JP2010525303A - 神経の過度な興奮を緩和する薬剤 - Google Patents
神経の過度な興奮を緩和する薬剤 Download PDFInfo
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Abstract
Description
本願は、2007年4月5日出願の米国仮特許出願第60/922,082号の利益を主張し、この出願はその全体が参照により本明細書中に援用される。
アメリカ連邦政府は、国立衛生研究所(the National Institutes of Health)によって与えられた助成金番号AG022074、AG11385、およびNS054811に従って本発明に一定の権利を有することができる。
米国特許出願公開第2004/0241854号明細書
Rapoportら(2002)Proc.Natl.Acad.Sci.USA 99:6364〜6469
Dickeyら(2006)Mol.Neurodegener.1:6
本明細書中で用いられる用語「興奮毒性」は、細胞の機能不全および/または神経回路網の機能不全および/または細胞死を引き起こす神経の過度な興奮を特徴とする病態生理学的過程を指す。
本発明は、興奮毒性関連障害を治療するための候補薬剤を識別する方法を提供する。in vitro法およびin vivo法の両方が提供される。
in vitro法は、一般にタウ遺伝子産物を産生する細胞をin vitroで試験薬剤と接触させるステップ、およびもしあれば細胞中のタウ遺伝子産物のレベルに及ぼすその試験薬剤の効果を判定するステップを含む。細胞中のタウ遺伝子産物のレベルを低下させる試験薬剤は、興奮毒性関連障害の治療用候補薬剤と考えられる。幾つかの実施形態では主題のスクリーニング法はin vitroで行われ、例えば細胞はin vitroで試験薬剤と接触し、また判定のステップはin vitroで行われる。
幾つかの実施形態では主題のスクリーニング法は、タウ核酸を産生する細胞を試験薬剤と接触させ、もしあればタウ核酸レベルに及ぼすその試験薬剤の効果を判定することを含む。タウ核酸は、タウmRNA、タウmRNAのcDNAコピーなどを含む。細胞中のタウ核酸のレベルを検出するための好適な方法には、核酸ハイブリッド形成法および/または核酸増幅法が挙げられる。例えば核酸ハイブリッド形成法は、細胞中のタウmRNAか、またはタウmRNAのcDNAコピーを検出する核酸プローブを用いて行うことができる。核酸増幅法は、タウmRNA(またはタウmRNAのcDNAコピー)を特異的に増幅する核酸プライマーを用いて行うことができる。幾つかの実施形態ではタウ特異的プライマーを用いた核酸増幅の後に、タウ特異的プローブを用いた核酸ハイブリッド形成が続く。
上記で言及したように幾つかの実施形態では主題のスクリーニング法は、試験薬剤を、タウ遺伝子産物を普通に産生する哺乳動物細胞と接触させるステップを含むことになる。他の実施形態では主題のスクリーニング法は、試験薬剤を、タウ遺伝子産物を産生するように遺伝的修飾を加えた哺乳動物細胞と接触させるステップを含むことになる。これらの実施形態では外来の核酸を親哺乳動物細胞中に導入する。この場合、外来の核酸(「タウ核酸」)は、タウ遺伝子産物を産生する遺伝的に修飾された哺乳動物細胞を生み出すタウ遺伝子産物をコードするヌクレオチド配列を含む。
好適な核酸プローブには、タウmRNA(またはcDNA)とハイブリッドを形成し、その検出を可能にする核酸プローブが挙げられる。好適な核酸プローブは、幾つかの実施形態においては、ヌクレオチドの長さが10から50個、12から45個、15から40個、20から35個、25から30個などのヌクレオチドの長さが10〜50個の範囲内にある。例えばプローブは、幾つかの実施形態においては、ヌクレオチドの長さが18から40個、19から35個、20から30個、21から29個、22から28個、23から27個、24から25個の間の範囲内にあり、また言及した範囲の間の任意の長さであることになる。長さが約20から22個のヌクレオチドのプローブが、幾つかの実施形態においては特に考察の対象である。
