation of IGF-I mRNA and inhibit the secretion of IGF-I peptide by these cells.
  • Type I IGF receptors which transduce mitogenic and differentiation signals provided by the IGFs, are also present in the brain.
  • concentration and distribution of this receptor varies during development.
  • brain Type I receptor levels are quite high (4-10 times higher than in the adult) , and the receptor is especially abundant in the superficial cortical layers, nucleus accumbens and hippocampus.
  • Type I receptor levels are reduced and the receptor is more evenly distributed. There is some receptor enrichment in adult superficial and deep cortical layers, olfactory bulb, endopiriform nucleus, basomedial nucleus of the amygdala, thalamic nuclei and hippocampus.
  • Brain Type I IGF receptor is present in two forms, a normal sized form and a somewhat smaller form than that found in peripheral tissues. Hence this size difference is largely due to reduced glycosylation of the smaller of the brain species.
  • bFGF increases the synthesis of Type I IGF- receptors in cultured neuronal and glial cells.
  • IGFBP KDa IGFBP.
  • the glial cultures secreted approximately 5 times as much IGFBP-2 as did the embryonic neuronal cultures, and IGFBP-2 was the only IGFBP secreted by choroid plexus cultures. In contrast, gliomas and astrocytes synthesized predominantly IGFBP-3.
  • the regulation of IGFBP synthesis has not been extensively studied, but it is known that bFGF treatment greatly increases IGFBP secretion by neuronal cultures and inhibits IGFBP secretion in glial cultures. IGF-I stimulated IGFBP secretion in both cultures and in the rat neuroblastoma cell line B104.
  • IGF-I and IGF-II are mitogenic (ie. stimulate cell division) for oligodendrocyte precursor cells from cultured perinatal rat cerebrum explants, embryonic rat sympathetic neuroblasts, human neuroblastoma cells, newborn rat astroglial cells, and neonatal rat cerebral cortex astrocytes.
  • IGF-I has been shown to promote the survival of various types of cultured nervous system cells.
  • IGF-I acts as a survival factor in cultured embryonic mouse neuroepithelial cells.
  • bFGF which is mitogenic for these cells, induces endogenous production of IGF-I, which is required for the expression of the mitogenic effect of bFGF.
  • autocrine production of IGF-I has been implicated as the mediator of at least part of the mitogenic effect of epidermal growth factor (EGF) on cultured newborn rat astroglial cells.
  • EGF-I epidermal growth factor
  • IGF-I has also been shown to protect rat hippocampal and septal neuronal cell cultures from hypoglycemia-induced damage by stabilizing neuronal calcium homeostasis.
  • IGF-II nerve growth factor
  • IGF-II substantially stimulate rapid neurite outgrowth in embryonic chick spinal cord motor neurons in culture.
  • IGF-II administered daily to mouse gluteus muscle caused rapid, marked terminal and nodal neuronal sprouting of neurites. This effect was detectable after as little as 3 days of treatment and produced 10 fold more neurite sprouts in IGF-II treated than control muscle after one week of treatment.
  • IGF-II treatment also caused a nearly 5-fold increase in the number of endplates that had formed neurite sprouts.
  • transgenic mice expressing a human IGF-IA transgene developed substantially larger brains than their control littermates.
  • the brains of the transgenic mice expressing hIGF-I also contained substantially more myelin than did the brains of their control littermates.
  • IGF insulin-like growth factor
  • IGFBP-3) in an amount sufficient to alleviate said condition.
  • the IGF used in the complex is provided as IGF-I.
  • IGF and IGF are provided as IGF-I.
  • IGFBP are present in equimolar amounts.
  • both IGF and IGFBP-3 are human proteins obtained from recombinant sources.
  • the complex of IGF and IGFBP-3 is administered parenterally. In a further embodiment, the complex is administered by subcutaneous injection.
  • the subject to whom the complex is administered is a mammal.
  • the method provides for treating a subject for exposure to neurotoxins, cerebrovascular hemorrhage, neuronal scission during surgery, meningitis or other infection of tissues of the nervous system.
  • the method includes administration of the IGF/IGFBP-3 complex in an amount sufficient to alleviate the condition.
