WO2000006725A1 - Procede pour diagnostiquer des maladies hereditaires au moyen du gene de semaphorine w - Google Patents

Procede pour diagnostiquer des maladies hereditaires au moyen du gene de semaphorine w Download PDF

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Publication number
WO2000006725A1
WO2000006725A1 PCT/JP1999/004120 JP9904120W WO0006725A1 WO 2000006725 A1 WO2000006725 A1 WO 2000006725A1 JP 9904120 W JP9904120 W JP 9904120W WO 0006725 A1 WO0006725 A1 WO 0006725A1
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gene
semaphorin
disease
mutation
genetic
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English (en)
Japanese (ja)
Inventor
Toru Kimura
Jeffrey Adam Encinas
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Sumitomo Pharma Co Ltd
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Sumitomo Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a method for diagnosing a genetic disease using a semaphorin W gene. More specifically, the present invention provides a method for diagnosing a genetic disease by analyzing the presence or absence of a mutation in a semaphorin W gene on a chromosome, or a method for determining the gene type of a semaphorin W gene carried in an individual, or Semaphorin in the diagnostic or determining method
  • the present invention relates to a DNA or RNA that can be used for analyzing the presence or absence of a mutation in a W gene, and a therapeutic agent for a genetic disease containing a semaphorin W gene as an active ingredient.
  • adenosine deaminase deficiency is known to be an immune disease caused by a mutation in the adenosine deaminase gene. Therefore, the onset can be suppressed by replacement of adenosine deaminase or bone marrow transplantation as replacement therapy, and in the future, by applying gene therapy, the onset can be suppressed for a lifetime.
  • genetic diagnosis of parents allows them to know in advance whether their newborn child may have the disease and prepare for treatment. Therefore, finding the causative gene of a so-called genetic disease, which is surely caused by genetic factors, is extremely important in medical practice, and it is necessary to diagnose the disease or the possibility of its development, and even to treat it. It is also possible, and its industrial utility is extremely high.
  • semaphorin W is a novel semaphorin cloned by the present inventors (WO 98 / 1562S pamphlet), but its location on the chromosome of semaphorin W and its association with genetic diseases and the like are not discussed. , Has not been revealed at all.
  • An object of the present invention is to provide a method for diagnosing a genetic disease using a semaphorin W gene. That is, the present invention provides a method for diagnosing a genetic disease by analyzing the presence or absence of a mutation in the semaphorin W gene, a method for determining the genotype of the semaphorin W gene retained in an individual, or the method for diagnosis or determination.
  • An object of the present invention is to provide a DNA or RNA that can be used for analyzing the presence or absence of a mutation in the semaphorin W gene, and a therapeutic agent for a genetic disease containing the semaphorin W gene as an active ingredient.
  • the present inventors have identified a novel neurite outgrowth inhibitor, semaphorin W (WO 98/15628).
  • the present inventors have now accurately determined the chromosomal location of the human and mouse semaphorin W gene using the radiation hybridization method, and compared them with known genetic diseases and mutations. As a result, they found that in mice, this semaphorin W gene maps to the same position as a genetic disease called mnd2, for which the causative gene has not yet been identified.
  • mapping of the human semaphorin W gene on the chromosome revealed that it was present on the short arm 2pl3 of chromosome 2.
  • 2 P 13 of the 2 short arm of chromosome a variety of genetic diseases, i.e. Parkinson's disease, Alstrom syndrome, limb-girdle muscular resist opening buoy one 2 B-type, Miyoshi distal muscular dystrophy, neuroblastoma, bar one Kit lymphoid fl., Colon adenocarcinoma, goiter, schizophrenia, cleft palate, cleft lip, chronic linno leukemia, keratocystoma, and multiple congenital malformations. It is the position where it is locked.
  • the mouse 'semaphorin w gene is considered to be a causative gene of a genetic disease called mnd2 as described above and also a causative gene of a similar genetic disease in humans, Also, it was concluded that the semaphorin W gene is a causative gene of a genetic disease, and specifically, is a causative gene of a genetic disease mapped to 2p13 on the short arm of chromosome 2 as described above.
  • the semaphorin W gene is also a causative gene for various genetic diseases.
  • the position of the semaphorin W gene on the chromosome is determined for the first time in the present invention, and it is clarified that the semaphorin W is a causative gene for the genetic disease as described above. It has become possible to provide methods for diagnosis and treatment, as well as a method for raising breeding efficiency in model animals with genetic diseases.