幾つかの実施形態では主題の方法は、タウ核酸(例えば、タウmRNA、タウmRNAのcDNAコピー)を増幅することを含む。核酸増幅法は、タウmRNA(例えば、タウmRNAのcDNAコピー)を特異的に増幅する核酸プライマーを用いて行うことができる。幾つかの実施形態ではタウ特異的プライマーを用いた核酸増幅の後に、タウ特異的プローブを用いた核酸ハイブリッド形成が続く。一般にプライマーは、タウ標的核酸増幅産物(また「単位複製配列」とも呼ばれる)を産生するためのタウ標的核酸の増幅を可能にする。プライマーは、幾つかの実施形態においては核酸プローブと共に使用されることになる。5’プライマーは、一般に標的核酸の増幅を可能にする領域と結合し、また多くの実施形態においては標的配列の5’部分と結合する。
上記プライマーおよびプローブは、本明細書中で開示される配列に基づいて設計され、また標準的手法、例えば米国特許第4,458,066号明細書および同第4,415,732号明細書(参照により本明細書中に援用される)、Beaucageら(1992)Tetrahedron 48:2223〜2311、およびApplied Biosystems User Bulletin No.13(1 Apr.1987)中に開示されているようなホスホルアミダイト化学反応による固相合成によって容易に合成される。他の化学合成法には、例えばNarangら、Meth.Enzymol.(1979)68:90に記載のホスホトリエステル法およびBrownら、Meth.Enzymol.(1979)68:109に記載のホスホジエステル法が挙げられる。ポリ(A)またはポリ(C)、あるいは他の非相補的ヌクレオチド伸長部を、これらの同じ方法を用いてプローブ中に組み込むことができる。ヘキサエチレンオキシド伸長部を、当業界で知られている方法によってプローブと共役させることができる。Cloadら(1991)J.Am.Chem.Soc.113:6324〜6326、Levensonらの米国特許第4,914,210号明細書、Durandら(1990)Nucleic Acids Res.18:6353〜6359、およびHornら(1986)Tet.Lett.27:4705〜4708。
幾つかの実施形態では主題の方法は、細胞中のタウポリペプチドのレベルを検出することを含む。タウポリペプチドのレベルを検出するための好適な方法には、免疫学的測定法、例えば酵素免疫吸着測定法、ラジオイムノアッセイ、免疫沈降、タンパク質(「ウェスタン」)ブロット、タウ融合タンパク質の融合パートナーを検出するアッセイなどが挙げられる。
幾つかの実施形態では主題の方法はin vivoで行われる。例えば、試験薬剤を興奮毒性障害の非ヒト動物モデルに投与し、もしあればタウ遺伝子産物のレベルに及ぼすその試験薬剤の効果を判定する。例えば、試験薬剤を興奮毒性関連障害の非ヒト動物モデルに投与し、もしあればタウ遺伝子産物のレベルに及ぼすその試験薬剤の効果を判定する。幾つかの実施形態ではこの方法は、その興奮毒性関連障害に対する読み出し情報を得るためのアッセイを行うステップをさらに含む。興奮毒性関連障害に対する読み出し情報には、これらに限定されないが、a)発作の回数および/または重症度および/または発症の時期、b)興奮毒性関連障害に付随する行動の欠陥、およびc)興奮毒性関連障害に付随するカルシウム応答遺伝子産物の異常レベルが含まれる。
興奮毒性関連障害の治療方法を提供する。一般にこれら方法は、個体におけるニューロン中のタウ遺伝子産物のレベルを低下させる有効量の薬剤を、それが必要な個体に投与することを含む。
