EP1165604A2 - Proteines associees a la regeneration neuronale et leur utilisation - Google Patents

Proteines associees a la regeneration neuronale et leur utilisation

Info

Publication number
EP1165604A2
EP1165604A2 EP00904750A EP00904750A EP1165604A2 EP 1165604 A2 EP1165604 A2 EP 1165604A2 EP 00904750 A EP00904750 A EP 00904750A EP 00904750 A EP00904750 A EP 00904750A EP 1165604 A2 EP1165604 A2 EP 1165604A2
Authority
EP
European Patent Office
Prior art keywords
hnprap
nerve
cells
expression
growth
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Withdrawn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
EP00904750A
Other languages
German (de)
English (en)
Inventor
Peter H. St. George-Hyslop
Paul E. Fraser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Toronto
Original Assignee
University of Toronto
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by University of Toronto filed Critical University of Toronto
Publication of EP1165604A2 publication Critical patent/EP1165604A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/48—Nerve growth factor [NGF]
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to the treatment of neurological injury and dysfunction associated with central nervous system trauma.
  • the invention is directed to the identification of proteins which induce neuronal regeneration.
  • the peripheral nervous system comprises highly organized groups of axon fibers or nerves external to the brain and spinal cord, such as the nerves in the limbs. In response to nerve damage, the peripheral nervous system often attempts to repair itself. While the return of lost functions is usually incomplete, generally the injured organism can adapt and function.
  • CNS central nervous system
  • NPRAP Neural Plakophilin Related Armadillo Protein
  • the method comprises contacting nerve cells with an hNPRAP stimulating agent in an amount sufficient to induce the expression of an hNPRAP and cause nerve cell growth.
  • a further related aspect of the invention is directed to a method of stimulating neuronal regeneration in a mammal, which method comprises administering to the mammal in need thereof an effective amount of an hNPRAP or an effective amount of an hNPRAP expression stimulating agent as set forth above.
  • a further aspect of the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising an hNPRAP having nerve growth stimulating activity, and a pharmaceutically acceptable carrier.
  • Yet another aspect of the invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising an hNPRAP expression stimulating agent and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an hNPRAP gene therapy vector, which vector comprises a polynucleotid encoding hNPRAP and a promoter for expressing hNPRAP, and a carrier.
  • hNPRAP gene therapy vector which vector comprises a polynucleotid encoding hNPRAP and a promoter for expressing hNPRAP, and a carrier.
  • gene therarpy vectors are also part of the invention as well.
  • a further aspect of the invention relates to a method for identifying substances that modulate the expression of hNPRAP, which method comprises contacting cultured cells that express hNPRAP with a test substance measuring levels of hNPRAP, as compared to a control in which the same cells that express hNPRAP are not contacted with the test substance, as an indication of modulatory activity of said test substance.
  • the human Neural Plakophilin Related Armadillo Protein (also described as GT24) consensus cDNA (SEQ ID NO 3) encodes a protein (SEQ ID NO 4) of 1084 amino acid residues with a unique N-terminus, but with homology to proteins with armadillo (arm) repeat motifs at its C-terminus
  • hNPRAP or functional derivatives thereof containing one or more armadillo repeats, causes the development of numerous long, dendritic processes which typically terminate upon distantly located cells
  • target cells need not necessarily be expressing hNPRAP
  • the hNPRAP induced cellular extensions are highly similar to the axonal sprouting seen during neuronal regeneration and synapse formation
  • Nucleotides 2920-2997 of the hNPRAP cDNA overlap the anonymous microsatellite locus D5S478, therefore placing the hNPRAP gene on chromosome 5pl5 near the Cri-du-Chat deletion locus, a syndrome associated with congenital malformation and gross mental retardation hNPRAP is described in detail in copending commonly assigned U S Application Serial Nos 08/888,077, filed July 3,
  • hNPRAP is known to interact with Presenilin I ("PS1 ") and Presenilin II ("PS2”) by direct protein protein interaction studies
  • PS1 Presenilin I
  • PS2 Presenilin II
  • the domain of the PS1 protein that interacts with hNPRAP has also been shown to interact with other proteins, such as armadillo repeat proteins p0071 and $-catenin
