WO2020024773A1 - Utilisation de yap et de foxd1 dans la préparation d'un produit pour traiter et/ou prévenir l'ostéoarthrite chez les animaux - Google Patents

Utilisation de yap et de foxd1 dans la préparation d'un produit pour traiter et/ou prévenir l'ostéoarthrite chez les animaux Download PDF

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Publication number
WO2020024773A1
WO2020024773A1 PCT/CN2019/095172 CN2019095172W WO2020024773A1 WO 2020024773 A1 WO2020024773 A1 WO 2020024773A1 CN 2019095172 W CN2019095172 W CN 2019095172W WO 2020024773 A1 WO2020024773 A1 WO 2020024773A1
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WIPO (PCT)
Prior art keywords
sequence
osteoarthritis
stem cells
mesenchymal stem
senescence
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PCT/CN2019/095172
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English (en)
Chinese (zh)
Inventor
曲静
刘光慧
付丽娜
任若通
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中国科学院动物研究所
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Priority claimed from CN201810871204.0A external-priority patent/CN108607103B/zh
Priority claimed from CN201810870040.XA external-priority patent/CN108743920B/zh
Application filed by 中国科学院动物研究所 filed Critical 中国科学院动物研究所
Publication of WO2020024773A1 publication Critical patent/WO2020024773A1/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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the YAP coding gene in A2) can be obtained by deleting a codon for one or several amino acid residues in the DNA sequence shown at positions 4694-6217 of sequence 3 or 4664-6217 at sequence 3, and / Alternatively, one or several base pairs of missense mutations are obtained, and / or a coding sequence obtained by attaching a tag shown in the table above to the 5 ′ end and / or 3 ′ end of the missense mutation is obtained. Among them, the DNA molecule shown in positions 4664-6217 of sequence 3 encodes the protein shown in sequence 2.
  • the transgenic cell line may or may not include propagation material.
  • E4 a recombinant vector containing the expression cassette of E2)
  • the microorganism may be a virus, yeast, bacteria, algae or fungus.
  • the virus may be a lentivirus.
  • the biological material also belongs to the protection scope of the present invention.
  • the product may be a drug or a vaccine.
  • Figure 1 shows the role of YAP in the replicative senescence of human mesenchymal stem cells.
  • A Detection of SA- ⁇ -gal activity in young (2nd generation) and aging (12th generation) human mesenchymal stem cells;
  • B young (2nd generation) and aging (12th generation) human mesenchymal stem cells Expression of YAP;
  • C Cell growth curve after infection with Luc and YAP lentivirus in human mesenchymal stem cells of the fifth generation;
  • D After infection of Luc and YAP lentivirus by human mesenchymal stem cells in the fifth generation, respectively, continue Detection of SA- ⁇ -gal activity cultured to the 10th passage.
  • human mesenchymal stem cells differentiated from human embryonic stem cells can be continuously passaged from the first generation to the twelfth generation under in vitro culture conditions.
  • the growth of the mesenchymal stem cells of the 12th generation was completely retarded, the cell volume became larger, and the morphology was flat, showing a classic cell aging phenotype.
  • the SA- ⁇ -gal staining results (A in Figure 1) showed that the activity of SA- ⁇ -gal in the 12th generation of mesenchymal stem cells was much higher than that in the 2nd generation.
  • Example 1 Eight mouse models of osteoarthritis induced by anterior cruciate ligament severance were established. On day 7 after surgery, lentivirus-mediated gene therapy was performed. The lentivirus encoding the YAP gene obtained in Example 1 was resuspended in 20 ⁇ L of mesenchymal stem cell culture medium, and the lentivirus encoding Luc in Example 1 was used as a control.
  • bits 1 to 165 of sequence 6 are 5 'non-coding regions; bits 166 to 1563 are coding sequences (CDS) of the FOXD1 protein; bits 1564 to 2272 are 3' non coding regions.
  • primers were designed to perform PCR of the coding sequence of FOXD1 using the total cDNA of human mesenchymal stem cells as a template.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne l'utilisation de YAP et de FOXD1 dans la préparation d'un produit pour le traitement et/ou la prévention de l'ostéoarthrite chez les animaux. La présente invention a découvert que YAP et FOXD1 possèdent les fonctions suivantes : le traitement et/ou la prévention de l'ostéoarthrite chez les animaux ; le traitement et/ou la prévention de l'ostéoarthrite induite par la transsection du ligament croisé antérieur ou de l'ostéoarthrite provoquée par la sénescence physiologique chez les animaux ; le retardement de la sénescence de cellules souches mésenchymateuses ; et le retardement de la sénescence de la reproduction des cellules souches mésenchymateuses. Le YAP a également pour fonction de retarder la sénescence pathologique de cellules souches mésenchymateuses. Des expériences dans la présente invention vérifient que YAP et FOXD1 ont la fonction de retarder la sénescence de cellules souches mésenchymateuses et ont également un effet thérapeutique clair dans les maladies de type l'ostéoarthrite. La présente invention offre une nouvelle idée de développement d'une thérapie génique pour l'ostéoarthrite et étend la plage sélectionnable de thérapie génique clinique.
PCT/CN2019/095172 2018-08-02 2019-07-09 Utilisation de yap et de foxd1 dans la préparation d'un produit pour traiter et/ou prévenir l'ostéoarthrite chez les animaux WO2020024773A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810871204.0A CN108607103B (zh) 2018-08-02 2018-08-02 Foxd1在制备治疗和/或预防动物骨关节炎产品中的应用
CN201810870040.X 2018-08-02
CN201810870040.XA CN108743920B (zh) 2018-08-02 2018-08-02 Yap在制备治疗和/或预防动物骨关节炎产品中的应用
CN201810871204.0 2018-08-02