  • the present invention has been completed based on the above findings.
  • a method for diagnosing a genetic disease which comprises analyzing the presence or absence of a mutation in a semaphorin W gene on a chromosome;
  • Genetic diseases include Parkinson's disease, Alstroem syndrome, limb-girdle muscular dystrophy, oral type 1B, Miyoshi-type distal muscular dystrophy, neuroblastoma, Baikit's lymphoma, colon adenocarcinoma, goiter, The method of (1) or (2), wherein the method is selected from schizophrenia, cleft palate / cleft lip, chronic lymphocytic leukemia, keratocytoma or multiple congenital malformations;
  • a therapeutic agent for a genetic disease comprising at least a part of the semaphorin W gene as an active ingredient
  • the diagnosis method is a method for diagnosing a genetic disease by analyzing the presence or absence of a mutation in a semaphorin W gene on a chromosome.
  • the diagnostic method also diagnoses the possibility of developing a genetic disease.
  • the ⁇ semaphorin W gene '' includes all exons of mammalian semaphorin W such as human, rat, mouse, etc., and all introns and transcription regulatory regions sandwiched therebetween, transcription termination site, etc. Semaphorin Refers to all regions that control the structure and expression control of the w gene.
  • the semaphorin w gene is a causative gene for a genetic disease, but it has once been revealed that it is a causative gene for a genetic disease.
  • the total length of the semaphorin W gene exceeds tens of thousands of nucleotides. It takes time to analyze the entire base sequence. Therefore, it is actually more efficient to use the stepwise method as shown below. That is, as a first step, the nucleotide sequence of the semaphorin w gene of one healthy patient is determined.
  • a known human semaphorin W cDNA can be obtained from a human chromosomal DNA such as the YAC library (Research Genetics, USA) or the BAC library (Research Genetics, USA).
  • a human chromosomal DNA such as the YAC library (Research Genetics, USA) or the BAC library (Research Genetics, USA).
  • FERM BP-6089 Depositary institution: 1-3 1-3 Higashi, Tsukuba, Ibaraki Prefecture, Research Institute of Biotechnology, Industrial Technology Institute; Deposit Date: Heisei (August 29, 9) Screening may be performed by a conventional method using as a probe.
  • the gene can be obtained by requesting Genome Systems, Inc. in the United States after setting appropriate primers.
  • ⁇ 5 -agcatccctgactctcat-3 (Torumi system U number: 17)
  • 5 '-tagggggaagccctgatt-3' Toromi column number: 18
  • 5 '-cagaaagcagttctgatt-3' 3 primers (SEQ ID NO: 19) were set and 547 bp by PCR using primers of SEQ ID NO: 17 and SEQ ID NO: 18.
  • Semaphorin W was obtained by requesting Genome Systems, Inc., etc., to conduct screening using the appearance of a band and the appearance of a 523 bp band by PCR using primers of SEQ ID NO: 17 and SEQ ID NO: 19 as an index. Gene can be easily obtained.
  • the gene is amplified by PCR for some sequences of about 500 to 2000 bases in some patients and healthy people, and for each fragment, for example, We analyzed whether there is a difference between the gene of a patient and a healthy person by the RFLP method, the PCR method, the SSCP method, or the enzymatic cleavage method of a mutant base pair, which is one of the genetic diagnosis methods described in detail below.
  • the entire nucleotide sequence of the region where the difference was found may be determined. This makes it possible to determine exactly what kind of mutation is strictly and easily. Such methods are generally well known and
  • detection of this mutation site can be performed as follows. That is, chromosomal DNA extracted from a part of a subject's tissue, blood, etc. by a standard method is used as a test sample.
  • the reagent for mutation detection used in such diagnosis is, for example, a DNA or RNA having a part of the sequence of the semaphorin W gene and a DNA or RNA that can be analyzed for the presence or absence of a mutation in the semaphorin Wit gene. Any NA or RNA May be selected as appropriate at the discretion of those skilled in the art.
  • the DNA can be used as a PCR primer or a probe for hybridization, and the RNA can be used as a probe for hybridization (the DNA and RNA will be described later).
  • a “genetic disease” diagnosed by analyzing a mutation in the semaphorin W gene refers to a disease in which the semaphorin W gene (a gene located on the semaphorin W gene) is the causative gene. Point. That is, in humans, it refers to a genetic disease that is mapped to 2p13 on the short arm of chromosome 2, and specifically includes a genetic disease that causes abnormalities in the nervous system, muscle, or immune system.