タウ遺伝子産物のレベルを低下させる薬剤には、細胞中のタウmRNAおよび/またはタウポリペプチドのレベルを低下させる薬剤が挙げられる。幾つかの実施形態では、細胞中のタウ遺伝子産物のレベルを低下させる薬剤は、細胞と接触した場合、その薬剤が存在しない細胞中のタウ遺伝子産物のレベルと比較して、少なくとも約5%、少なくとも約10%、少なくとも約15%、少なくとも約20%、少なくとも約25%、少なくとも約30%、少なくとも約35%、少なくとも約40%、少なくとも約45%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、または少なくとも約90%、タウおよび/またはタウポリペプチドのレベルを低下させる薬剤である。例えば好適な薬剤には、その薬剤を投与しない場合のニューロン中のタウ遺伝子産物のレベルと比較して、少なくとも約10%、少なくとも約15%、少なくとも約20%、少なくとも約25%、少なくとも約30%、少なくとも約35%、少なくとも約40%、少なくとも約45%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、または少なくとも約90%、タウ遺伝子産物のレベルを低下させる薬剤が挙げられる。
細胞中の、例えばニューロン中のタウ遺伝子産物のレベルを低下させる薬剤には、アンチセンス核酸が挙げられる。例えば、アンチセンス核酸を用いて細胞中の(例えばニューロン中の)タウ遺伝子の発現を下方制御することができる。そのアンチセンス試薬は、アンチセンスオリゴヌクレオチド(ODN)、例えば天然の核酸からの複数の化学修飾を有する合成ODNか、またはこのようなアンチセンス分子をRNAとして発現させる核酸構築物であることができる。アンチセンス配列は、標的にされる遺伝子(例えばタウ)のmRNAに相補的であり、標的にされる遺伝子産物の発現を抑制する。アンチセンス分子は、様々な機構により、例えばRNアーゼHの活性化、または立体障害を通して翻訳に利用可能なmRNAの量を低下させることによって遺伝子発現を抑制する。アンチセンス核酸の1種類または組合せを投与することができ、その場合、組合せは多様な異なる配列を含むことができる。
細胞中のタウ遺伝子産物のレベルを低下させる好適な薬剤には、干渉核酸、例えば干渉RNA分子が挙げられる。一実施形態ではタウ遺伝子産物レベルの低下は、細胞を、短鎖干渉核酸(siNA)、短鎖干渉RNA(siRNA)、二本鎖RNA(dsRNA)、マイクロRNA(miRNA)、または短鎖ヘアピンRNA(shRNA)分子などの小型核酸分子と接触させることによるRNA干渉(RNAi)により、あるいはタウ遺伝子産物のレベルの低下を可能にするように低分子干渉RNA(siRNA)の発現を調節することにより達成される。
標的領域1:
5’−AATCACACCCAACGTGCAGAA−3’(配列番号10、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第918番〜第938番に該当する)、
標的領域2:
5’−AACTGGCAGTTCTGGAGCAAA−3’(配列番号11、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1344番〜第1364番に該当する)、
標的領域3:
5’−gacctg aagaatgtca agtccaagat cggctccact gagaacctga agcaccagcc gggaggcggg aaggtgcaga taattaataa gaagctg−3’(配列番号12、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1705番〜第1797番に該当する)、
標的領域4:
5’−gat cttagcaacg tccagtccaa gtgtggctca aaggataata tcaaacacgt cccgggaggc ggcagtgtgc aaatagtcta caaaccagtt−3’(配列番号13、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1798番〜第1890番に該当する)、
標的領域5:
5’−gacctgagca aggtgacctc caagtgtggc tcattaggca acatccatca taaaccagga ggtggccagg tggaagtaaa atctgagaag ctt−3’(配列番号14、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1891番〜第1983番に該当する)、
