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VACCINE FOR TREATMENT OF TAUTOPATHY

Foreign code F110005788
File No. 2810
Posted date Sep 15, 2011
Country WIPO
International application number 2011JP050616
International publication number WO 2011083881
Date of international filing Jan 11, 2011
Date of international publication Jul 14, 2011
Priority data
  • P2010-003424 (Jan 8, 2010) JP
Title VACCINE FOR TREATMENT OF TAUTOPATHY
Abstract Disclosed is a vaccine for preventing or treating tautopathy, comprising a vector carrying a nucleic acid encoding a mutant tau protein linked to a secretion signal sequence as an active ingredient. The vaccine can induce an antibody against an (optionally phospholylated) tau protein in a subject in a further sustained manner compared with a case where the mutant tau protein is administered directly.
Outline of related art and contending technology BACKGROUND ART
Tau in the normal brain protein is bound to the microtubules within the cell is present in the soluble phosphorylated protein, microtubule polymerization accelerators and stabilization of the contribute, deviates from the microtubule binding repeats are maintained in an equilibrium state. This equilibrium is phosphorylated, dephosphorylation enzyme is disrupted due to an error, free within the cytoplasm of the tau protein is increased, so as to appear to aggregation or fibrosis. Fronto-temporal dementia Alzheimer's disease including dementia of the elderly in the majority of, without necessarily amyloid accumulation, accumulation of tau protein aggregation in neurodegenerative disease can be recognized as characteristic for the lesion, are collectively referred to as ETLHI (non-patent document 1). 65 Years old or older Climate in dementia is observed at about 7%, about 10% reaches the mild dementia is applied. 7 Is the interrupt By ETLHI type dementia, the number of patients is about 200 million. Amyloid β dementia ongoing research and development up to now the prior research (A β) and protein, amyloid β peptide drug in a clinical immunity are performed, inoculated in the middle of the 6% patient clinical trial of the clinical trial which caused the meninges encephalitis are discontinued (non-patent document 2). Is taken out of the study, post-vaccinal encephalitis occurs after frequent interruptions, different disease for patients who died by case report, neurodegeneration senile plaques by vaccination was quenching effect of the projections has been confirmed (non-patent document 3). In addition, a subsequent follow-up vaccination studies, this vaccine administration, necropsy patients with confirmed the disappearance of the senile plaques also confirmed that the disease progresses, this vaccine is not effective in preventing the progression of the disease suggesting that the (non-patent document 4). In addition, the antibodies against amyloid β is effective in passive immunization studies showed that hitherto but, is known about the effect of suppressing the progress of the disease (non-patent document 5) is not. Adeno-associated virus (AAV) vector further equipped with an amyloid β verified the effect of the vaccine. In mice, this AAV vector through intestinal mucosa by oral administration of the antibody production against amyloid β effect, the effect of improving the learning function (non-patent document 6) was observed, then a decrease in the monkey experiments but was observed in senile plaques, a clear progression inhibitory effect was not ascertained. On the other hand, tau for proteins, such as far as a therapeutic target for treatment of Alzheimer's disease has not been great account, in recent years, an alternative to amyloid β protein with a therapeutic agent as a target for Alzheimer's, with excess accumulation of tau protein in the treatment and vaccine target ETLHI (non-patent document 7) becoming. As a therapeutic agent for connection with the present invention, adeno-associated virus gene encoding the amyloid β is mounted Alzheimer's therapeutic agent (Patent Document 1, 2, non-patent document 8), and by inoculation of the protein with a method of treating Alzheimer ETLHI (patent document 3, non-patent document 9) is reported and the like, or protein tau opal qi model mouse inoculated in coordinated movement, but the effect of improving learning motion was observed in the lack of social, a reduction in force congeneric dementia patients characteristically seen in the effect of improving symptoms have not been observed.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 分泌シグナル配列に連結された変異型タウ蛋白質をコードする核酸を含むベクターを有効成分として含むタウオパチーの予防または治療用ワクチンであって、該変異型タウ蛋白質が、タウ蛋白質のアミノ酸配列において、配列番号1の257位、260位、266位、272位、279位、280位、284位、296位、301位、303位、305位、315位、317位、320位、335位、336位、337位、342位、352位、369位、389位および406位からなる群から選択される少なくとも1つの位置に相当する位置のアミノ酸残基の変異を含むものであり、および、該ベクターが被験者において変異型タウ蛋白質の直接投与と比べてより持続的にタウ蛋白質に対する抗体を誘導することができる、前記ワクチン。

[請求項2]
 前記変異が、K257T、I260V、L266V、G272V、N279K、K280Δ、L284L、N296Δ、N296H、P301L、P301S、G303V、S305N、L315R、K317M、S320F、G335S、G335V、Q336R、V337M、E342V、S352L、K369I、G389RおよびR406W(ここでΔは欠失である。)からなる群から選択される少なくとも1つの変異である、請求項1記載のワクチン。

[請求項3]
 前記変異が、少なくともP301L、P301SまたはP301Tの変異を含む、請求項1または2記載のワクチン。

[請求項4]
 前記分泌シグナル配列が、アミロイド前駆蛋白質シグナル配列またはCD59シグナル配列である、請求項1~3のいずれか1項記載のワクチン。

[請求項5]
 前記ベクターがセンダイウイルスベクターである、請求項1~4のいずれか1項記載のワクチン。

[請求項6]
 前記ベクターがプラスミドベクターである、請求項1~4のいずれか1項記載のワクチン。

[請求項7]
 鼻腔内投与用に製剤化されている、請求項1~6のいずれか1項記載のワクチン。

[請求項8]
 タウオパチー型認知症の改善作用を有する、請求項1~7のいずれか1項記載のワクチン。

[請求項9]
 被験者において社会的行動異常、不安様行動異常および記憶障害の少なくとも1つの症状の改善作用を有する、請求項1~8のいずれか1項記載のワクチン。

[請求項10]
ワクチンが被験者の脳内のミクログリアを活性化し、これによって変異型タウ蛋白質の蓄積を抑制する作用を有する、請求項1~9のいずれか1項記載のワクチン。

[請求項11]
タウ蛋白質はリン酸化されている、請求項1~10のいずれか1項記載のワクチン。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KYOTO UNIVERSITY
  • NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES
  • Inventor
  • INOUE, Haruhisa
  • TAKEUCHI, Hiroki
  • TAKAHASHI, Ryosuke
  • HIGUCHI, Makoto
  • JI, Bin
  • SUHARA, Tetsuya
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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