WO2000024427A1 - Remedes contre les rhumatismes contenant un gene fadd en qualite d'ingredient actif - Google Patents

Remedes contre les rhumatismes contenant un gene fadd en qualite d'ingredient actif Download PDF

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Publication number
WO2000024427A1
WO2000024427A1 PCT/JP1999/005988 JP9905988W WO0024427A1 WO 2000024427 A1 WO2000024427 A1 WO 2000024427A1 JP 9905988 W JP9905988 W JP 9905988W WO 0024427 A1 WO0024427 A1 WO 0024427A1
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WO
WIPO (PCT)
Prior art keywords
fadd
rheumatism
fadd gene
gene
cells
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Application number
PCT/JP1999/005988
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English (en)
Japanese (ja)
Inventor
Kusuki Nishioka
Hirohumi Hamada
Original Assignee
St. Marianna University School Of Medicine
Santen Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by St. Marianna University School Of Medicine, Santen Pharmaceutical Co., Ltd. filed Critical St. Marianna University School Of Medicine
Publication of WO2000024427A1 publication Critical patent/WO2000024427A1/fr

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to a therapeutic agent for rheumatism containing a FAD (Fas associated death domain protein) gene as an active ingredient.
  • FAD Fes associated death domain protein
  • Rheumatism is a group of diseases based on the proliferation of synovial cells with various immunological abnormalities caused by internal and external factors. It is thought to be an abnormal proliferation of synovial cells accompanied by bone erosion (bone erosion and the appearance of bone erosion). Rheumatoid arthritis is characterized by regression of proliferating synovial cells, followed by replacement with fibrous tissue (Fassbender HG: Pathology of Rheumatic Diseases. Berlin, Heidelberg, Springer- Verlag, 1975), however, the mechanism of regression and rebirthment remains largely unknown. However, tissue destruction mainly in the affected joints in chronic rheumatoid arthritis may be due to abnormal production or excessive release of cytokines from synovial cells and inflammatory synovial infiltrating cells. .
  • synovial tissue cells (synovial cells and inflammatory synovial infiltrating cells) play an important role in rheumatoid arthritis.
  • synovial villi are proliferated and the synovial tissue cells are multi-layered.
  • Synovial tissue cells are abnormally proliferating (by Daniel J. McCarty, Arthritis and allied conditions, A textbook of rheumatology 11th edition). If the abnormal proliferation of these synovial tissue cells could be suppressed, it would be useful for rheumatism treatment.
  • anti-inflammatory drugs such as steroids, gold drugs, and immunomodulators are used for drug treatment of rheumatism, but drugs that specifically suppress abnormal growth of synovial tissue cells are still in practical use. It has not been converted.
  • apoptosis a physiological cell death that occurs due to normal cell turnover (Br. J. Cancer, 26, 239 (1972)).
  • This apoptosis is a form of programmed cell death.
  • Cell necrosis involves processes that involve high fever, attack by antibodies and complement, or release of cell membrane contents by chemical factors, etc.Programmed cell death is programmed to die in vivo in advance.
  • Cell death in certain groups of cells accompanied by phenomena such as cell surface curvature, nuclear chromatin condensation, and chromosomal DNA fragmentation.
  • Fas-L Fas-L
  • Fas-L Fas-L
  • the FADD molecule was one of the molecules that played an important role in signaling of apoptosis via the Fas / Fas-L system in 1995.
  • the cells are cloned (J. Biol. Chem., 270, 7795 (1995)), and that apoptosis is induced by high expression of itself (Cell, 81, 505 (1995)).
  • the nucleotide sequence of the FADD gene is also disclosed in International Patent Publication WO96Z3163. Research has also been conducted on the application of the FADD gene to medical treatment, and it has been reported that the FADD gene transfer may be useful for treating brain tumors (Human Gene Therapy, 9_, 1599 (1998)). However, the application of the FADD gene to rheumatic therapy based on its action on synovial tissue has not yet been reported. Disclosure of the invention
  • the present inventors have focused on the fact that rheumatic symptoms are not improved despite apoptosis due to the Fas / Fas-L system in the synovial tissue of rheumatic patients.
  • FADD was found to be useful for the treatment of rheumatism.
  • the present invention relates to a therapeutic agent for rheumatism containing the FADD gene as an active ingredient.
  • the above-mentioned FADD gene preferably induces apoptosis, a form of programmed cell death, in synovial cells of rheumatic patients.
  • the F ADD gene may be integrated into a vector, especially an adenovirus vector.
  • Figure 1 shows the mortality of cells 48 hours after infection of cultured dendritic synovial cells with Aden0-FADD or Adeno-LacZ, and untreated control. This is a graph showing the mortality rate in such cases.
  • Figure 2 shows the expression levels of FADD molecules 12 and 24 hours after infection of cultured synovial cells from rheumatic patients with Aden0-FADD or Adno-LacZ. It shows the results of the above.
  • FIG. 3 is a graph showing the day-to-day change of arthritis score in type I collagen-induced arthritis.
  • ⁇ indicates the results of the A deno-FADD introduction group (mean of 5 to 7 cases)
  • ⁇ indicates the results of the A deno-Lac Z introduction group (mean of 5 to 7 cases)
  • ⁇ indicates the result of the group.
  • the results for the control group are shown.
  • the present inventors introduced the FADD gene into synovial cells separated and cultured from the synovial tissue of a rheumatic patient using an adenovirus vector, and examined the effects thereof.
  • adenovirus vector As explained in the pharmacological test section below, most cultured synovial cells were killed by FADD gene transfer. This indicates that in vitro it was confirmed that apoptosis was induced in synovial tissue cells due to high expression of FADD molecules, and the usefulness of FADD gene transfer as rheumatic therapy. Suggests.
  • the effect of the FADD gene transfer using an adenovirus vector in a collagen-induced arthritis model which is widely used as an animal model for examining the effects on rheumatism, was also examined.
  • the FADD gene As a method of introducing the FADD gene, it has been reported that the FADD gene is transferred (or introduced) to glioma cells by incorporating the FADD gene into an adenovirus vector (Human Gene Therapy, 9_, 1983 (1998)). Therefore, the effect of introducing the FADD gene into synovial cells of rheumatic patients was examined according to the method described in this document.
  • the ratio of the titer of A deno-FADD to the cultured synovial cells (hereinafter abbreviated as MOI) is 5, 10, 50, 100, and 200.
  • Figure 1 shows the mortality rate of cultured synovial cells from rheumatic patients.
  • a deno-Lac Z an adenovirus vector incorporating the yS-galactosidase gene
  • Adeno-FADD killed cultured synovial cells from rheumatic patients in a viral titer-dependent manner, while Adeno-LacZ had no effect.
  • FADD molecule The expression of FADD molecule in synovial cells after Adeno-FADD infection was examined.
  • a deno- the F AD D or A deno- L ac Z are infected with MO I 1 0 0, 1 2 and 2 4 hours after the cytoplasm The protein was extracted and subjected to immunoprototyping using an anti-FADD antibody.
  • FIG. 2 shows the results of an immunoblot showing the expression of FADD molecules in synovial cells infected with Adeno-FADD or Adeno-LacZ.
  • the effect of introducing the FADD gene in type II collagen-induced arthritis was examined using the degree of arthritis as an index.
  • Emulsion was prepared by mixing 0.05 N acetic acid solution (4 mg Zml) of type II collagen derived from articular cartilage and an equal volume of complete Freund's adjuvant.
  • the marjon was administered intradermally at the base of the ridge of DBAZ1J mice at 100 Ojt1 (type II collagen: 200; equivalent to zgZ mice). Twenty-one days after the primary sensitization, this emulsion was administered again to the skin at the base of the ridge of mice in a dose of 1001 (secondary sensitization).
  • the onset of arthritis was determined when swelling of the joint site with erythema was observed.
  • the degree of arthritis was scored according to the following arthritis evaluation criteria.
  • Fig. 3 shows the scoring of arthritis in the Adeno-FADD injection group, the Adeno-FADD injection group and the vehicle injection group (hereinafter referred to as the control group).
  • the present invention relates to a novel means for treating rheumatism by specifically inducing apoptosis in abnormally proliferating synovial cells of a rheumatic patient.
  • a therapeutic agent for rheumatism comprising a FADD (Fas associated death domain protein) gene as an active ingredient.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pain & Pain Management (AREA)