標的領域6:
5’−gacttca aggacagagt ccagtcgaag attgggtccc tggacaatat cacccacgtc cctggcggag gaaataaaaa gattgaaacc cacaagctg−3’(配列番号15、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1984番〜第2079番に該当する)、
標的領域7:
5’−aagtcgccgt cttccgccaa gagccgcctg−3’(配列番号16、これは図6Bで表わされ、また配列番号2に示したヌクレオチド配列のヌクレオチド第1651番〜第1680番に該当する)、
標的領域8:
5’−gccaagacag accacggggc ggagatcgtg−3’(配列番号17、これは図6Bで表わされ、配列番号2に示したヌクレオチド配列のヌクレオチド第2101番〜第2130番に該当する)。
1)5’−tcgaagtgatggaagatcacgc−3’(配列番号18)、
2)5’−cagccgggagtcgggaaggtgc−3’(配列番号19)、
3)5’−acgtcctcggcggcggcagtgtgc−3’(配列番号20)、
4)5’−acgtctccatggcatctcagc−3’(配列番号21)、
5)5’−gtggccagatggaagtaaaatc−3’(配列番号22)、
6)5’−gtggccacatggaagtaaaatc−3’(配列番号23)、および
7)5’−gtggccagatgcaagtaaaatc−3’(配列番号24)。
被検体への送達のための当該薬剤の処方およびこれら薬剤(前述のsiNA分子、アンチセンス核酸などを含む)の送達方法は当業界において入手可能である。これらには薬剤の全身的送達を行うための処方および送達方法ならびに薬剤の局所的送達を行うための処方および送達方法(例えば、特定の器官または区画に対して行うための(例えば中枢神経系(CNS)に対して送達を行うための)など)が含まれる。これら薬剤は被検体に投与するための送達用賦形剤、担体、および増量剤と、それらの塩とを含むように処方することができ、かつ/または薬剤は薬学的に許容できる製剤中に存在することができる。
主題の方法による治療に適した個体には、これらに限定されないが神経毒関連障害と診断された個体、神経毒関連障害について治療されたが治療の効果を現わさなかった個体、および神経毒関連障害について治療され再発した個体が含まれる。好適な被検体には、頭部損傷を受けた個体が含まれる。
材料および方法
マウス:スウェーデン(K670M/N671L)およびインディアナ(V717F)家族性アルツハイマー病(AD)変異を有するhAPPミニジーンをPDGFプロモーターの制御下で発現するJ20系統(1)を、Tau−/−マウス(2)と交配させた。hAPP/Tau+/−×Tau+/−交配由来の同胞の子孫について検討を行った。雄のみを試験した水迷路試験を除いては雄および雌の両方が使用された。7つの別々のコホートにおいて解析される454匹(1遺伝子型につき66〜83匹)のマウス全体が、行動および/または神経病理学的実験において試験された。
アミロイド−β−ペプチド(Aβ)およびタウの沈着は、アルツハイマー病(AD)の病理学的証明である。Aβの産生、クリアランス、および凝集に照準を定めた治療は、すべて臨床実験中である。しかしながら標的としてのタウへの関心は、部分的にはタウ病変がAβの川下で起こるように見える(1〜4)ために弱められてきた。また、ADにおいてタウは翻訳後に修飾され(5〜8)、どの修飾を標的にするべきかに関して論争が続いている。タウレベル全体を低下させることは代替のアプローチである(9)。若干高いタウ発現を後押しするタウハプロタイプはADのリスクを増す(10)。Aβ産生を増加させる家族性AD変異によりヒトアミロイド前駆体タンパク質(hAPP)を発現するトランスジェニックマウスにおける認知障害に及ぼす内因性タウ発現の低下の影響を測定した。