  • the method provides a treatment for multiple sclerosis, amyotrophic lateral sclerosis or Charcot-Marie-Tooth disease, in which the subject is parenterally administered a complex of IGF/IGFBP-3 in an amount sufficient to alleviate said condition.
  • the IGF/IGFBP complex can be administered using normal parenteral routes for the treatment of peripheral nervous system disorders or for the treatment of central nervous system disorders in which the blood brain barrier is compromised (eg. multiple sclerosis) , thus allowing the passage of complex into the brain.
  • the IGF/IGFBP complex can be administered directly to the CNS by intracranial administration, such as by an implanted shunt into the ventricles of the brain.
  • the Inventors propose that the administered complex of IGF and IGFBP-3 results in the gradual release of free IGF in elevated levels. This graded, long lasting increase in bioavailable IGF stimulates the growth, survival and maturation of neuronal tissue cells without causing the local or systemic side effects commonly observed in treatments with free IGF (eg. hypoglycemia, receptor down regulation, growth hormone suppression) .
  • Subjects are defined as humans and mammalian farm animals, sport animals and pets. Farm animals include, but are not limited to, cows, hogs and sheep. Sport animals include, but are not limited to, dogs and horses. The category pets includes, but is not limited to, cats and dogs.
  • IGF insulin-like growth factor
  • IGF-I comprises a family of factors, including, but not limited to, IGF-I and IGF-II.
  • IGF is a polypeptide having a molecular weight of about 7500 daltons. IGF may be obtained from natural sources or prepared by recombinant means.
  • IGFBPs Insulin-like growth factor binding proteins
  • IGFBPs comprises a family of binding proteins, including but not limited to IGFBP-1, IGFBP-2, IGFBP-3,
  • IGFBP-4, IGFBP-5 and IGFBP-6 IGFBP may be obtained from natural sources or prepared by recombinant means. At least one form of IGFBP (for example, IGFBP-3) complexes with IGF and with a third molecule known as ALS.
  • a "therapeutic composition” as used herein is defined as comprising IGF complexed with its binding protein IGFBP-3. The therapeutic composition also contains other substances such as water, minerals and carriers such as proteins. "Alleviation of the condition" is said to occur when the subject to whom the IGF/IGFBP-3 complex is administered exhibits improved function of affected nervous tissue.
  • improvements include, but are not limited to, improved coordination of movement, improved muscle function and strength, decreased pain, reduced numbness of extremities, and increased sensory function (eg. touch) .
  • improvements include, but are not limited to, improved ability to reason, improved memory, improved speech, improved coordination or movement, reduced pain and improved sensory function (eg. sight, hearing) .
  • the method of the present invention contemplates treating neurological disorders by administering a complex of IGF and IGFBP-3.
  • IGFBP-3 IGF/IGFBP-3 normally circulates in the form of a complex in humans and other mammals. This complex associates with a third protein (ALS) , which is present in excess over the concentration of IGF and IGFBP-3. Therefore, ALS is found both associated with the IGF/IGFBP-3 complex and in the free form.
  • the resultant ternary complex has a size of about 150 kd.
  • Conditions which are treated by the method of the present invention include Huntington's disease, Alzheimer's disease, exposure to neurotoxins, cerebrovascular hemorrhage, neuronal scission during surgery, meningitis, other infection of the tissues of the nervous system, multiple sclerosis, amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease.
  • Huntington's disease is defined as an autosomal dominant disorder usually beginning in middle age and characterized by choreif ⁇ rm movements and progressive intellectual deterioration. There are estimated to be about 25,000 cases in the United States. It is diagnosed on CT scans by characteristic "boxcar ventricles" which result from atrophy of the caudate nucleus.
  • GABA neurotransmitters
  • substance P an 11-amino acid peptide
  • somatostatin and neuropeptide y may be relatively increased in the caudate nucleus and putamen.
  • glutamate receptor agonists that act on the N-methyl-D-aspartate subclass of glutamate receptors.
  • IGF/IGFBP-3 Intracellular neurotrophic factor/IGFBP-3 helps this condition through its trophic effects on nerve growth and maintenance.
