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WO2008038599A1 - Promoteur de régénération axonale - Google Patents

Promoteur de régénération axonale Download PDF

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Publication number
WO2008038599A1
WO2008038599A1 PCT/JP2007/068449 JP2007068449W WO2008038599A1 WO 2008038599 A1 WO2008038599 A1 WO 2008038599A1 JP 2007068449 W JP2007068449 W JP 2007068449W WO 2008038599 A1 WO2008038599 A1 WO 2008038599A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
acid sequence
seq
peptide
axon
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.)
Ceased
Application number
PCT/JP2007/068449
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English (en)
Japanese (ja)
Inventor
Toshihide Yamashita
Masayoshi Suda
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.)
Chiba University NUC
Original Assignee
Chiba University NUC
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 Chiba University NUC filed Critical Chiba University NUC
Priority to JP2008536361A priority Critical patent/JPWO2008038599A1/ja
Publication of WO2008038599A1 publication Critical patent/WO2008038599A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an axonal regeneration promoting agent capable of promoting regeneration of nerve cells, in particular, axons of nerve cells of the central nervous system.
  • RGM Repulsive Guidance Molecule
  • RGM Repulsive Guidance Molecule
  • it has a neutralizing activity of inhibitory activity! (For example, see Patent Document 1 and Non-Patent Document 5 below).
  • RGM was first identified as a protein involved in the formation of retinal lid processes in chicken fetuses, and RGM caused repulsion of the optic nerve axon during development (see Non-Patent Documents 6 and 7 below). It is reported that the expression of this protein increases when the spinal cord is damaged (see Non-Patent Document 8 below), and that the expression increases in human brain ischemia and brain trauma (see Non-Patent Document 9 below). It has been tell.
  • Patent Document 1 International Publication WO2005 / 087268 Pamphlet
  • Non-patent literature 1 S. David et al., Science, 214, 931-933, 1981
  • Non-patent literature 2 MS Chen et al., Nature, 403, 434-439, 2000
  • Non-patent document 3 G. Mukhopadhyay et al., Neuron, 13, 757-767, 1994
  • Non-patent document 4 V. Kottis et al., J. Neurochem., 82, 1566-1569, 2002
  • Non-patent document 5 Hata et al., J. Biol. Cell, 173 (1), 47-58, 2005
  • Non-Patent Document 6 Muller et al., Curr Biol., 6 (11), 1497, 1996
  • Non-Patent Document 7 Monnier et al., Nature, 419 (6905), 392, 2002
  • Non-Patent Document 8 Schwab et al., Eur. J. Neurosci., 21, 1569-1576, 2005
  • Non-Patent Document 9 Schwab et al., Arch. Neurol., 62, 1561-1568, 2005 Disclosure of the Invention
  • an object of the present invention is to provide a novel axonal regeneration accelerator that solves the above-mentioned problems.
  • the present inventor has intensively studied the above problem! /, however, has found that a partial peptide derived from the amino acid sequence of the RGM protein can suppress the effect of RGM, and completed the present invention. I came to let you. That is, the axonal regeneration promoter according to one means for solving the above problems contains at least one of the following (a) to (d) as an active ingredient.
  • amino acid sequence according to any one of SEQ ID NOs: 1 to 4, consisting of an amino acid sequence in which one or several amino acids are deleted, substituted or added, and the RGMa protein axon growth inhibitory activity Peptides with a function to neutralize [0009]
  • amino acid sequence described in SEQ ID NO: 1 corresponds to a part of the amino acid sequence of human RGMa protein, and more specifically, the 243rd force of the human RGMa protein is the 256th amino acid sequence.
  • amino acid sequence described in SEQ ID NO: 2 corresponds to a part of the amino acid sequence of human RGMa protein, and more specifically from the 326th position.
  • amino acid sequence described in SEQ ID NO: 5 shows the amino acid sequence of human RGMa protein
  • SEQ ID NO: 6 shows the base sequence of the DNA.
  • amino acid sequence set forth in SEQ ID NO: 3 corresponds to a part of the amino acid sequence of rat RGMa protein, and more specifically, the 243rd to 256th amino acid sequences of rat RGMa protein. Corresponds to the second amino acid sequence.
