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PROPHYLACTIC/THERAPEUTIC AGENT FOR ARTHRITIS, TEST KIT FOR ARTHRITIS, AND METHOD FOR SCREENING FOR PROPHYLACTIC/THERAPEUTIC AGENT FOR ARTHRITIS

Foreign code F160008755
File No. (S2014-1467-N0)
Posted date Jun 2, 2016
Country WIPO
International application number 2015JP074556
International publication number WO 2016031996
Date of international filing Aug 24, 2015
Date of international publication Mar 3, 2016
Priority data
  • P2014-174638 (Aug 28, 2014) JP
Title PROPHYLACTIC/THERAPEUTIC AGENT FOR ARTHRITIS, TEST KIT FOR ARTHRITIS, AND METHOD FOR SCREENING FOR PROPHYLACTIC/THERAPEUTIC AGENT FOR ARTHRITIS
Abstract The present invention provides: a prophylactic/therapeutic agent for arthritis including rheumatoid arthritis, which comprises a Tet3 expression inhibitor; a kit for diagnosing arthritis including rheumatoid arthritis; and a means for searching for a novel substance having a prophylactic and/or therapeutic activity on arthritis including rheumatoid arthritis.
Outline of related art and contending technology BACKGROUND ART
Is rheumatoid arthritis, systemic chronic inflammation at a joint of the refractory autoimmune disease occurs. Proliferation of synovial tissue within the joint, cartilage and bone destruction and increased progressively. Rheumatoid arthritis synovial fibroblasts is stimulated by macrophage and lymphocyte (FLS) (TNF α, to inflammatory cytokines IL-1β) is activated, the activated synovial fibroblasts, inflammatory cytokine or chemokine production, on the other hand cause joint destruction by matrix degradation enzyme secretion, proliferation, enhancement of the invasive potential, such as a reduction in apoptosis-sensitive cancer cells also have similar properties. In recent years, as a result of GWAS (Genome-Wide Association Study) of genetic polymorphisms of about 30 and the development of rheumatoid arthritis severity involves has become known. On the other hand, the development of abnormal HDAC and severity of rheumatoid arthritis as suggested involves deep becomes. DNA methylation of one of the exemplary mechanisms HDAC, the entire genome in rheumatoid arthritis, or specific promoter region of the gene of which there is an abnormality DNA methylation has been reported. The inventors have recently, genome DNA methylation analysis by exhaustive, synovial fibroblasts derived from patients with rheumatoid arthritis disease specific to the DNA methylation pattern is present, the aberrant methylation of a gene involved in the pathology of rheumatoid arthritis many deep (non-patent document 1) indicated. Biological formulations targeted inflammatory cytokines rheumatoid arthritis treatment, but the induction of remission in a familiar to those, the treatment of rheumatoid arthritis is a so-called 'Window of Opportunity' is present, the delay of onset of the therapeutic effect as the same time. This is, the duration of the inflammatory environment itself, present at the site of inflammation in the synovial membrane cells and more aggressive treatment-resistant depression are altered to phenotype suggests the possibility that, although the detailed mechanism was unknown in. The inventors, synovial inflammation in rheumatoid arthritis, osteoarthritis and plays a pivotal role destruction IL-1β TNF α is, in methylation enzymes DNA FLS (DNMT) and decreased the expression of, promotes passive demethylation shown in, disease-specific DNA methylation patterns in one end of the molecular mechanism of formed (non-patent document 2) revealed. However, it is an active DNA demethylation was unknown mechanism for, methylated DNA, picture of the dynamism of the demethylation was unknown. In recent years, demethylated DNA Tet (Ten-Eleven translocation) that functions as an enzyme family of proteins identified, 5 - methylcytosine (5mC) Tet protein 5 - (5hmC) and hydroxide synthesized hydroxycytosine reported, such as DNA methylation in ES cells rapidly dynamism studies show their evolution. However, more of the activities of Tet in rheumatoid arthritis has still not been revealed, treating rheumatoid arthritis Tet protein can be targeted at all whether or not it was still unknown.
