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1. WO2021049633 - DRUG FOR CURATIVE THERAPY OF INTRACTABLE HEREDITARY RENAL ALPORT SYNDROME

Publication Number WO/2021/049633
Publication Date 18.03.2021
International Application No. PCT/JP2020/034538
International Filing Date 11.09.2020
IPC
A61K 38/13 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
12Cyclic peptides
13Cyclosporins
A61P 13/12 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
13Drugs for disorders of the urinary system
12of the kidneys
A61P 43/00 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
43Drugs for specific purposes, not provided for in groups A61P1/-A61P41/108
C12N 5/10 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
5Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
10Cells modified by introduction of foreign genetic material, e.g. virus-transformed cells
CPC
A61K 38/13
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
38Medicinal preparations containing peptides
04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
12Cyclic peptides ; , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
13Cyclosporins
A61P 13/12
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
13Drugs for disorders of the urinary system
12of the kidneys
A61P 43/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
43Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
C12N 5/10
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
5Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor;
10Cells modified by introduction of foreign genetic material
Applicants
  • 国立大学法人熊本大学 NATIONAL UNIVERSITY CORPORATION KUMAMOTO UNIVERSITY [JP]/[JP]
Inventors
  • 甲斐 広文 KAI, Hirofumi
  • 首藤 剛 SHUTO, Tsuyoshi
  • スイコ メリーアン SUICO, Mary Ann
  • 塚本 佐知子 TSUKAMOTO, Sachiko
  • 三隅 将吾 MISUMI, Shogo
  • 河原 哲平 KAWAHARA, Teppei
  • 人羅 勇気 HITORA, Yuki
  • 加藤 光 KATO, Hikaru
  • 小谷 俊介 KOTANI, Shunsuke
  • 荒木 喜美 ARAKI, Kimi
Agents
  • 名古屋国際特許業務法人 NAGOYA INTERNATIONAL PATENT FIRM
  • 中谷 智子 NAKATANI Tomoko
Priority Data
2019-16558311.09.2019JP
Publication Language Japanese (JA)
Filing Language Japanese (JA)
Designated States
Title
(EN) DRUG FOR CURATIVE THERAPY OF INTRACTABLE HEREDITARY RENAL ALPORT SYNDROME
(FR) MÉDICAMENT DESTINÉ AU TRAITEMENT CURATIF DU SYNDROME D'ALPORT RÉNAL HÉRÉDITAIRE RÉFRACTAIRE
(JA) 難治性遺伝性腎疾患アルポート症候群の根治療法のための薬剤
Abstract
(EN)
Through screening using a high-throughput evaluation system related to the promotion of the formation and extracellular secretion of trimers of COL4A3/A4/A5, which are causative proteins that have decreased expression levels in the renal tissue of Alport syndrome (AS) patients, it was discovered that ciclosporin A has a facilitating action on the formation and extracellular secretion of type IV collagen trimers. With further research, it was discovered that Alisporivir and NIM258, which do not inhibit calcineurin, also have a facilitating action on the extracellular secretion of type IV collagen. The inventors discovered that these actions are based on a cyclophilin D inhibition mechanism, and arrived at the discovery of a fundamental therapeutic agent for AS via cyclophilin D inhibition. The present invention provides: a composition for promoting collagen trimer secretion in cells having a mutated type IV collagen gene, said composition containing a cyclophilin D inhibitor as an active ingredient; an AS treatment/prevention agent; and the like.
(FR)
Selon l'invention, par criblage au moyen d'un système d'évaluation à haut rendement lié à la promotion de la formation et de la sécrétion extracellulaire de trimères de COL4A3/A4/A5, qui sont des protéines responsables présentant des niveaux d'expression réduits dans le tissu rénal de patients atteints du syndrome d'Alport (AS), il a été découvert que la ciclosporine A présente une action de facilitation sur la formation et la sécrétion extracellulaire de trimères de collagène de type IV. Des recherches complémentaires ont montré que l'Alisporivir et le NIM258, qui n'inhibent pas la calcineurine, présentent également une action de facilitation sur la sécrétion extracellulaire du collagène de type IV. Les inventeurs ont découvert que ces actions sont basées sur un mécanisme d'inhibition de la cyclophiline D, et ont fait la découverte d'un agent thérapeutique fondamental contre le syndrome d'Alport par l'intermédiaire de l'inhibition de la cyclophiline D. La présente invention concerne : une composition destinée à promouvoir la sécrétion de trimères de collagène dans des cellules présentant un gène de collagène de type IV muté, ladite composition contenant comme principe actif un inhibiteur de la cyclophiline D ; un agent de traitement/prévention de l'AS ; et analogue.
(JA)
アルポート症候群(AS)の患者の腎組織で低下した原因タンパク質COL4A3/A4/A5の3量体形成と細胞外分泌を促進に関するハイスループット評価系を用いたスクリーニングにより,シクロスポリンAにIV型コラーゲンの3量体形成と細胞外分泌を促す作用があることを見出した。さらなる検討から,カルシニューリンを阻害しないAlisporivirやNIM258についても,IV型コラーゲンの細胞外分泌を促す作用があることを見出した。さらに,本発明者らはこれらの作用がシクロフィリンD阻害メカニズムに基づくことを見出し、シクロフィリンD阻害によるASの根本治療薬を見出すに至った。本発明は,シクロフィリンD阻害剤を有効成分として含有する,変異を有するIV型コラーゲン遺伝子を有する細胞におけるコラーゲン3量体の分泌を促進するための組成物やAS治療/予防薬を提供するものである。
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