  • the hNPRAP gene is expressed as a range of transcripts of 3 9 to 5 0 kb in several regions of adult human brain, but is expressed at only very low levels in most non-neurologic tissues Studies have shown that PS1 and hNPRAP are both expressed in the same cell types and in adjacent/contiguous subcellular compartments
  • hNPRAP in non-confluent transfected cell cultures, has a predominantly perinuclear cytoplasmic distribution contiguous with that of PS1. In contrast, in confluent cells with abundant celkcell contacts, hNPRAP is predominantly located near the cell membrane close to inter-cellular contact zones while PS1 retains its predominantly perinuclear distribution.
  • hNPRAP is defined herein as a biologically active polypeptide that contains a sequence of hNPRAP that mediate its nerve cell growth stimulating activity, e.g., the armadillo repeats.
  • hNPRAP includes full-length (naturally occurring) hNPRAP, as well as biologically active analogues thereof.
  • analogues it is meant modifications such as point mutations, amino acid substitutions, additions or deletions, or other mammalian homologues, such as mouse (SEQ ID NO: 5 and SEQ ID NO: 6), which have similar activity to hNPRAP, the identification and selection of which are well-known to those skilled in the art.
  • hNPRAP the use of recombinant proteins such as pl20cas and chimeric proteins having all or parts of the C-terminal armadillo-like repeat and C-terminal unique sequences of hNPRAP may also be utilized in the practice of this invention. Analogues of these proteins which replicate the effects thereof may also be utilized in the practice of this invention.
  • the invention provides a method of stimulating growth of nerve cells, comprising contacting nerve cells with an hNPRAP.
  • a second embodiment is directed to a method of stimulating growth of nerve cells, comprising contacting nerve cells with an hNPRAP stimulating agent in an amount sufficient to induce the expression of hNPRAP.
  • agents may induce the expression of hNPRAP by positively binding to the hNPRAP gene to induce expression, or may alter the interaction of hNPRAP with an inhibitor of hNPRAP expression, e.g., by binding to the inhibitor itself or to hNPRAP such that the inhibitor no longer modulates the expression of hNPRAP
  • the expression of hNPRAP may be induced by the use of an appropriate viral vector system, or by the administration of recombinant proteins, biological molecules or small molecules which simulate or resemble either the armadillo binding domain of the presenilins or the armadillo repeats of hNPRAP.
  • Another embodiment is directed to a method for identifying substances that simulate or resemble (mimic) either the armadillo binding domain of the presenilins or the armadillo repeats of hNPRAP, and which substances cause neural growth
  • Candidate compounds which are shown to mimic either the armadillo binding domain of the presenilins or the armadillo repeats of hNPRAP may be produced in pharmaceutically useful quantities for use in the treatment of neurological injury and dysfunction associated with central nervous system trauma
  • Candidate compounds include endogenous cellular components which interact with the presenilins in vivo and which, therefore, provide new targets for pharmaceutical and therapeutic interventions, as well as recombinant, synthetic and otherwise exogenous compounds which may have presenilin binding capacity and, therefore, may be candidates for pharmaceutical agents
  • cell lysates or tissue homogenates e.g., human brain homogenates, lymphocyte lysates
  • tissue homogenates e.g., human brain homogenates, lymphocyte lys
  • the presenilin domain that interacts with PS-interacting proteins has been identified as including or being contained in the sequence of amino acid residues from about 260 to about 409 of PS1 or corresponding residues from about 260 to about 390 in PS2. More preferably, the interacting domain contains or is contained in amino acid residues from about 372 to about 399 of PS1 or corresponding residues from about 350 to about 380 in PS2.
  • the amino acid sequences of wild-type human PS1 and PS2 are shown in SEQ ID NOJ and SEQ ID NOJ, respectively.
  • Binding may be detected by indirect functional measures reflecting the functional consequences of the interaction (e.g., changes in intracellular Ca 2+ , Na + , KT, or GTP/GDP ratio, changes in apoptosis or microtubule associated protein phosphorylation, changes in A$ peptide production or changes in the expression of other downstream genes which can be monitored by differential display, 2D gel electrophoresis, differential hybridization, or SAGE methods) or by direct measures such as immunoprecipitation, the Biomolecular Interaction Assay (BIAcore) or alteration of protein gel electrophoresis.