Abstract

Cette invention concerne un système qui permet de traiter les rhumatismes et qui induit l'apoptose de manière spécifique parmi les cellules synoviales proliférant de manière anormale chez les patients atteints de rhumatismes. Cette invention concerne également des remèdes contre les rhumatismes qui contiennent un gène FADD en qualité d'ingrédient actif. Ce gène FADD consiste de préférence en un gène capable d'induire l'apoptose, un mode de mort cellulaire programmée, parmi les cellules synoviales de patients atteints de rhumatismes. Le gène FADD peut être intégré à un vecteur, tel qu'un vecteur d'adénovirus.
PCT/JP1999/005988 1998-10-28 1999-10-28 Remedes contre les rhumatismes contenant un gene fadd en qualite d'ingredient actif WO2000024427A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/306573 1998-10-28
JP30657398 1998-10-28

Publications (1)

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WO2000024427A1 true WO2000024427A1 (fr) 2000-05-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031603A2 (fr) * 1995-04-03 1996-10-10 The Regents Of The University Of Michigan Procedes et compositions pour reguler le niveau de la proteine 'fadd'
WO1998003648A1 (fr) * 1996-07-19 1998-01-29 Takeda Chemical Industries, Ltd. Proteine similaire au ligand fas, son procede de production et d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031603A2 (fr) * 1995-04-03 1996-10-10 The Regents Of The University Of Michigan Procedes et compositions pour reguler le niveau de la proteine 'fadd'
WO1998003648A1 (fr) * 1996-07-19 1998-01-29 Takeda Chemical Industries, Ltd. Proteine similaire au ligand fas, son procede de production et d'utilisation

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