  • amino acid sequence described in SEQ ID NO: 4 corresponds to a part of the amino acid sequence of rat RGMa protein, and more specifically, the 326th position.
  • the peptide consisting of the amino acid sequence set forth in SEQ ID NO: 3 and the peptide consisting of the amino acid sequence set forth in SEQ ID NO: 4 are both those of rats. Since it is preserved, it is effective as a human axon regeneration promoter.
  • SEQ ID NO: 7 shows the amino acid sequence of rat RG Ma protein
  • SEQ ID NO: 8 shows the base sequence of the DNA.
  • the axon is preferably a central axon, although not limited thereto.
  • the “central nervous system” refers to the brain and spinal cord, and is not limited to, for example, the corticospinal tract nerve and the spinal thalamic tract nerve.
  • a novel axonal regeneration accelerator can be provided.
  • This axonal regeneration accelerator is particularly effective for regeneration of central nervous system axons. As a result, it is possible to contribute to the treatment of patients with damage to the central nervous system such as the spinal cord.
  • the axon regeneration accelerator (hereinafter referred to as "the axon regeneration accelerator") according to this embodiment is as follows.
  • One of the characteristics is that it contains at least one of the peptides (a) to (d).
  • This axon regeneration promoter contains a peptide having a part of the RGMa protein as an active ingredient, which can neutralize the axon growth inhibitory activity of the RGMa protein in neurons. Can be promoted. That is, the axonal regeneration promoter is useful as a pharmaceutical composition for treating a patient who has damaged the central nervous system.
  • the peptide in the present axon regeneration promoter is not limited as long as it exhibits the above-described effects.
  • a peptide consisting of an amino acid sequence in which several amino acids are deleted, substituted or added can also be used.
  • the above-mentioned effects are not lost! /, Substitution to an amino acid having a degree of chemical modification, addition of a polymer or a sugar chain. Substitution with other amino acids.
  • amino acid or a fusion protein that facilitates formulation at least one of the N-terminal side and the C-terminal side of the peptides shown in SEQ ID NOS: 1 to 4 can be added.
  • amino acids which are convenient for expressing the peptide
  • amino acids which are convenient for producing and producing the peptide
  • the present axon regeneration promoter is an ordinary pharmaceutically acceptable carrier, binder, stabilizer, excipient, diluent (eg, distilled water), pH buffering agent. It can contain various preparation ingredients such as (for example, phosphate buffered saline), disintegrants, solubilizers, solubilizers, and isotonic agents.
  • the axon regeneration promoter can be administered orally or parenterally, for example, depending on the form of use.
  • oral administration it is possible to adopt commonly used administration forms such as powders, granules, tablets, capsules, solutions, suspensions, oils, emulsifiers and the like.
  • parenteral administration a commonly used administration form, for example, a method of administering the above-mentioned solution, suspension or the like directly to the injured site, a form of administration by injection or the like can be adopted.
  • the dose of the axonal regeneration promoter is determined by the patient's weight, sex, degree of nerve damage, It can be selected appropriately according to the law.For example, when administered parenterally and administered directly to the site of injury, for example, adults per day, the above peptide should be included in the range of 1 mg to 10 mg per injury site. Is more preferably 5 mg or more and 50 mg or less. In the case of parenteral administration other than this, for example, in the case of injection, it is preferably about 10 times this.
  • the peptide according to the present axon regeneration promoter can be produced by a known method without limitation.
  • it can be produced by an ordinary chemical synthesis method, an enzymatic degradation method of a protein molecule, a gene recombination technique, or the like.
  • the usual chemical synthesis method is not limited, but for example, a solid phase synthesis method using a peptide synthesizer can be preferably used.
  • a solid phase synthesis method using a peptide synthesizer can be preferably used.