1. R. Tanzi, L. Bertram, Cell 120, 545 (2005).
2. J. Lewis et al., Science 293, 1487 (2001).
3. M. Rapoport, H. N. Dawson, L. I. Binder, M. P. Vitek, A. Ferreira, Proc. Natl. Acad. Sci. USA 99, 6364 (2002).
4. S. Oddo, L. Billings, J. P. Kesslak, D. H. Cribbs, F. M. LaFerla, Neuron 43, 321 (2004).
5. C. X. Gong, F. Liu, I. Grundke-Iqbal, K. Iqbal, J Neural Transm 112, 813 (2005).
6. K. Iqbal et al., Biochim Biophys Acta 1739, 198 (2005).
7. W. H. Stoothoff, G. V. Johnson, Biochim. Biophys. Acta 1739, 280 (2005).
8. I. Khlistunova et al., J Biol Chem 281, 1205 (2006).
9. C. A. Dickey et al., FASEB J. 20, 753 (2006).
10. A. J. Myers et al., Hum. Mol. Genet. 14, 2399 (2005).
11. L. Mucke et al., J. Neurosci. 20, 4050 (2000).
12. H. N. Dawson et al., J. Cell Sci. 114, 1179 (2001).
13. J. J. Palop et al., Proc. Natl. Acad. Sci. USA 100, 9572 (2003).
14. D. T. Kobayashi, K. S. Chen, Genes Brain and Behav. 4, 173 (2005).
15. O. Steward, J. Loesche, W. C. Horton, Brain Res. Bull. 2, 41 (1977).
16. K. K. Hsiao et al., Neuron 15, 1203 (1995).
17. J. Chin et al., J. Neurosci. 24, 4692 (2004).
18. S. Lesne et al., Nature 440, 352 (2006).
19. E. Planel et al., J. Neurosci. 24, 2401 (2004).
20. S. Y. Park, A. Ferreira, J. Neurosci. 25, 5365 (2005).
21. T. Liu et al., J. Neurochem. 88, 554 (2004).
22. K. SantaCruz et al., Science 309, 476 (2005).
23. R. B. Knowles et al., Proc. Natl. Acad. Sci. USA 96, 5274 (1999).
24. J. W. Geddes et al., Science 230, 1179 (1985).
25. M. P. Mattson, Nature 430, 631 (2004).
26. J. W. Olney, D. F. Wozniak, N. B. Farber, Arch. Neurol. 54, 1234 (1997).
27. J. C. Amatniek et al., Epilepsia 47, 867 (2006).
28. R. A. Del Vecchio, L. H. Gold, S. J. Novick, G. Wong, L. A. Hyde, Neurosci. Lett. 367, 164 (2004).
29. J. J. Palop, J. Chin, L. Mucke, Nature 443, 768 (2006).
30. J. R. Lupski, Nat. Genet. 38, 974 (2006).
31. F. Holsboer, Curr Opin Investig Drugs 4, 46 (2003).
Chin, J., Palop J. J., Yu G.-Q., Kojima N., Masliah E., Mucke L. 2004. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J. Neurosci. 24, 4692-4697.
Chin, J., Palop J. J., Puolivaeli J., Massaro C., Bien-Ly N., Gerstein H., Scearce-Levie K., Masliah E., Mucke L. 2005. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. 25, 9694-9703.
Naegerl, U. V., Mody I., Jeub M., Lie A. A., Elger C. E., Beck H. 2000. Surviving granule cells of the sclerotic human hippocampus have reduced Ca2+ influx because of a loss of calbindin-D28K in temporal lobe epilepsy. J. Neurosci. 20, 1831-1836.
Palop, J. J., Chin J., Mucke L. 2006. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768?773.
Palop, J. J., Jones B., Kekonius L., Chin J., Yu G.-Q., Raber J., Masliah E., Mucke L. 2003. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proc. Natl. Acad. Sci. USA 100, 9572?9577.
Vezzani, A., Sperk G., Colmers W. F. 1999. Neuropeptide Y: Emerging evidence for a functional role in seizure modulation. Trends Neurosci 22, 25-30.