  • indirect functional measures reflecting the functional consequences of the interaction (e.g., changes in intracellular Ca 2+ , Na + , KT, or GTP/GDP ratio, changes in apoptosis or microtubule associated protein phosphorylation, changes in A$ peptide production or changes in the expression of other downstream genes which can be monitored by differential display, 2D gel electrophoresis, differential hybridization, or SAGE methods) or
  • the preferred methods involve variations on the following techniques: (1) direct extraction by affinity chromatography; (2) co- isolation of presenilin components and bound proteins or other compounds by immunoprecipitation; (3) BIAcore analysis; and (4) the yeast two-hybrid systems.
  • Other procedures include methods which detect abnormal processing of PS1, PS2, APP, or proteins reacting with PS1, PS2, or APP (e.g., abnormal phosphorylation, glycosylation, glycation amidation or proteolytic cleavage) alterations in presenilin transcription, translation, and post-translational modification; alterations in the intracellular and extracellular trafficking of presenilin gene products; or abnormal intracellular localization of the presenilins.
  • the proteins or other compounds identified by these methods may then be assayed for their ability to promote sprouting in axons of neuronal cultures or dendrite formation in non-neurological cells using morphometric analyses which are well-known to those skilled in the art of neuronal regeneration.
  • assays for regeneration following sectioning of the optic nerve, spinal cord, etc. in animals may be performed. Such assays are well-known to those in the field of neuronal regeneration.
  • the proteins or other compounds identified by these methods may be purified and characterized by any of the standard methods known in the art.
  • Proteins may, for example, be purified and separated using electrophoretic (e.g., SDS-PAGE, 2D PAGE) or chromatographic (e.g., HPLC) techniques and may then be microsequenced
  • electrophoretic e.g., SDS-PAGE, 2D PAGE
  • chromatographic e.g., HPLC
  • cleavage e.g., by CNBr and/or trypsin
  • Further purification/characterization by HPLC and microsequencing and/or mass spectrometry by conventional methods provides internal sequence data on such blocked proteins
  • standard organic chemical analysis techniques e.g., IR, NMR and mass spectrometry, functional group analysis, X-ray crystallography
  • hNPRAPs, and compounds which activate hNPRAP may be employed in combination with a suitable pharmaceutical, physiologically acceptable carrier
  • Administration of hNPRAP of this invention can be through the administration of hNPRAP peptides agonists or antagonists synthesized
  • hNPRPA and/or activating agent(s) are administered as pharmaceutical compositions comprising an effective amount of hNPRAP and/or activating agent(s) in a pharmaceutical carrier
  • reagents can be combined for therapeutic use with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers or diluents, e.g., immunogenic adjuvants, along with physiologically innocuous stabilizers and excipients
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for delivering the compositions of the invention to a patient
  • treatment dosages should be titrated to optimize safety and efficacy Animal testing of effective doses for treatment of particular injuries will provide further predicative indication of human dosage Various considerations are described, e.g.
  • Polypeptides and other compounds of the present invention which activate or inhibit hNPRAP may be employed alone or in conjunction with other compounds, such as therapeutic compounds
  • the candidate compounds may then be produced in quantities sufficient for pharmaceutical administration or testing (e.g., mg or mg or greater quantities), and formulated in a pharmaceutically acceptable carrier (see, e.g., Remington's, supra)
  • compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrro done, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat
  • compositions of the present invention may be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir
  • parenteral ion exchangers
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions
  • These oil solutions or suspensions may also contain
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions
  • carriers which are commonly used include lactose and corn starch Lubricating agents, such as magnesium stearate, are also typically added
  • useful diluents include lactose and dried corn starch
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents
  • certain sweetening, flavoring or coloring agents may also be added
  • compositions of this invention may be administered in the form of suppositories for rectal administration
  • suppositories for rectal administration
  • suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug
  • Such materials include cocoa butter, beeswax and polyethylene glycols
  • the pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract Suitable topical formulations are readily prepared for each of these areas or organs Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation Topical ly-transdermal patches may also be used
