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Fibrotic non-human animal, and use thereof

外国特許コード F210010274
整理番号 3667
掲載日 2021年1月8日
出願国 欧州特許庁(EPO)
出願番号 13851788
公報番号 2915881
出願日 平成25年10月31日(2013.10.31)
公報発行日 平成27年9月9日(2015.9.9)
国際出願番号 JP2013079623
国際公開番号 WO2014069597
国際出願日 平成25年10月31日(2013.10.31)
国際公開日 平成26年5月8日(2014.5.8)
優先権データ
  • 201261721301 (2012.11.1) US
  • 2013JP79623 (2013.10.31) WO
発明の名称 (英語) Fibrotic non-human animal, and use thereof
発明の概要(英語) The present invention provides a non-human animal IKK² which shows fibrosis of tissue, since it lacks IKK² gene in a myofibroblast- and/or smooth muscle cell-specific manner. Since the non-human animal shows pathology highly similar to scleroderma, it is extremely useful as an animal model of scleroderma.
従来技術、競合技術の概要(英語) Background Art
Fibrosis of tissue accompanying deposition of collagenous fiber is a phenomenon that occurs during wound healing process in the body as a terminal state of an inflammation reaction, and plays an important role in wound healing and the like in the body. On the other hand, excessive fibrosis of tissue is considered an onset or aggravating factor of various diseases based on inflammation, for example, dermatic disease, cardiac disease, respiratory disease, autoimmune disease, collagen disease, cancer, arteriosclerosis, diabetes and the like. Moreover, the mechanism of fibrosis has not been sufficiently elucidated, and the treatment of these diseases accompanying fibrosis is difficult.
Scleroderma (systemic scleroderma) which is one of the collagen diseases, is a disease mainly comprising enhanced synthesis and accumulation of collagenous fiber in the skin and internal organs. The disease characteristically shows a male-to-female ratio of about 1:9, and occurs in many females in the middle age of 30 - 50 years old. The pathology thereof also includes skin lesions such as Raynaud's symptoms, skin hardening and the like, as well as internal organ diseases such as lung fibrosis, renopathy, reflux oesophagitis and the like. Therefore, scleroderma is an intractable disease that affects not only the quality of life but also life prognosis, and at present, an effective treatment method and the like have not been established.
Conventionally, an animal model used for fibrosis, particularly, scleroderma, is a mouse having an artificially-developed fibrosis by the administration of drugs such as bleomycin and the like, cytokines such as TGFβ (transforming growth factor beta), CTGF (connective tissue growth factor), bFGF (basic fibroblast growth factor) and the like (non-patent documents 1, 2), or Tight skin mouse having gene abnormality at Fibrillin-1 (non-patent documents 3, 4). However, these known animal models have problems since, when, for example, a mouse is administered with cytokine in the skin, the skin of the administration site is only topically hardened, Tight skin mouse shows skin hardening of the equivalent level for male and female, and renopathy, reflux oesophagitis and the like are not observed, and the like. Therefore, all known animal scleroderma models are not sufficient in terms of the similarity to the pathology in human, artificiality and the like. Moreover, since Fibrillin-1 was reported to be a responsible gene of Stiff Skin Syndrome, which is a genetic disease completely different from scleroderma (non-patent document 5) in recent years, usefulness of tight skin mouse as a scleroderma model mouse has been questioned.
[Document List]
[non-patent documents]
non-patent document 1: Yamamoto T. et al., Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma, (1999), J. Invest. Dermatol., vol.112, no.4, p.456-462
non-patent document 2: Mori T. et al., Role and interaction of connective tissue growth factor with transforming growth factor- β in persistent fibrosis: A mouse fibrosis model, (1999), J. Cell Physiol., vol.181, no.1, p.153-159
non-patent document 3: Green M.C. et al., Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton, (1976), Am. J. Pathol., vol.82, no.3, p.493-512
non-patent document 4: Siracusa L.D. et al., A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation, (1996), Genome Res., vol.6, no.4, p.300-313
non-patent document 5: Loeys B.L. et al., Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome, (2010), Sci. Transl. Med., vol.2, no.23, p.23ra20.
特許請求の範囲(英語) [claim1]
1. A non-human animal showing fibrosis of tissue, which lacks IKKβ gene in a myofibroblast- and/or smooth muscle cell-specific manner, or a part of the living body thereof.

[claim2]
2. The non-human animal or a part of the living body thereof according to claim 1, wherein the fibrosis of tissue reproduces fibrosis associated with a disease selected from the group consisting of autoimmune disease, collagen disease, dermatic disease, cardiac disease, respiratory disease, oesophagus disease, stomach gastrointestinal disease, hepatic disease, renal disease, cranial nerve disease, cancer and diabetes.

[claim3]
3. The non-human animal or a part of the living body thereof according to claim 1, which is a scleroderma model.

[claim4]
4. The non-human animal or a part of the living body thereof according to claim 1, wherein the animal is rodent.

[claim5]
5. A method of screening for a substance for the prophylaxis and/or treatment of fibrosis of tissue, comprising
(a) a step of contacting a test substance with the non-human animal or a part of the living body thereof according to claim 1, and
(b) a step of analyzing fibrosis of a tissue of the aforementioned non-human animal or a part of the living body thereof according to claim 1.

[claim6]
6. A method of screening for a substance for the prophylaxis and/or treatment of scleroderma, comprising
(a) a step of contacting a test substance with the non-human animal or a part of the living body thereof according to claim 1, and
(b) a step of analyzing an event reflecting pathology scleroderma of the aforementioned non-human animal or a part of the living body thereof according to claim 1.
  • 出願人(英語)
  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
  • KYOTO UNIVERSITY
  • 発明者(英語)
  • ASHIDA NOBORU
  • YOKODE MASAYUKI
  • KARIN MICHAEL
  • NGUYEN TIEN DAT
国際特許分類(IPC)
指定国 Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
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