Claims (28)
- 興奮毒性関連障害の治療用候補薬剤を識別するin vitro法であって、
a)タウ遺伝子産物を産生する細胞を、試験薬剤とin vitroで接触させるステップ、および
b)前記細胞中の前記タウ遺伝子産物のレベルに及ぼす前記試験薬剤の効果を、もしあれば測定するステップ
を含み、前記細胞中の前記タウ遺伝子産物のレベルを低下させる試験薬剤が、興奮毒性関連障害の治療用候補薬剤である、方法。 - 前記細胞が神経細胞である、請求項1に記載の方法。
- 前記タウ遺伝子産物がタウポリペプチドであり、かつ前記タウポリペプチドのレベルが免疫アッセイを用いて検出される、請求項2に記載の方法。
- タウポリペプチドのレベルに及ぼす前記試験薬剤の効果が、前記タウポリペプチドのリン酸化状態に無関係であり、かつ前記タウポリペプチドの溶解性状態に無関係である、請求項3に記載の方法。
- 前記タウポリペプチドが、非過リン酸化タウポリペプチドである、請求項3に記載の方法。
- 前記タウポリペプチドが、可溶性タウポリペプチドである、請求項3に記載の方法。
- 前記タウ遺伝子産物が、タウと、検出可能なシグナルを与えるポリペプチドとを含む融合タンパク質であり、かつタウのレベルが前記シグナルのレベルを検出することによって検出される、請求項1に記載の方法。
- 検出可能なシグナルを与える前記ポリペプチドが、蛍光タンパク質であるか、化学発光タンパク質であるか、または検出可能な産物を産生する酵素である、請求項7に記載の方法。
- 前記タウ遺伝子産物がタウ核酸であり、かつ前記タウ核酸のレベルが核酸増幅によるアッセイを用いて検出される、請求項1に記載の方法。
- 前記タウ遺伝子産物がタウ核酸であり、かつ前記タウ核酸のレベルが核酸ハイブリダイゼーションアッセイを用いて検出される、請求項1に記載の方法。
- 前記タウ遺伝子産物が、野生型タウ対立遺伝子によってコードされる、請求項1に記載の方法。
- 興奮毒性関連障害の治療用候補薬剤を識別するin vivo法であって、
a)興奮毒性関連障害の非ヒト動物モデルに試験薬剤を投与するステップ、および
b)前記動物の細胞または組織中の前記タウ遺伝子産物のレベルに及ぼす前記試験薬剤の効果を、もしあれば測定するステップ
を含み、前記細胞または組織中の前記タウ遺伝子産物のレベルを低下させる試験薬剤が、興奮毒性関連障害の治療用候補薬剤である、方法。 - カルシウム依存性遺伝子産物のレベルと、発作の回数および/または重症度および/または頻度と、興奮毒性関連障害に伴う行動機能障害との1つまたは複数に及ぼす前記試験薬剤の効果を、もしあれば測定するステップをさらに含む、請求項12に記載の方法。
- 個体のニューロン中の神経細胞の過剰刺激に応じて興奮毒性を低下させる方法であって、前記個体に前記ニューロン中のタウ遺伝子産物のレベルを低下させる薬剤を投与することを含み、前記薬剤が前記ニューロン中のタウ遺伝子産物のレベルを選択的に低下させる核酸を含む、方法。
- 前記タウ遺伝子産物が、野生型タウ対立遺伝子によってコードされる、請求項14に記載の方法。
- 前記タウ遺伝子産物がタウmRNAである、請求項14に記載の方法。
- 前記タウ遺伝子産物がタウポリペプチドである、請求項14に記載の方法。
- 前記タウポリペプチドが、非過リン酸化可溶性タウポリペプチドである、請求項16に記載の方法。
- 個体における興奮毒性関連障害の治療方法であって、前記個体中のニューロン中のタウ遺伝子産物のレベルを低下させる薬剤を前記個体に投与することを含み、前記薬剤が前記ニューロン中のタウ遺伝子産物のレベルを選択的に低下させる核酸を含む、方法。
- 前記興奮毒性関連障害が、アルツハイマー病、筋委縮性側索硬化症、多発性硬化症、ハンチントン病、卒中、パーキンソン病、および発作から選択される、請求項19に記載の方法。
- 前記タウ遺伝子産物が、野生型タウ対立遺伝子によってコードされる、請求項19に記載の方法。
- 前記タウ遺伝子産物がタウmRNAである、請求項19に記載の方法。
- 前記タウ遺伝子産物がタウポリペプチドである、請求項19に記載の方法。
- 前記タウポリペプチドが、非過リン酸化可溶性タウポリペプチドである、請求項23に記載の方法。
- 少なくとも1種類の追加の治療薬の有効量を投与することをさらに含む、請求項19に記載の方法。
- a)細胞中のタウ遺伝子産物のレベルを特異的に低下させる核酸薬剤、および
b)薬学的に許容できる医薬品添加剤
を含む医薬組成物。 - 前記薬学的に許容できる医薬品添加剤が、血液脳関門を越えることを可能にする薬剤を含む、請求項26に記載の組成物。
- 前記タウ遺伝子産物が、野生型タウ対立遺伝子によってコードされる、請求項26に記載の組成物。
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JP2019510754A (ja) * | 2016-03-01 | 2019-04-18 | マックォーリー・ユニバーシティ | 神経学的症状の治療のためのリン酸化tau及びp38ガンマの使用 |
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Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10266585B2 (en) * | 2009-08-28 | 2019-04-23 | The Board Of Regents Of The Univerity Of Texas System | Methods of treating brain injury |
US8648044B2 (en) * | 2009-09-24 | 2014-02-11 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | FKBP52-tau interaction as a novel therapeutical target for treating the neurological disorders involving tau dysfunction |