  • well-known purification methods such as salting-out, Filtration, reversed-phase chromatography, ion exchange chromatography, affinity chromatography, etc. are preferably used.
  • the gene recombination technique is not limited.
  • a DNA fragment encoding the target amino acid sequence is incorporated into an appropriate expression vector, and microorganisms and animal cells are transformed using this expression vector.
  • a technique for obtaining a peptide having a desired amino acid sequence by culturing the transformed microorganism or animal cell after conversion can be employed.
  • the expression vector used here is not limited, and a well-known one can be employed.
  • plasmids, virus vectors, and the like can be used.
  • the cell extract or the culture supernatant is collected from the cultured medium, and the above-described purification method is used. It is preferable to use it.
  • Custom Peptide Synthesis (3 ⁇ 4igma Genosys ⁇ ⁇ ⁇ ⁇ A peptide consisting of IJ was synthesized.
  • RGMa-expressing cells were prepared using Flp-InSystem (Invitrogen) and following the manufacturer's guidelines.
  • the HA-RGMa fragment containing the signal peptide was prepared from the pSecTag2 vector using two restriction endonucleases and ligated to pcDN A5FRT (Invitrogen).
  • This construct pcDNA5FRT / lg ⁇ leader / HA / RGMa
  • pOG44 were co-transformed into Flp-inCHO cells and grown for 2 weeks in a medium containing Neugromycin B (500 ag / ml; Invitrogen).
  • Cells stably expressing HA-RGMa hereinafter referred to as “RGMa-CHO cells”) were obtained.
  • the expression of HA-RGMa was confirmed by immunodetection using Western blot and immunocytochemistry.
  • Cerebellar granule cells from pup rats 7-9 days after birth were isolated by trypsinization (0.25% trypsin in PBS, 37 ° C, 15 minutes), resuspended in serum-containing medium, Milled and washed 3 times with PBS. Neurons were seeded on confluent monolayers of RGMa-CHO cells or subject CHO cells in chamber slides (Lab Tek II; Nunc). Pepl or Pep2 was added to the cultures at the indicated concentrations (1 M, 4 M, 10 M) for neutralization assays. Cultures were grown in serum-free DMEM / F12 medium for 24 hours.
  • the cells were fixed with 4% (wt / vol) paraformaldehyde and immunostained with a monoclonal antibody (Tujl) (l: 1000; Covance) that recognizes the neuron-specific 13 tubulin III protein.
  • Tujl monoclonal antibody
  • the length of the longest neurite was measured for each ⁇ -tubulin III positive neuron.
  • control indicates the target CHO cell
  • RGM— indicates that RGM protein is expressed (hereinafter referred to as “RGM—CHO cell”)
  • peerp l 1 ⁇ indicates 1 pep l.
  • peerpl 4 ⁇ is added when 4 ⁇ of pep l is added.
  • pep l ⁇ ⁇ ⁇ means pep l is ⁇ ⁇ ⁇ ⁇ p
  • pep2 1 M means pep2 is 1 M ⁇
  • 10 ⁇ indicates the case of adding 1 ⁇ of pep2.
  • the vertical axis is the average length of the longest neurite per neuron, and the data is the average soil S. .. ⁇ . Of three independent experiments.
  • Pep l and Pep2 can potently reverse the inhibitory effect of RGMa in a dose-dependent manner. This indicates that these peptides function as neutralizing reagents for RGMa in vitro, and that these peptides can be used as axon growth promoters by using them as active ingredients. It could be confirmed.
  • the axonal regeneration promoter according to the present invention has industrial applicability as a therapeutic agent for a patient who has damaged the central nervous system.
  • FIG. 1 is a diagram showing the inhibitory effect of RGMa protein by the peptide of the present invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un nouveau promoteur de régénération axonale. Ce promoteur de régénération axonale comprend, comme principe actif, un peptide possédant une séquence d'acides aminés comportant, sous forme de délétion, de substitution ou d'addition, un ou plusieurs résidus d'acides aminés dans la séquence d'acides aminés représentée dans n'importe laquelle des séquences SEQ ID NO:1 à 4 dans la liste de séquences. Ce promoteur peut agir pour neutraliser l'activité d'inhibition de la croissance axonale de la protéine RGMa.
PCT/JP2007/068449 2006-09-25 2007-09-21 Promoteur de régénération axonale Ceased WO2008038599A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008536361A JPWO2008038599A1 (ja) 2006-09-25 2007-09-21 軸索再生促進剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006258336 2006-09-25
JP2006-258336 2006-09-25