Publications (1)

Publication Number Publication Date
WO2020024773A1 true WO2020024773A1 (fr) 2020-02-06

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PCT/CN2019/095172 WO2020024773A1 (fr) 2018-08-02 2019-07-09 Utilisation de yap et de foxd1 dans la préparation d'un produit pour traiter et/ou prévenir l'ostéoarthrite chez les animaux

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WO (1) WO2020024773A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108607103A (zh) * 2018-08-02 2018-10-02 中国科学院动物研究所 Foxd1在制备治疗和/或预防动物骨关节炎产品中的应用
CN108743920A (zh) * 2018-08-02 2018-11-06 中国科学院动物研究所 Yap在制备治疗和/或预防动物骨关节炎产品中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108607103A (zh) * 2018-08-02 2018-10-02 中国科学院动物研究所 Foxd1在制备治疗和/或预防动物骨关节炎产品中的应用
CN108743920A (zh) * 2018-08-02 2018-11-06 中国科学院动物研究所 Yap在制备治疗和/或预防动物骨关节炎产品中的应用

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ALEXANDRA KARYSTINOU, ET AL: "Yes-associated protein (YAP) is a negative regulator of chondrogenesis in mesenchymal stem cells", ARTHRITIS RESEARCH AND THERAPY, vol. 17, no. 1, 30 May 2015 (2015-05-30), pages 147, XP021223424 *
ALEXANDRA, KARYSTINOU ET AL.: "Yes-associated Protein (YAP) is a Negative Regulator of Chondrogenesis in Mesenchymal Stem Cells", ARTHRITIS RESEARCH & THERAPY, vol. 17, no. 1, 30 May 2015 (2015-05-30), pages 147, XP021223424 *
DATABASE Nucleotide 15 July 2018 (2018-07-15), LEE JY ET AL.: "Homo sapiens Yes associated protein 1 (YAP1), transcript variant 9, mRNA", XP055684664, retrieved from NCBI Database accession no. NM_001282101.1 *
DATABASE Nucleotide 30 August 1996 (1996-08-30), ERNSTSSON, S. ET AL.: "Human transcription factor, forkhead related activator 4 (FREAC-4) mRN", XP055684649, retrieved from NCBI Database accession no. U59832.1 *
DATABASE Protein 10 May 2018 (2018-05-10), "forkhead box protein D1 [Homo sapiens]", XP055684656, retrieved from NCBI Database accession no. NP_004463. 1 *
DATABASE Protein 15 July 2018 (2018-07-15), "transcriptional coactivator YAP1 isoform 9 [Homo sapiens]", XP055684660, retrieved from NCBI Database accession no. NP_001269030.1 *
F. COLELL A ET AL.: "566 YAP Targeting in Synovial MSCs as a Novel Therapeutic Approach for Osteoarthritis", OSTEOARTHRITIS AND CARTILAGE, vol. 26, 30 April 2018 (2018-04-30), pages S301, XP055684645 *
F. COLELLA ET AL.: "566 YAP Targeting in Synovial MSCs as a Novel Therapeutic Approach for Osteoarthritis", OSTEOARTHRITIS AND CARTILAGE, vol. 26, 30 April 2018 (2018-04-30), pages S301, XP055684645 *

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