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum
  • compositions of this invention may also be administered by nasal aerosol or inhalation
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents
  • the methods and compositions of this invention may be used to treat nerve damage caused by a wide variety of diseases or physical traumas These include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, peripheral neuropathy, particularly neuropathy associated with diabetes, spinal cord injuries and facial nerve crush.
  • ALS amyotrophic lateral sclerosis
  • hNPRAP polynucleotides, polypeptides, agonists and antagonists that are polypeptides may be employed in accordance with the present invention by expression of such polypeptides in treatment modalities often referred to as "gene therapy"
  • cells from a patient may be engineered with a polynucleotide, such as a DNA or RNA, to encode a polypeptide ex vivo
  • the engineered cells can then be provided to a patient to be treated with the polypeptide
  • cells may be engineered ex vivo, for example, by the use of a retroviral plasmid vector containing RNA encoding a polypeptide of the present invention
  • retroviral plasmid vector containing RNA encoding a polypeptide of the present invention Such methods are well-known in the art and their use in the present invention will be apparent from the teachings herein
  • cells may be engineered in vivo for expression of a polypeptide in vivo by procedures known in the art
  • a polynucleotide of the invention may be engineered for expression in a replication defective retroviral or viral vector, as discussed above
  • the retroviral expression construct may then be isolated
  • a packaging cell is transduced with a retroviral plasmid vector containing RNA encoding a polypeptide of the present invention, such that the packaging cell now produces infectious viral particles containing the gene of interest
  • These viral particles may be administered to a patient for engineering cells in vivo and expression of the polypeptide in vivo
  • Retroviruses or viruses from which the plasmid vectors hereinabove- mentioned may be derived include, but are not limited to, SimiForest Virus, Lenti- virus, Moloney Murine Leukemia Virus, Spleen Necrosis Virus, Rous Sarcoma Virus, Harvey Sarcoma Virus, Avian Leukosis Virus, Gibbon Ape Leukemia Virus, Human Immunodeficiency Virus, Adenovirus, Myeloproliferative Sarcoma Virus, and Mammary Tumor Virus
  • the retroviral plasmid vector is derived from Moloney Murine Leukemia Virus
  • Such vectors will include one or more promoters for expressing the polypeptide
  • Suitable promoters which may be employed include, but are not limited to, the retroviral LTR, the SV40 promoter, and the human cytomegalovirus (CMV) promoter described in Miller et al, Biotechniques, 1989, 7 980-990
  • CMV human cytomegalovirus
  • Cellular promoters such as eukaryotic cellular promoters including, but not limited to, the hi stone, RNA polymerase III, and $-actin promoters, can also be used
  • Additional viral promoters which may be employed include, but are not limited to, adenovirus promoters such as the adenoviral major late promoter, thymidine kinase (TK) promoters such as the Herpes Simplex thymidine kinase promoters, the respiratory syncytial virus (RSV) promoters, and B19 parvovirus promoters
  • TK
  • the nucleic acid sequence encoding the polypeptide of the present invention may be placed under the control of an inducible promoter Suitable inducible promoters which may be employed include, but are not limited to, the MMT promoter, the metallothionein promoter, heat shock promoters, the albumin promoter, the ApoAI promoter, human globin promoters, viral thymidine kinase promoters, and human growth hormone promoters
  • the promoter may also be the native promoter which controls the gene encoding the polypeptide
  • the retroviral plasmid vector is employed to transduce packaging cell lines to form producer cell lines
  • packaging cells which may be transfected include, but are not limited to, the PE501, PA317, PSI -2, omega -AM, PA12, T19-14X, VT-19-17-H2, omega CRE, omega CRIP, GP+E-86, GP+envAml2, and DAN cell lines as described in Miller, A , Human Gene Therapy, 1990, 1 5-14
  • the vector may be transduced into the packaging cells through any means known in the art Such means include, but are not limited to, electroporation, the use of liposomes, and CaPO 4 precipitation
  • the retroviral plasmid vector may be encapsulated into a liposome, or coupled to a lipid, and then administered to a host
  • the producer cell line will generate infectious retroviral vector particles, which include the nucleic acid sequence(s) encoding the polypeptides Such retroviral vector particles may then be employed to transduce