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JOP20200228A1 (ar) | 2015-12-21 | 2017-06-16 | Novartis Ag | تركيبات وطرق لخفض تعبير البروتين tau |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10509797A (ja) * | 1994-11-14 | 1998-09-22 | アセナ ニューロサイエンシーズ, インコーポレイテッド | アミロイドβペプチド(X−≧41)およびタウを測定することによりアルツハイマー病の診断を補助する方法 |
JP2005512550A (ja) * | 2001-12-20 | 2005-05-12 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | アルツハイマー病のトリプル・トランスジェニックマウス・モデル |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0600951A4 (en) * | 1991-08-01 | 1996-10-30 | Paul H Voorheis | Diagnostic method for alzheimer's disease. |
AU5961994A (en) | 1993-01-22 | 1994-08-15 | University Research Corporation | Localization of therapeutic agents |
GB9316727D0 (en) * | 1993-08-12 | 1993-09-29 | Inst Of Psychiatry | Models of alzheimers's disease |
US6027721A (en) * | 1996-05-20 | 2000-02-22 | Cytotherapeutics, Inc. | Device and method for encapsulated gene therapy |
WO1999062548A1 (en) | 1998-06-01 | 1999-12-09 | Advanced Research And Technology Institute | Methods and compositions for diagnosing tauopathies |
ES2229817T3 (es) | 1998-09-08 | 2005-04-16 | Innogenetics N.V. | Uso de la tau como un marcador para la deteccion temprana del daño del sistema nervioso central (cns). |
US6787318B1 (en) * | 1999-06-01 | 2004-09-07 | Roskamp Research Institute, Llc | Assay for evaluating the therapeutic effectiveness of agents in reducing Alzheimer's disease pathology |
US6420122B1 (en) * | 1999-09-27 | 2002-07-16 | Massachusetts Institute Of Technology | Methods of screening for agents that inhibit aggregation of polypeptides |
US20040110938A1 (en) | 2000-02-24 | 2004-06-10 | Parekh Rajesh Bhikhu | Proteins, genes and their use for diagnosis and treatment of schizophrenia |
AU2001241849A1 (en) * | 2000-02-29 | 2001-09-12 | Karen Duff | Transgenic mice comprising a genomic human tau transgene |
US20030212022A1 (en) | 2001-03-23 | 2003-11-13 | Jean-Marie Vogel | Compositions and methods for gene therapy |
US6503914B1 (en) * | 2000-10-23 | 2003-01-07 | Board Of Regents, The University Of Texas System | Thienopyrimidine-based inhibitors of the Src family |
US6573276B2 (en) * | 2001-05-09 | 2003-06-03 | Boehringer Ingelheim Pharma Kg | Muscarinic M1 agonist as an inhibitor of beta-amyloid (Aβ40 and Aβ42)-synthesis |
JP2003102332A (ja) * | 2001-07-26 | 2003-04-08 | Taizo Taniguchi | 変異型ヒトタウ遺伝子発現マウス |
US20040241854A1 (en) * | 2002-08-05 | 2004-12-02 | Davidson Beverly L. | siRNA-mediated gene silencing |
EP1635763B1 (en) * | 2003-06-09 | 2012-08-08 | Alnylam Pharmaceuticals Inc. | Method of treating neurodegenerative disease |
AU2003904328A0 (en) * | 2003-08-13 | 2003-08-28 | Garvan Institute Of Medical Research | Diagnosis and treatment of neurodegenerative disorders |
JP4454986B2 (ja) * | 2003-08-25 | 2010-04-21 | 国立精神・神経センター総長 | タウ遺伝子中の遺伝子多型を利用したアルツハイマー病の発症リスクの予測法およびこれに用いるための核酸分子 |