  • Alzheimer's disease is a form of progressive atrophy of the brain. It is the commonest cause of dementia in the elderly and has a frequency of almost 20% in those over 80 years old. The primary feature is death and disappearance of cells from the brain, resulting in extensive convolutional atrophy. Acetylcholine- transmitting neurons are particularly affected. Loss of peptidergic neurons in the cerebrum is associated with reduced somatostatin and corticotropin releasing factor concentrations.
  • Somatostatin is also abnormally low in the CSF.
  • An early symptom is memory loss, followed by slow disintegration of judgment and affect.
  • the clinician must rule out organic causes, such as drug overdoses, vitamin deficiencies, alcohol, ischemic conditions, etc.
  • IGF/IGFBP-3 complex administration such as with an improved sense of well-being, affect and/or memory.
  • Another condition in which the IGF/IGFBP complex promotes healing is exposure to neurotoxins.
  • Polyneuropathy can result from exposure to the following environmental toxins: acrylamide (herbicide, grout), arsenic (herbicide, insecticide) , buckthorn, carbon disulfide, diphtheria, dimethylamino propionitrile, y- diketone hexacarbon solvents, inorganic lead, organophosphates and thallium (rat poison) .
  • Many drugs have neurologic adverse reactions. See, for example, Tables 363-1-3, which list polyneuropathies associated with systemic disease, drugs or environmental toxins, and genetically determined conditions, respectively (Harrison's Principles of Internal Medicine. 12th ed. McGraw-Hill, New York City, 1991, pp. 2099-2103).
  • animal toxins such as the tetanus- toxin and the toxins of various snakes and scorpions, damage the nervous system and interfere with respiration, heart rate, etc.
  • the specific or underlying disorder must be treated, and vital functions may need to be supported.
  • the administration of the IGF/IGFBP-3 complex speeds healing and encourages the sprouting of new neurites.
  • Cerebrovascular hemorrhage is characterized by rupture of a cerebral blood vessel and bleeding into the intracranial space, which compresses and may damage cerebral nerve and glial cells. Similarly, during surgery, nerves may be inadvertently or necessarily compressed or severed (scission) . In both situations, the administration of IGF/IGFBP-3 will help nervous tissue recover.
  • Acute viral encephalitis is an acute inflammation of the brain due to virus or hypersensitivity caused by a virus or other foreign protein. If the spinal cord structures also are affected, the condition is called encephalomyelitis. It is frequently called “aseptic” because no organisms are found. Cerebral edema is present, along with numerous small hemorrhages which are scattered throughout the brain, brainstem, cerebellum and sometimes the spinal cord. Viral invasion may cause nerve necrosis and/or inclusion bodies. Demyelinating lesions sometimes are seen around veins. Therapy of the underlying infection is the primary concern.
  • General therapy includes antiviral and/or antibacterial therapy, fluid therapy without overhydration, and if indicated steroid therapy to counteract the swelling associated with meningitis.
  • IGF/IGFBP-3 administration helps restore nerve and glial cells.
  • IGF/IGFBP can be administered intracranially with other therapies. Meningitis also is associated with a number of non-bacterial/viral conditions, such as fungal infections (especially with AIDS or immunosuppressive therapy) , TB, dissemination of malignant cells as in leukemia, metastatic carcinoma (especially of lung and breast) , gliomas, syphilis and sarcoidosis.
  • Current therapy includes treatment of the underlying disorder, as well as steroids (such as prednisone) to reduce inflammation.
  • administration of IGF/IGFBP-3 enhances recovery of injured nervous and glial tissue.
  • Multiple sclerosis has been characterized as "a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations.”
  • THE MERCK MANUAL 15th ed., Merck & Co., Rahway, N.J., 1987, pp. 1414-17.
  • the administration of IGF/IGFBP-3 will encourage the replacement of neurites and glial cells.
  • amyotrophic lateral sclerosis primarily affects motor neurons, producing muscular weakness and atrophy. Cramps are an early sign. Later fasciculations, spasticity and hyperactive reflexes are observed. IGF/IGFBP-3 administration will encourage the formation of new neurites.
  • Charcot-Marie-Tooth disease is an autosomally dominant disorder of the peripheral nervous system in which weakness and atrophy, particularly of the peroneal and distal leg muscles, gradually develops over years. Biopsy may show segmental demyelination and remyelination. At present there is no specific treatment, aside from bracing weak muscles such as to limit foot drop. The administration of IGF/IGFBP-3 is supportive therapy, intended to enhance remyelination.