Publications (1)

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WO2008038599A1 true WO2008038599A1 (fr) 2008-04-03

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2185587A1 (fr) * 2007-09-06 2010-05-19 Abbott GmbH & Co. KG Domaines de liaison de la protéine morphogénétique de l'os de la famille protéique des molécules de guidage répulsif, leurs fragments fonctionnels et leur utilisation
US8906864B2 (en) 2005-09-30 2014-12-09 AbbVie Deutschland GmbH & Co. KG Binding domains of proteins of the repulsive guidance molecule (RGM) protein family and functional fragments thereof, and their use
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
US9102722B2 (en) 2012-01-27 2015-08-11 AbbVie Deutschland GmbH & Co. KG Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration
US9175075B2 (en) 2009-12-08 2015-11-03 AbbVie Deutschland GmbH & Co. KG Methods of treating retinal nerve fiber layer degeneration with monoclonal antibodies against a retinal guidance molecule (RGM) protein
WO2016175236A1 (fr) * 2015-04-28 2016-11-03 田辺三菱製薬株式会社 PROTÉINE DE LIAISON À RGMa ET SON UTILISATION

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051438A2 (fr) * 2000-12-22 2002-07-04 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Utilisation de rgm et de ses modulateurs
WO2003089608A2 (fr) * 2002-04-18 2003-10-30 The General Hospital Corporation Famille de genes drg11 (dragon)
WO2004003150A2 (fr) * 2002-06-26 2004-01-08 Yale University Modulateurs et modulation de l'interaction entre les rgm et la neogenine
WO2005087268A1 (fr) * 2004-03-11 2005-09-22 Bioclues, Inc Promoteur de regeneration d'axones
WO2007039256A2 (fr) * 2005-09-30 2007-04-12 Abbott Gmbh & Co. Kg Domaines de liaison de proteines de la famille proteinique des molecules de guidage repulsif (rgm), fragments fonctionnels de ces domaines et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051438A2 (fr) * 2000-12-22 2002-07-04 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Utilisation de rgm et de ses modulateurs
WO2003089608A2 (fr) * 2002-04-18 2003-10-30 The General Hospital Corporation Famille de genes drg11 (dragon)
WO2004003150A2 (fr) * 2002-06-26 2004-01-08 Yale University Modulateurs et modulation de l'interaction entre les rgm et la neogenine
WO2005087268A1 (fr) * 2004-03-11 2005-09-22 Bioclues, Inc Promoteur de regeneration d'axones
WO2007039256A2 (fr) * 2005-09-30 2007-04-12 Abbott Gmbh & Co. Kg Domaines de liaison de proteines de la famille proteinique des molecules de guidage repulsif (rgm), fragments fonctionnels de ces domaines et leur utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
NIEDERKOFLER V. ET AL: "REPULSIVE GUIDANCE MOLECULE (RGM) GENE FUNCTION IS REQUIRED FOR NEURAL TUBE CLOSURE BUT NOT RETINAL TOPOGRAPHY IN THE MOUSE VISUAL SYSTEM", J. NEUROSCI., vol. 24, no. 4, 2004, pages 808 - 818, XP002345929 *
RAJAGOPALAN S. ET AL: "NEOGENIN MEDIATES THE ACTION OF REPULSIVE GUIDANCE MOLECULE", NAT. CELL BIOL., vol. 6, no. 8, 2004, pages 756 - 762, XP002424999 *
YAMASHITA T: "Chusu Shinkei Saisei Sogai Kiko no Kaimei to Soyaku eno Oyo ni Kansuru Kenkyu", VENTURE BUSINESS LABORATORY CHIBA UNIVERSITY NENPO, no. 7, 1 September 2006 (2006-09-01), pages 155 - 158, XP003021733 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8906864B2 (en) 2005-09-30 2014-12-09 AbbVie Deutschland GmbH & Co. KG Binding domains of proteins of the repulsive guidance molecule (RGM) protein family and functional fragments thereof, and their use
EP2185587A1 (fr) * 2007-09-06 2010-05-19 Abbott GmbH & Co. KG Domaines de liaison de la protéine morphogénétique de l'os de la famille protéique des molécules de guidage répulsif, leurs fragments fonctionnels et leur utilisation
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
US9605069B2 (en) 2008-02-29 2017-03-28 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM a protein and uses thereof
US9175075B2 (en) 2009-12-08 2015-11-03 AbbVie Deutschland GmbH & Co. KG Methods of treating retinal nerve fiber layer degeneration with monoclonal antibodies against a retinal guidance molecule (RGM) protein
US9102722B2 (en) 2012-01-27 2015-08-11 AbbVie Deutschland GmbH & Co. KG Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration
US9365643B2 (en) 2012-01-27 2016-06-14 AbbVie Deutschland GmbH & Co. KG Antibodies that bind to repulsive guidance molecule A (RGMA)
US10106602B2 (en) 2012-01-27 2018-10-23 AbbVie Deutschland GmbH & Co. KG Isolated monoclonal anti-repulsive guidance molecule A antibodies and uses thereof
WO2016175236A1 (fr) * 2015-04-28 2016-11-03 田辺三菱製薬株式会社 PROTÉINE DE LIAISON À RGMa ET SON UTILISATION
US10287346B2 (en) 2015-04-28 2019-05-14 Mitsubishi Tanabe Pharma Corporation RGMa binding protein and use thereof
US11008388B2 (en) 2015-04-28 2021-05-18 Mitsubishi Tanabe Pharma Corporation RGMa binding protein and use thereof

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