Scope of claims (In Japanese)[請求項1]
Tet 3(Ten-Eleven translocation 3)の発現阻害物質を含有する、関節炎の予防及び/又は治療剤。
[請求項2]
Tet 3の発現阻害物質が、
(a)Tet 3遺伝子の転写産物に対するアンチセンス核酸、
(b)Tet 3遺伝子の転写産物に対するリボザイム核酸、又は
(c)Tet 3遺伝子の転写産物に対してRNAi活性を有する核酸もしくはその前駆体である、請求項1に記載の剤。
[請求項3]
関節炎が関節リウマチ、乾癬性関節炎または脊椎関節炎である、請求項1または2に記載の剤。
[請求項4]
以下の(1)~(3)の工程を含む、関節炎の予防及び/又は治療薬のスクリーニング方法:
(1)Tet 3遺伝子もしくは該遺伝子の転写調節領域の制御下にあるレポータータンパク質をコードする核酸を含む細胞を、被検物質に接触させる工程、
(2)前記細胞におけるTet 3遺伝子もしくはTet 3タンパク質又はレポータータンパク質の発現量を測定する工程、
(3)被検物質の非存在下において測定した場合と比較して、Tet 3遺伝子もしくはTet 3タンパク質又はレポータータンパク質の発現量を低下させた被検物質を、関節炎の予防及び/又は治療薬の候補として選択する工程。
[請求項5]
Tet 3と被検物質とを接触させ、Tet 3と結合能を有する被検物質を関節炎の予防及び/又は治療剤の候補として選択することを特徴とする、関節炎の予防及び/又は治療薬のスクリーニング方法。
[請求項6]
関節炎の予防及び/又は治療薬の候補として選択された被検物質を関節炎モデルに適用し、該モデルにおける炎症反応を抑制するか否かを検定することをさらに含む、請求項5に記載の方法。
[請求項7]
以下の(1)~(3)の工程を含む、関節炎の予防及び/又は治療薬のスクリーニング方法:
(1)滑膜線維芽細胞を、被検物質に接触させる工程、
(2)前記細胞のゲノムの5-メチルシトシン(5mC)の脱メチル化または浸潤性の程度を測定する工程、
(3)被検物質の非存在下において測定した場合と比較して、前記細胞のゲノムの5-メチルシトシン(5mC)の脱メチル化または浸潤性を抑制した被検物質を、関節炎の予防及び/又は治療薬の候補として選択する工程。
[請求項8]
関節炎が関節リウマチ、乾癬性関節炎または脊椎関節炎である、請求項4~7のいずれか1項に記載の方法。
[請求項9]
被験者由来の試料から、下記(a)または(b)を用いてTet 3遺伝子の転写産物または翻訳産物を検出または定量することを含む、関節炎の検査方法:
(a)Tet 3遺伝子の転写産物を特異的に検出し得る核酸プローブまたは核酸プライマー
(b)Tet 3遺伝子の翻訳産物を特異的に認識する抗体。
[請求項10]
関節炎が関節リウマチ、乾癬性関節炎または脊椎関節炎である、請求項9に記載の方法。
[請求項11]
下記(a)および/または(b):
(a)Tet 3遺伝子の転写産物を特異的に検出し得る核酸プローブまたは核酸プライマー
(b)Tet 3遺伝子の翻訳産物を特異的に認識する抗体
を含有してなる、関節炎検査用キット。
[請求項12]
関節炎が関節リウマチ、乾癬性関節炎または脊椎関節炎である、請求項11に記載のキット。
[請求項13]
Tet 3(Ten-Eleven translocation 3)の発現阻害物質の有効量を対象に投与することを含む、関節炎の予防及び/又は治療方法。
[請求項14]
関節炎の予防及び/又は治療に使用するための、Tet 3(Ten-Eleven translocation 3)の発現阻害物質。
[請求項15]
関節炎の予防及び/又は治療剤を製造するための、Tet 3(Ten-Eleven translocation 3)の発現阻害物質の使用。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH, JAPAN
  • Inventor
  • NAKANO, Kazuhisa
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG

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