  • IGF and IGFBP-3 Systemic administration of IGF and IGFBP-3, either from natural or recombinant sources, as a preformed complex results in the formation of the normal ternary complex with the excess ALS.
  • This type of treatment produces a prolonged increase in the level of circulating IGF, which is gradually released from the ternary complex.
  • This mode of administration avoids the detrimental side effects associated with administration of free IGF-I, namely, hypoglycemia, suppression of growth hormone and ALS production, and release of endogenous IGF-II since administered exogenous free IGF-I replaces endogenous IGF-II in normally circulating IGF-11/IGFBP-3 complexes.
  • the formulation, method of administration and dosage will depend upon the disorder to be treated and the medical history of the patient. These factors are readily determined in the course of therapy. Suitable patients with neurological disorders can be identified by medical history, physical findings and laboratory tests. The medical history may reveal such facts as loss of coordination, muscle weakness, tremors, dizziness, headache, loss of memory, impaired speech, cognitive difficulties and the specific findings associated with the individual conditions discussed above. Patients may have physical findings such as muscle weakness, impaired reflexes, impaired coordination, disorientation, memory loss, impaired language function, impaired sensory function as well as specific findings associated with the individual conditions discussed above.
  • the formulation comprises a complex of IGF and IGFBP-3.
  • the IGF is IGF-I, although IGF-II also is useful.
  • IGF and IGFBP-3 naturally complex in a 1:1 molar ratio, a composition of equimolar amounts of IGF and IGFBP-3 is preferred.
  • the product can be formulated with IGF:IGFBP-3 molar ratios ranging from about 0.5 to 1.5. More preferably, the molar ratio is about 0.9 to 1.3; and most preferably, the product is formulated with approximately a 1:1 molar ratio.
  • the IGF and IGFBP-3 are human proteins obtained from natural or recombinant sources. Most preferably, IGF and IGFBP-3 are human IGF-I and IGFBP-3 made by recombinant means and designated rhIGF-I and rhIGFBP-3, respectively. rhIGFBP-3 may be in glycosylated or non-glycosylated form. E. coli is a source of the non-glycosylated IGFBP-3. Glycosylated IGFB -3 may be obtained from Chinese hamster ovary (CHO) cells.
  • CHO Chinese hamster ovary
  • the method of the present invention provides for formulating the complex in modes which are readily apparent to those skilled in the art.
  • the IGF and IGFBP-3 are complexed prior to administration to the treated subject.
  • the complex is formed by mixing approximately equimolar amounts of IGF-I and IGFBP-3 dissolved in physiologically compatible carriers such as normal saline solution or phosphate buffered saline solution.
  • physiologically compatible carriers such as normal saline solution or phosphate buffered saline solution.
  • a concentrated solution of rhIGF-I and a concentrated solution of rhIGFBP-3 are mixed together for a sufficient time to form an equimolar complex.
  • compositions of the complex may be in the form of solid, semi-solid or liquid dosage preparations, such as for example, tablets, pills, powders, capsules, liquids, suspensions or the like.
  • Physiologically compatible carriers include intravenous solutions, such as normal saline, serum albumin, 5% dextrose, plasma preparations, and other protein-containing solutions.
  • the preferred carrier for parenteral administration of the complex is a sterile, isotonic aqueous solution, such as normal saline or 5% dextrose.
  • a solution of the complex may be placed, into an implant, such as an osmotic pump, for the slow release of the complex over an extended period of time.
  • the complex may be provided in sustained release carrier formulations such as semi-permeable polymer carriers in the form of suppositories or microcapsules.
  • sustained release carrier formulations such as semi-permeable polymer carriers in the form of suppositories or microcapsules. See, for instance, U.S. Patent No. 3,773,919 for Microcapsular Sustained Release Matrices Including Polylactides; Sidman et al., Biopolymers 22 (1) : 547-556 (1983) for copolymers of L- glutamic acid and 7-ethyl-L-glutamate; Langer et al. , J Biomed Res 15: 267-277 (1981) for poly(2-hydroxyethylmethacrylate) or the like.