  • Parkinson's disease Alstroem syndrome, limb girdle muscular dystrophy type 2B, Miyoshi type distal muscular dystrophy, neuroblastoma, Burkitt's lymphoma, colon adenocarcinoma, goiter, schizophrenia, palate Cleft Z cleft lip, chronic Rinno ,. It is selected from diseases that map to 2p13 on the short arm of chromosome 2, such as leukemia, keratokeratomas, or multiple congenital malformations. Among them, Parkinson's disease and Alstroem syndrome are preferable from the viewpoint of mapping in more detail. From another viewpoint, a human genetic disease corresponding to mnd2 in mice can be mentioned.
  • mnd2 diseases that cause abnormalities in nerves, muscles or the immune system, and in which the causative gene is mapped to the same position as the semaphorin W gene.
  • the diagnostic method of the present invention it is possible to diagnose not only the onset of the genetic disease as described above but also the possibility of the future onset of the genetic disease.
  • the semaphorin W gene may also be a causative gene for various genetic diseases.
  • diseases that cause semaphorin W as a causative gene That is, for a disease in which the causative gene is mapped at the same position as the semaphorin W gene, diagnosis can be performed based on the method for identifying a mutation in the semaphorin W gene and the method for detecting the mutation as described above. it can.
  • the present invention further provides a method for determining the genotype of the semaphorin W gene retained in an individual by analyzing the presence or absence of a mutation in the semaphorin W gene.
  • semaphorin W gene genotype means a homozygote (-/-) that has a semaphorin w gene mutation in both alleles and a heterozygote that has a semaphorin w gene mutation in one of the alleles. (+/-) and wild-type (+ / +)
  • V refers to any genotype.
  • model animals with genetic mutations is widely used in disease research and drug development.
  • One major problem is that often homozygous mutants are difficult to subculture, so they are usually passaged by heterozygotes, and homozygotes are selected from them for experiments. Then the method of using it is taken. However, it is often difficult to select homozygotes in young individuals, which greatly hinders research using such mutant animals.
  • the causative gene of the mutation is found, the genotype can be easily detected by analyzing the gene by a known method such as PCR, and the efficiency of breeding can be greatly improved. Since the present invention revealed that semaphorin W was the causative gene of mnd2, the genotype of mnd2 mouse could be easily determined by analyzing the semaphorin W gene, Can be quickly and efficiently selected.
  • the semaphorin W gene mutant animals include not only mnd2 mice, but also diseases that cause abnormalities in the nerves, muscles, or immune system as described above, and have the same causative gene as the semaphorin W gene. Have a disease that maps to a location Mutant animals are included.
  • the present invention also provides a DNA or RNA that can be used for analyzing the presence or absence of a mutation in the semaphorin W gene in the above-described diagnostic methods and genotype determination methods. As described above, once a mutation site in the semaphorin W gene is identified, DNA or RNA for detecting the mutation can be easily selected by a conventional method.
  • DNA that is a part of the semaphorin W gene and that is capable of analyzing the mutation of the semaphorin W gene can be used as a probe in a diagnosis method based on a dimension.
  • an RNA corresponding to a DNA consisting of a part of the semaphorin Wit gene can be used, and the RNA can be used as a probe for hybridization.
  • the semaphorin W gene is, for example, in the case of human, the human semaphorin W is compared to the human chromosome DNA YAC library 1 (Research Genetics, USA) or BAC library 1 (Research The Genetics, USA).
  • Cloning can be performed by screening using cDNA (described in WO 98/15628 pamphlet, accession number: FEM BP-6089) as a probe by a conventional method. Further, as described above, if appropriate primers such as SEQ ID NO: 17 to SEQ ID NO: 19 are set, the semaphorin W gene can be easily obtained by requesting Genome Systems, Inc. can do.
  • cDNA of semaphorin W is also a DNA consisting of a part of the semaphorin W gene, a part of the cDNA can be used as the DNA for mutation analysis of the present invention.
  • the nucleotide sequence of cDNA (human and rat) is described in WO 98/15628 pamphlet, and the human is deposited under accession number: FERM BP-6089.
  • FERM BP-6089 accession number
  • cDNA of semaphorin W can be easily obtained based on the nucleotide sequence.
  • the DNA for mutation analysis of the present invention can be appropriately prepared by a conventional method such as DNA synthesis. Whether or not these DNAs are DNAs that can analyze mutations in the semaphorin W gene can be determined by the method for identifying a site having the mutation described above (Current Protocols in Human Genetics (1998) Edt. Boyle et al. John Wiley & Sons, Inc.) and the method of detecting the mutation site.
