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INTERFERON-α MODULATOR

Foreign code F110002542
File No. F2010-008
Posted date Mar 18, 2011
Country WIPO
International application number 2010JP068209
International publication number WO 2011046221
Date of international filing Oct 15, 2010
Date of international publication Apr 21, 2011
Priority data
  • P2009-239801 (Oct 16, 2009) JP
  • P2010-107544 (May 7, 2010) JP
Title INTERFERON-α MODULATOR
Abstract Disclosed are: an antisense nucleotide which contains a sequence complementary to IFN-α mRNA, especially a sequence complementary to a base sequence in the SL1 and/or SL2 region of IFN-α mRNA, and which is capable of enhancing the expression of IFN-α; an IFN-α expression enhancer and a prophylactic or therapeutic agent for viral infectious diseases or cancer, each containing the antisense nucleotide; a sense oligonucleotide which contains a sequence complementary to endogenous asRNA for IFN-α mRNA, especially a sequence homologous to a base sequence in the SL1 or SL2 region of IFN-α mRNA, and which is capable of modulating the expression of IFN-α; and an IFN-α expression modulator which contains the sense oligonucleotide.
Outline of related art and contending technology BACKGROUND ART
In the defense against viral infection, innate immunity is important as a rapid initial infection plays a role in the defense mechanism. I-type interferon (IFN) in innate immunity is a central role in the anti-viral activity responsible for a cytokine, secreted transiently by a viral infection, the surrounding cells to cause the anti-viral activity, cytostatic activity such as a variety of bioactivity. Type I IFN is IFN-α, - β, - ω, - ε, - κ divided into, among these IFN-α is, the first functionality of at least 9 on the chromosome the gene encoding the subtype 13 group exists. IFN-α and - β is, based on the physiological activities of these, plasma-derived formulations and genetically engineered to recombinant protein formulation, hepatitis B, viral infections such as Hepatitis C, treatment for various diseases or tumor (or adjuvant therapy) is used.
However, long-term administration IFN or overdosing, influenza-like symptoms (headache, fever, joint pain, muscle pain, anorexia, general malaise, nausea, vomiting and the like), autoimmune disease, depressive symptoms (insomnia or impatience feeling and the like), hair loss, abnormal thyroid function, such as dementia, various side effects may occur. Therefore, without any IFN, IFN in the living body by enhancing the production of, or protection against viral infection, improvement of such as cancer, in order to study treatment has also been carried out. However, many of which enhance the production IFN material such as a virus or infectious agent in, some of which are often a problem with stability.
Virus infection IFN-α, - β expression of type I IFN such as enhance the response if, in addition to various unknown prevention of viral infections, believed to be effective in the treatment. Recently, via Toll-like receptor (TLR) viral infection from the recognition of kinase cascade via the signaling pathways leading to the induction of expression of type I IFN pathway has been elucidated by increasingly, IFN be adjusted after the transfer of the gene, not yet well understood.
Antisense RNA is, with respect to mRNA, having a nucleotide sequence complementary to the RNA and, more specifically, the sense gene-encoding DNA chain (i.e. non-template strand mRNA) in the synthesized RNA as a template. Sense - 2 antisense RNA and duplex forming ability between, for example, when the stranded RNA 2 acts is required for interference RNA, referred to as small RNA and micro RNA degradation of messenger RNA by stranded RNA such as 2 known to be involved. Recent exhaustive cDNA analysis, a significant number of the antisense RNA is transferred and becomes clear (non-patent document 1, 2). For example, about 2,500 mice (non-patent document 3) pair, a pair of human (non-patent document 4) about 2,600 sense - antisense RNA pair suggesting the presence and, among them are coding for a protein which is not translated into the antisense RNA of which contains a large number.
Of the physiology of the antisense RNA is not a well - defined, from previous research, the antisense RNA, or stabilization of mRNA destabilization, translational mRNA or the like is suppressed, a variety of different physiologically function belonging to the group of controllability RNA has been found that the (non-patent document 5). For example, endothelial nitric oxide synthase (eNOS) mRNA antisense RNA is complementary to, the histone deacetylase inhibitor and the amount of increase in the presence of reduced eNOS mRNA have been reported (non-patent document 6). In addition, also in yeast, PHO84 gene antisense RNA of histone deacetylation via mRNA is known to inhibit the expression (non-patent document 7). On the other hand, the inventors of the present invention, inducible nitric oxide synthase (iNOS) mRNA of the 3 '- untranslated region (UTR) that is complementary to the endogenous antisense RNA (also referred to as' asRNA') is present, this antisense RNA is by hybridizing iNOS mRNA is stabilized and the iNOS mRNA and the production amount of an increase in the amount NO synthesis, oligonucleotides may be complementary to the asRNA, to inhibit the binding of asRNA iNOS mRNA of the mRNA by the destabilization, and the production of NO by iNOS could inhibit iNOS reported synthesis (Patent Document 1 and 2, non-patent document 8).
However, IFN-α for the same gene, whether endogenous asRNA even exists, has not been heretofore reported.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 インターフェロン-α mRNAに相補的な配列を含み、インターフェロン-αの発現を増強させ得るアンチセンスヌクレオチド。

[請求項2]
 インターフェロン-α mRNAのSL1および/またはSL2領域内の塩基配列に相補的な配列を含む、請求項1記載のアンチセンスヌクレオチド。

[請求項3]
 インターフェロン-α mRNAのBulged SL領域内の塩基配列に相補的な配列を含む、請求項2記載のアンチセンスヌクレオチド。

[請求項4]
 請求項1~3のいずれか1項に記載のアンチセンスヌクレオチドを含有してなるインターフェロン-α発現増強剤。

[請求項5]
 ウイルス感染症または癌の予防または治療用である、請求項4記載の剤。

[請求項6]
 インターフェロン-α mRNAに対する内因性アンチセンスRNAに相補的な配列を含み、インターフェロン-αの発現を調節し得るセンスオリゴヌクレオチド。

[請求項7]
 該配列がインターフェロン-α mRNAのSL1またはSL2領域内の塩基配列に相同な配列である、請求項6記載のセンスオリゴヌクレオチド。

[請求項8]
 該配列がBulged SL領域内の塩基配列に相同な配列である、請求項7記載のセンスオリゴヌクレオチド。

[請求項9]
 請求項6~8のいずれか1項に記載のセンスオリゴヌクレオチドを含有してなるインターフェロン-α発現調節剤。

[請求項10]
 免疫応答異常の予防または治療用である、請求項9記載の剤。

[請求項11]
 被験物質の存在下および非存在下で、インターフェロン-α mRNAとそれに対する内因性アンチセンスRNAとのハイブリダイゼーションを検出・比較することを特徴とする、インターフェロン-α発現増強または抑制物質のスクリーニング方法。

[請求項12]
 インターフェロン-α mRNAとそれに対する内因性アンチセンスRNAとを発現する細胞に被験物質を接触させ、該細胞における該mRNA量および/またはインターフェロン-αタンパク質量の変化を測定することを特徴とする、請求項11記載の方法。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • The Ritsumeikan Trust
  • KANSAI MEDICAL UNIVERSITY
  • Amino Up Chemical Co., Ltd.
  • Inventor
  • KIMURA, Tominori
  • NISHIZAWA, Mikio
  • JIANG, Shiwen
  • NISHIKAWA, Masao
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH 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 IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU 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 SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD 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 ML MR NE SN TD TG
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