  • the mode of administration delivers the complex to the subject in a safe, physiologically effective manner.
  • the complex may be given by intranasal, subcutaneous, intravenous, intramuscular, intraperitoneal, intracranial or other conventional routes of administration.
  • the complex is injected subcutaneously, intravenously or intramuscularly.
  • the complex is administered by subcutaneous injection. By subcutaneous injection, the complex appears not to be toxic or mitogenic at the injection site.
  • the dose of complex to be administered can be readily determined by those skilled in the art, based on the usual patient symptoms discussed above.
  • the dosage of complex is about 0.01 to 10 mg of IGF-I or IGF- Il/kg of body weight/day, complexed to an equimolar amount of IGFBP-3.
  • the daily dosage of the complex for humans is about 0.05 to 7.5 mg IGF/kg/day, complexed to an equimolar amount of IGFBP-3.
  • the daily dosage of the complex for humans is about 0.1 to 5 mg IGF/kg/day, complexed to an equimolar amount of IGFBP-3.
  • each dose of complex is preferably about 0.05 to 10 mg IGF/kg of body weight, complexed to an equimolar amount of IGFBP-3. More preferably, for twice weekly administration, the dose of the complex is about 0.1 to 7.5 mg IGF/kg, complexed to an equimolar amount of IGFBP-3. Most preferably, for twice weekly administration, the dose of the complex is about 0.5 to 5 mg IGF/kg, complexed to an equimolar amount of IGFBP-3.
  • the patient is started with a relatively low dose of the complex, such as 0.05 mg IGF/kg of body weight/day.
  • a relatively low dose of the complex such as 0.05 mg IGF/kg of body weight/day.
  • Physical examinations, functional tests and diagnostic procedures such as those outlined above should be performed on the treated patients to determine if there is improvement.
  • the patient shows improvements in the structure and/or function of the peripheral or central nervous tissue affected by the neurological disorder following such treatment. If the patient improves with the low dose, the low dose preferably should be continued until acceptable clinical endpoints have been achieved. If the patient does not respond to low dose IGF/IGFBP-3 complex with sufficient clinical improvement, the dose of complex should be increased gradually until such an outcome is achieved.
  • the invention has been disclosed by direct description. Following are examples showing the efficacy of the IGF/IGFBP-3 complex in stimulating processes critical to the growth, survival and functioning of neurological tissue. The examples are only examples and should not be taken in any way as limiting to the scope of the process.
  • Example 1 This example is designed to demonstrate the ability of the rhIGF-I/IGFBP-3 complex to stimulate the sprouting of neurites (nerve processes) in cultured embryonic chick spinal cord motor neurons.
  • the sprouting of neurites leads to the re-establishment of innervation and consequently full function of partially denervated neuromuscular junctions and disrupted central nervous system neural connections.
  • cultures of motor neuron cells are prepared from embryonic chick spinal cord tissue. Dissociated lumbar and brachial spinal cord cells are purified by differential Ficoll gradient centrifugation, and the motor neuron fraction is isolated. Primary cultures of these cells are plated in laminin coated tissue culture dish wells in enriched L15 medium containing 20% horse serum and 20 ⁇ g/ml embryonic chick hind limb muscle protein extract. The majority of the cells in this culture are neurons with large multipolar cell bodies, and non-neuronal cells represent only a few percent of the total. Cells are plated in either the above medium alone, or in medium containing 1 to 100 ng/ml rhIGF-I complexed to an equimolar amount of rhIGFBP-3. The extent of neurite outgrowth in each set of cultures is assessed by light microscopy daily for up to 7 days. The effect of each treatment is determined by measuring the total- length of the neurite tree for each neuron at each time point.
  • Example 2 This example is designed to demonstrate the ability of the IGF-I/IGFBP-3 complex to stimulate regeneration of severed neurons. Traumatic or surgical injury to peripheral nerves is troublesome since the regeneration of damaged nerves is often slow and functionally incomplete. There is a clinical need for agents that can promote more rapid and completely functional regeneration of such damaged nerves.
  • groups of rats have the osmotic pump filled with various concentrations rhlGF- 1/IGFBP-3 complex (0.1-1 mg/ml of rhIGF-I complexed to an equimolar amount of rhIGFBP-3) in physiological saline plus 1% rat serum albumin (RSA) .