  • DNA for mutation analysis of the present invention include the following.
  • CXGZGXC a change in the number of three-base repeating sequences
  • the DNA for mutation analysis of the present invention include a DNA probe or primer capable of detecting the mutation of the number of the CTG or leucine.
  • the present invention further provides a therapeutic agent for a genetic disease, which comprises at least a part of the semaphorin W gene as an active ingredient. That is, since the semaphorin W gene is a causative gene of a genetic disease, it can be used for treating the genetic disease.
  • a retrovirus for example, a retrovirus, an adenovirus, an adeno-associated virus, a herpes virus, a vaccinia virus, a box virus, a polio virus, a simbis virus, or the like, may be used as the DNA virus or the RNA virus of the present invention.
  • a method of incorporating and introducing DNA There is a method of incorporating and introducing DNA.
  • a method using a retrovirus, an adenovirus, an adeno-associated virus, a vaccinia virus and the like is particularly preferable.
  • DNA vaccine method direct injection of the expression plasmid into the muscle
  • liposomal method lipofectin method
  • microinjection method phosphoric acid / residue method
  • electoral poration method phosphoric acid / residue method
  • DNA vaccine method and the ribosome method are preferred.
  • the in vivo method When administered by the in vivo method, it can be administered by an appropriate route depending on the disease, symptom, and the like for the treatment. For example, it can be administered to a vein, artery, subcutaneous, intradermal, intramuscular, and the like.
  • it When administered by the in vivo method, for example, it may be in the form of a liquid preparation or the like, but it is generally prepared as an injection containing the DNA of the present invention as an active ingredient.
  • a carrier may be added.
  • liposome or membrane-fused ribosome such as Sendai virus (HVJ) -ribosome
  • liposomes such as a suspending agent, a cryogen, and a centrifugal concentrated cryogen are used.
  • a pharmaceutical preparation In the form of a pharmaceutical preparation.
  • the content of the DNA of the present invention in the preparation can be appropriately adjusted depending on the disease to be treated, the age and weight of the patient, etc., and usually 0.000001 to 100 mg, preferably 0.001 to 10 mg of the present invention.
  • the DNA of the invention is administered once every few days to several months.
  • FIG. 1 shows the frame map of chromosome 6 of the mouse in which the semaphorin W gene is present and the position of the semaphorin W gene (Semaw).
  • rat semaphorin W cDNA of the C57BL / 6 BAC genomic library of the U.S. Genome System Co., Ltd. No. 1 or SEQ ID NO: 2) was used as a probe, and 2) a mouse genomic DNA library was screened using the PCR screening service of the 129 / SVJ BAC genomic library.
  • the nucleotide sequences of the DNAs of these clones were determined using a Perkin-Elmera ⁇ ⁇ type 377 DNA sequencer. The reaction was performed using a prism dye termination kit (PerkinElmer). From the nucleotide sequence analysis results, it was confirmed that these clones definitely contained the semaphorin W gene.
  • the human semaphorin W gene maps to a position on the chromosome at 2 ⁇ 13.
  • the principle of conserved synteny (DeBry et al.
  • the region containing the human semaphorin W gene is located on chromosome 6 in mice. Further detailed location of the semaphorin W gene was determined as follows. In the case of mouse, since a framework for a marker sequence required for mapping has not yet been prepared, a frame of this region on chromosome 6 was prepared as follows. Using the various primers contained in Map Pairs Microsatellite Marker-1 (US Research's Genetics) to perform PCR on a T31 radiation hybrid panel (U.S.A. Research Genetics) and performing PCR on the results The Map 'Manager QT (Manly,
  • mice semaphorin W gene has two microsatellite markers. It was found to be located between D6Mit71 and D6Mit9, at 122.4cR from D6Mit71 and 59.9cR from D6Mit9. To determine the location of this gene in more detail, it is known from the Mouse-Genome Database http: // www. Informatics, jax.org/ that it is located near the location of the semaphorin W gene previously determined. There are six microsatellite cameras, namely D6Mit4, D6M6, D6Mit70,
  • D6Mit99, D6Mitl89, and D6M189 were examined by PCR for the presence of each of the four mouse semaphorin W chromosomal DNA clones obtained in Example 1. As a result, it was revealed that D4M189 was present in all four clones, and that D6Mit89 and D6Mit70 were both present in one clone, and that both markers and the mouse semaphorin W gene were identical on the BAC clone. (About 150 kb).
