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Fibrotic non-human animal, and use thereof

Foreign code F210010274
File No. 3667
Posted date Jan 8, 2021
Country EPO
Application number 13851788
Gazette No. 2915881
Date of filing Oct 31, 2013
Gazette Date Sep 9, 2015
International application number JP2013079623
International publication number WO2014069597
Date of international filing Oct 31, 2013
Date of international publication May 8, 2014
Priority data
  • 201261721301 (Nov 1, 2012) US
  • 2013JP79623 (Oct 31, 2013) WO
Title Fibrotic non-human animal, and use thereof
Abstract 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.
Outline of related art and contending technology 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.
Scope of claims [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.
  • Applicant
  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
  • KYOTO UNIVERSITY
  • Inventor
  • ASHIDA NOBORU
  • YOKODE MASAYUKI
  • KARIN MICHAEL
  • NGUYEN TIEN DAT
IPC(International Patent Classification)
Specified countries 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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