  • the pump is filled with physiological saline plus 1% RSA only.
  • the pumps are left in place to pump at a rate of approximately 0.5 ⁇ l/hr for approximately 3-4 weeks to allow nerve regeneration. At the end of the 3-4 week treatment period, the animals are sacrificed and the silicone blocks recovered.
  • the pumps are removed from the block and any tissue in the block is fixed by immersing the opened block in standard glutaraldehyde fixative. The fixed tissue is then stained with osmium tetroxide and dehydrated. Each channel in the block is cut into short lengths numbered starting from the severed nerve stump. Thin sections are cut from each short length of channel and are stained with methylene blue and azur II. Light microscopy is used to evaluate the presence of myelinated axons from the regenerated nerve in each short length of each channel.
  • Example 3 This example is designed to demonstrate the ability of the rhIGF-I/IGFBP-3 complex to stimulate the growth and myelination of nervous tissue in the central nervous system.
  • a variety of illnesses result in the demyelination of central nervous system neurons (eg. multiple sclerosis, acute disseminated encephalomyelitis) .
  • This demyelination results in defective nerve transmission and loss of sensory and motor function.
  • An agent that would stimulate myelin production in such cases would be a useful therapeutic.
  • myelin production is assessed in fetal rat brain aggregate cultures. Whole fetal rat brain cells are dissociated into single cells, filtered, and then placed into aggregate culture medium (Almazan et. al . , Dev.
  • oligodendrocytes are also quantitated by measuring the activity of the oligodendrocyte marker 2' -3' -cyclic nucleotide 3'- phosphohydrolase (CNP) in cell homogenates.
  • CNP oligodendrocyte marker 2' -3' -cyclic nucleotide 3'- phosphohydrolase

Abstract

L'invention concerne un procédé de traitement de certains troubles neurologiques par administration d'une composition contenant un complexe facteur de croissance insulinoïde (IGF)/protéine-3 fixatrice du facteur de croissance insulinoïde (IGFBP-3).
EP95901254A 1993-11-15 1994-11-15 Procede de traitement de troubles neurologiques Withdrawn EP0729361A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US15286893A 1993-11-15 1993-11-15
US152868 1993-11-15
PCT/US1994/013177 WO1995013823A1 (fr) 1993-11-15 1994-11-15 Procede de traitement de troubles neurologiques

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EP0729361A1 true EP0729361A1 (fr) 1996-09-04
EP0729361A4 EP0729361A4 (fr) 1996-11-06

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EP95901254A Withdrawn EP0729361A4 (fr) 1993-11-15 1994-11-15 Procede de traitement de troubles neurologiques

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EP (1) EP0729361A4 (fr)
JP (1) JPH09509140A (fr)
AU (1) AU693489B2 (fr)
CA (1) CA2176708A1 (fr)
WO (1) WO1995013823A1 (fr)

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US6440928B1 (en) 1988-12-06 2002-08-27 Colorado State University Research Foundation Method for treating diabetic neuropathy with NGF
WO1997021449A1 (fr) * 1995-12-13 1997-06-19 Aurogen Incorporated Procede permettant d'obtenir des modifications du systeme nerveux central par administration de igf-i ou de igf-ii
US6025368A (en) * 1997-02-25 2000-02-15 Celtrix Pharmaceuticals, Inc. Method for treating the symptoms of chronic stress-related disorders using IGF
US6015786A (en) * 1997-02-25 2000-01-18 Celtrix Pharmaceuticals, Inc. Method for increasing sex steroid levels using IGF or IGF/IGFBP-3
US6514937B1 (en) 1997-02-25 2003-02-04 Celtrix Pharmaceuticals, Inc. Method of treating psychological and metabolic disorders using IGF or IGF/IGFBP-3
EP1006794B1 (fr) 1997-03-12 2007-11-28 Robert W. Esmond Procede de traitement ou de prevention de la maladie d'alzheimer
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JPH09509140A (ja) 1997-09-16
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AU1057095A (en) 1995-06-06
AU693489B2 (en) 1998-07-02
WO1995013823A1 (fr) 1995-05-26

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