  • each clone contains the human semaphorin W gene! / Can be determined by generating a 520 bp fragment.
  • the human semaphorin W gene was expressed as 2
  • the marker sequence of chromosome short arm WI5987 revealed that it was located at the position 5.87cR on the centromere side, that is, at position 2pl3 of the chromosome 2 short arm.
  • Mouse semaphorin W cDNA was obtained by RT-PCR using 129 / SVJ mouse mRNA as type II as follows.
  • RNA was prepared from mouse brain by the usual method, and the obtained RNA is Using dT latex beads (Takara Shuzo), mRNA was prepared according to the protocol attached to the product.
  • l // g mRNA into type III, using a Superscript II cDNA synthesis system (manufactured by Gibco), according to the attached protocol, oligo dT-DNA and three synthetic primers, 5 '"GCCATAGCAGAGGGCTACAG-3' (sequence Nos .: 14), 5'-GAAGGCACACACAGCAGAAA-3 '(SEQ ID NO: 15), 5'-CTCACMTMCCCCGCACTT-3,
  • SEQ ID NO: 16 was used as a primer to synthesize cDNA. Subsequently, in order to obtain mouse semaphorin WcDNA, the cDNA synthesized above was transformed into type III, and PCR was performed using various synthetic primers under the same conditions as above. In order to further obtain a sequence at the 3 'end, the 3' RACE method was used. The obtained fragment was excised from the gel after agarose gel electrophoresis by a usual method, purified, and the nucleotide sequence was determined in the same manner as in Example 1.
  • the determined nucleotide sequence is shown in SEQ ID NO: 1, and the amino acid sequence is shown in SEQ ID NO: 2.
  • PCR primers are prepared for the semaphorin W gene mutation site and the site where the mutation is not observed as follows.
  • the sequence of the primer at the position where the mutation is recognized is the same between the mutant gene and the wild-type gene! /, So that the region is at the 5 'end of the primer and the different region is at the 3' end of the primer, and two types, one with the sequence of the wild-type gene (a) and one with the sequence of the mutant gene (a) Make it.
  • a primer having a wild-type sequence at a position where no mutation is observed as the third primer-( ⁇ ) is set at a position a suitable distance from the two primers.
  • genomic DNA is prepared from blood according to a standard method and used as a test sample. This genomic DNA is divided into two parts, A and B. A uses the primers (a) and (B), and B uses the primers (a) and ( ⁇ ). Perform PCR on the subject.
  • the amplified fragment obtained is subjected to agarose gel electrophoresis, and a band is detected by staining with bromide medium.
  • a band is detected by staining with bromide medium.
  • a method for diagnosing a genetic disease by analyzing the presence or absence of a mutation in the semaphorin W gene a method for determining the genotype of the semaphorin W gene retained in an individual, or the method for semaphorin W
  • the present invention can provide DNA or RNA which can be used for analyzing the presence or absence of a gene mutation, and a therapeutic agent for a genetic disease containing a semaphorin W gene as an active ingredient.

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Abstract

L'invention concerne un procédé permettant de diagnostiquer des maladies héréditaires par analyse de l'apparition d'une mutation dans le gène de sémaphorine W, ou bien un procédé permettant de déterminer le génotype du gène de sémaphorine W porté par un individu. L'invention concerne également un ADN ou un ARN pouvant être utilisé pour l'analyse de l'apparition d'une mutation dans le gène de sémaphorine W, réalisée selon ledit procédé de diagnostic ou selon ledit procédé de détermination. L'invention concerne en outre un remède contre des maladies héréditaires qui contient le gène de sémaphorine W comme principe actif.
PCT/JP1999/004120 1998-07-31 1999-07-30 Procede pour diagnostiquer des maladies hereditaires au moyen du gene de semaphorine w Ceased WO2000006725A1 (fr)

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JP21746798 1998-07-31
JP10/217467 1998-07-31
JP4683399 1999-02-24
JP11/46833 1999-02-24

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015628A1 (fr) * 1996-10-09 1998-04-16 Sumitomo Pharmaceuticals Company, Limited Nouveau gene de semaphorine: la semaphorine w

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015628A1 (fr) * 1996-10-09 1998-04-16 Sumitomo Pharmaceuticals Company, Limited Nouveau gene de semaphorine: la semaphorine w

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