WO2005071418A2 (en) * | 2003-10-29 | 2005-08-04 | Evotec Neurosciences Gmbh | Diagnostic and therapeutic use of the human dax- 1 gene and protein for neurodegenerative diseases |
WO2005118858A1 (en) | 2004-05-28 | 2005-12-15 | Board Of Regents, The University Of Texas System | Multigene predictors of response to chemotherapy |
US20080003570A1 (en) | 2004-12-22 | 2008-01-03 | The General Hospital Corporation | Translation enhancer elements of genes encoding human Tau protein and human alpha-synuclein protein |
US20060154370A1 (en) * | 2005-01-11 | 2006-07-13 | Yuzhi Chen | Efficient gene suppression using a transfer RNA promoter in herpes virus vectors to deliver small interference RNAs |
KR20080027384A (ko) * | 2005-07-08 | 2008-03-26 | 마텍 바이오싸이언스스 코포레이션 | 치매 및 치매-전단계와 관련된 용태의 치료를 위한다중불포화 지방산 |
GB0605337D0 (en) * | 2006-03-17 | 2006-04-26 | Genomica Sau | Treatment of CNS conditions |
-
2008
- 2008-04-04 US US12/098,328 patent/US20080249058A1/en not_active Abandoned
- 2008-04-04 EP EP08742560A patent/EP2145014B1/en active Active
- 2008-04-04 CA CA2682497A patent/CA2682497C/en active Active
- 2008-04-04 EP EP12192408.8A patent/EP2578692B1/en active Active
- 2008-04-04 JP JP2010502140A patent/JP5721426B2/ja active Active
- 2008-04-04 WO PCT/US2008/004408 patent/WO2008124066A1/en active Application Filing
-
2011
- 2011-04-07 US US13/082,170 patent/US9198982B2/en active Active
-
2013
- 2013-09-17 US US14/029,604 patent/US9084813B2/en active Active
-
2014
- 2014-12-08 JP JP2014247668A patent/JP5997241B2/ja active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10509797A (ja) * | 1994-11-14 | 1998-09-22 | アセナ ニューロサイエンシーズ, インコーポレイテッド | アミロイドβペプチド(X−≧41)およびタウを測定することによりアルツハイマー病の診断を補助する方法 |
JP2005512550A (ja) * | 2001-12-20 | 2005-05-12 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | アルツハイマー病のトリプル・トランスジェニックマウス・モデル |
Non-Patent Citations (1)
Title |
---|
JPN6013038421; DANIELA UBERTI et al.: 'Priming of cultured neurons with sabeluzole results in long-lasting inhibition of neurotoxin-induced' SYNAPSE Vol.26,No.2, 1997, P.95-103 * |
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EP2578692B1 (en) | 2016-06-08 |
US9198982B2 (en) | 2015-12-01 |
CA2682497A1 (en) | 2008-10-16 |
EP2578692A1 (en) | 2013-04-10 |
JP5997241B2 (ja) | 2016-09-28 |
EP2145014B1 (en) | 2012-12-12 |
US20120198573A1 (en) | 2012-08-02 |
EP2145014A4 (en) | 2010-06-23 |
WO2008124066A1 (en) | 2008-10-16 |
EP2145014A1 (en) | 2010-01-20 |
JP5721426B2 (ja) | 2015-05-20 |
CA2682497C (en) | 2017-08-08 |
US20080249058A1 (en) | 2008-10-09 |
JP2015107972A (ja) | 2015-06-11 |
US20140065206A1 (en) | 2014-03-06 |
US9084813B2 (en) | 2015-07-21 |
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