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de stimulation de la croissance nerveuse, notamment de régénération nerveuse, consistant à mettre en contact des cellules nerveuses avec la protéine humaine neuronale Armadillo (hNPRAP), apparentée à la Plakophiline. Dans un mode de réalisation spécifique, la protéine hNPRAP provoque le développement de nombreuses extensions cellulaires, longiformes, similaires à un bourgeonnement axonal observé lors de la régénération neuronale et de la formation de synapses. L'invention concerne encore des compositions pharmaceutiques comprenant la protéine hNPRAP, ou bien un vecteur de thérapie génique exprimant la protéine hNPRAP, de même que des procédés d'identification de substances modulant l'expression de la protéine hNPRAP.
EP00904750A 1999-02-12 2000-02-11 Proteines associees a la regeneration neuronale et leur utilisation Withdrawn EP1165604A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11983599P 1999-02-12 1999-02-12
US119835P 1999-02-12
PCT/CA2000/000126 WO2000047615A2 (fr) 1999-02-12 2000-02-11 Proteines associees a la regeneration neuronale et leur utilisation

Publications (1)

Publication Number Publication Date
EP1165604A2 true EP1165604A2 (fr) 2002-01-02

Family

ID=22386671

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00904750A Withdrawn EP1165604A2 (fr) 1999-02-12 2000-02-11 Proteines associees a la regeneration neuronale et leur utilisation

Country Status (6)

Country Link
EP (1) EP1165604A2 (fr)
JP (1) JP2002541060A (fr)
AU (1) AU2652600A (fr)
CA (1) CA2361034A1 (fr)
MX (1) MXPA01007944A (fr)
WO (1) WO2000047615A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4017873A4 (fr) * 2019-08-23 2023-12-20 Duke University Compositions et procédés pour le traitement de douleurs et de démangeaisons pathologiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000506375A (ja) * 1996-01-26 2000-05-30 エイチエスシー リサーチ アンド デベロップメント リミテッド パートナーシップ アルツハイマー病に関連する核酸およびタンパク質、ならびにその使用
JP2001510991A (ja) * 1996-12-02 2001-08-07 ザ ブリガム アンド ウイメンズ ホスピタル，インク． Ａｌａｒｍ関連ペプチドおよび核酸ならびにそれらを用いた診断

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0047615A2 *

Also Published As

Publication number Publication date
AU2652600A (en) 2000-08-29
JP2002541060A (ja) 2002-12-03
WO2000047615A2 (fr) 2000-08-17
WO2000047615A3 (fr) 2000-11-30
CA2361034A1 (fr) 2000-08-17
MXPA01007944A (es) 2003-09-10

Similar Documents

Publication Publication Date Title
Milbrandt et al. Persephin, a novel neurotrophic factor related to GDNF and neurturin
RU2477287C2 (ru) Стабилизированные полипептиды инсулиноподобного фактора роста
US8153580B2 (en) Nogo receptor binding protein
JP3990456B2 (ja) 血管形成の阻害剤として有用なトロポニンのサブユニットおよびフラグメント
US20130164297A1 (en) Modulation of activity of neurotrophins
CN101123978A (zh) 神经胚素变体
US5898066A (en) Trophic factors for central nervous system regeneration
KR20180025895A (ko) 노화와 연관된 질환을 치료하기 위한 방법 및 조성물
KR20140099526A (ko) 안구 건조증의 치료를 위한 jnk 신호 전달 경로의 세포-투과성 펩타이드 억제자의 용도
US20050164948A1 (en) Methods of treatment with prosaposin-derived peptides
US6486122B1 (en) Methods of increasing body weight in a subject by administering TGF-α
AU2002345669B9 (en) Antisense oligonucleotides which can inhibit the formation of capillary tubes by endothelial cells
US20100040623A1 (en) Neuritogenic and neuronal survival promoting peptides derived from the family of s-100 proteins
KR20200093465A (ko) Mls-stat3를 포함하는 면역질환의 예방 또는 치료용 조성물
WO1998039357A1 (fr) Procedes pour soulager les douleurs neuropathiques
CA2038208A1 (fr) Procede pour l'isolement et l'expression du facteur neuronotrophique a partir de la zone ciliaire humaine a l'aide d'une technique de l'adn recombinant
EP1165604A2 (fr) Proteines associees a la regeneration neuronale et leur utilisation
US6783982B1 (en) Proteins related to neuronal regeneration and uses thereof
EP2087905A2 (fr) Interleukine-20 dans le traitement et le diagnostic des états associés à la neovascularisation
CN113121668A (zh) PEG修饰的可抑制gp96的多肽、其制备方法及用途
KR19990007806A (ko) 전환 성장 인자 α ＨＩＩ
ZA200507501B (en) Nogo receptor binding protein
US20040266680A1 (en) FGF-8 methods of use
AU4267297A (en) Method of alleviating neuropathic pain
JP2003508545A (ja) 神経原性組成物および方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010806

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LT PAYMENT 20010806;LV PAYMENT 20010806

17Q First examination report despatched

Effective date: 20040730

17Q First examination report despatched

Effective date: 20040730

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080328