JP2022549116A - タウタンパク質の蓄積、凝集及びタングル形成抑制用組成物及びその抑制方法 - Google Patents
タウタンパク質の蓄積、凝集及びタングル形成抑制用組成物及びその抑制方法 Download PDFInfo
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Abstract
Description
(1)動物管理及び実験
3xFAD動物モデル実験に関する全ての手続は、承認番号2018-0047A下にハンヤング医学専門大学院動物実験倫理議員会(Institutional Animal Care and Use Committee,IACUC)の承認を受けた。また、3xFAD動物モデル実験に関する全ての手続は、ハンヤング大学校実験動物使用に関するガイドラインに従ってなされた。動物を12時間 、明/暗サイクルを用いた特定の無菌障壁施設に収容し、標準食物(5053 PicoLabR Rodent Diet 20)を提供した。本実験のための動物の大きさは、本実験の生体外分析及び予備試験によって、事前統計的演算無しで決定された。実験は、NIHガイドラインに従って実施された。偏向を最小化するために、挙動的分析は、概ね、2名の実験者によって盲検方式で行われた。18月齢及び15月齢アルツハイマー病遺伝子導入(transgenic)(3xTg-AD)マウス(Jackson Laboratory,Maine,USA)が実験に使用された。
18月齢(18m)及び15月齢(15m)アルツハイマー病遺伝子導入(3xTg-AD)マウス(Jackson Laboratory,Maine,USA)に、Nurr1-AAV9(1μl)+Foxa2-AAV9(1μl)(合計2μl、1012vg/μl、Nurr1+Foxa2群)又はNurr1-AAV9(1μl)+対照AAV9(1μl)(合計2μl、5×1011vg/μl、Nurr1単独群)、又はAAV9のみを有する対照群(2μl、1012vg/μl、対照群のみで構成)を含むウイルスベクターを、Rompum(93.28μg/kg)と混合されたZoletil 50(0.1mg/kg)によって誘導された麻酔状態で、10分にわたって、海馬(Hippocampus)(ブレグマから後方に1.5mm;ミッドラインから側面に±1mm;硬膜から腹側へ2mm(-2 mm ventral to the dura))及び脳室(Intracerebroventricle,ICV)(ブレグマから後方に0.9mm;ミッドラインから側面に±1.7mm;硬膜から腹側へ2.2mm(-2.2 mm ventral to the dura))に注射した。毎注射完了の後に、針(26ゲージ)は、前記注射部位に刺された状態で5~10分間置いた後、ゆっくり除去した。海馬(Hippocampus)及び脳室(Intracerebroventricle,ICV)部位における注射に誤りがあったと判明される場合、それらのマウスは分析から除外した。
CMVプロモーターの統制下に、Nurr1又はFoxa2を発現させるレンチウイルスベクターを、それぞれのcDNAをpCDH(System Biosciences社、Mountain View,CA)の多重クローニング部位に挿入することによって生成した。pGIPZ-shNurr1とpGIPZ-shFoxa2レンチウイルスベクターをOpen Biosystems社(Rockford,IL)から購入した。空(empty)のバックボーンベクター(pCDH又はpGIPZ)が陰性対照群として用いられた。レンチウイルスを、前述のように、生体外培養における形質導入のために製造して使用した(Yi SH,He XB,Rhee YH,Park CH,Takizawa T,Nakashima K,Lee SH(2014)Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation.Development 141:761-772)。レンチウイルスの力価は、QuickTiter(登録商標) HIVレンチウイルス定量キット(Cell Biolabs社、San Diego,CA)を用いて測定され、106個の形質導入ユニット(transducing unit,TU)/ml(60~70ng/ml)を含む200μl/ウェル(24ウェルプレート)又は2ml/6cm皿がそれぞれの形質導入反応に使用された。
培養細胞及び凍結切片化された脳切片を、次のような一次抗体で染色した:Nurr1(1:500、ウサギ、胚20日目、Santa Cruz Biotechnology社、Dallas,TX、及び1:1,000、マウス、R&D Systems社);Foxa2(1:500、ヤギ、Santa Cruz Biotechnology社);GFP(1:2,000、ウサギ、Life Technologies社);GFAP(1:200、マウス、MP Biomedicals社、Santa Ana,CA);Iba-1(1:200、ウサギ、Wako社)、NeuN(1:100、マウス、EMD Milipore社);TAU(1:500、マウス、Santa Cruz Biotechnology社);pTAU(1:500、ウサギ、ABcam社)
(5)-1.水迷路(Water Maze)法
水迷路法は、モーリスウォーター迷路とも呼ばれ、空間記憶と学習を研究する上で広く用いられている。動物は、粉状の無脂肪牛乳や無毒性ペイントで不透明に染めた水溜まりに置かれるが、そこから彼らは、隠された脱出プラットホームまで泳いで行かなければならない。動物は不透明な水中にいるため、プラットホームを見ることができず、匂いを頼りに脱出路を探すこともできない。代わりに、動物は外部或いは迷路外の手がかりを頼りにしなければならない。動物がそのことに熟練するにつれ、彼らはそのプラットホームをより速く探すことができる。1984年にリチャードG.モーリスによって開発されたこのパラダイムは、行動神経科学の「ゴールドスタンダード」の一つとなった。
Y迷路(Y-Maze)法は、空間学習と記憶を研究するための事前臨床研究において行動を評価するために広く用いられている。動物は、Y迷路法において、Y状の迷路で3個の腕(arm)のいずれか一方の腕の端に置かれるが、ここで、彼らは、別れ道から左側又は右側のどこへ移動するかを決定する。このようなテストは同一動物に数回反復されてよい。観察者は、Y迷路内で動物の一連の選択(例えば、特定腕を訪問した回数、3個の腕を訪問した総回数、動物基準で左側の腕を選択した回数、動物基準で右側の腕を選択した回数)を記録する。Y迷路テストの使用は、自発的交替テスト(spontaneous alternation test)と認識記憶力テストを含む。自発的交替テストにおいて、観察者は、動物が最近に訪問しなかった腕に訪問する傾向を示すかを観察して記録する(例えば、自発的交替数字を測定)。これらの検査は、海馬損傷、遺伝子操作、そして記憶喪失薬物に敏感であることが明らかにされた。
免疫染色及びDAPI-染色された細胞は、200倍又は400倍の倍率で接眼グリッド(eyepiece grid)を用いて、各培養カバースリップ内の無作為領域でカウントされた。全ての図に対してデータは平均±SEMで表示され、統計的検定は適切に立証される。統計学的比較は、スチューデントt検定(対応なし;unpaired)、又は、両側検定(2-tailed)又は一元配置分散分析(one-way ANOVA)、次いでSPSS(Statistics 21;IBM Inc.Bentonville,AR,USA)を用いたBonferroni post hoc分析で行われた。n、p-値及び統計分析方法は、図面凡例に表示されている。0.05未満のP値は有意なものと見なされた。
(1)Nurr1及びFoxa2遺伝子導入がタウオパチー(tauopathy)に及ぼす影響
アデノ随伴ウイルス(AAV)はヒトで免疫原性が非常に低いため、主に脳において神経細胞及び膠細胞に感染しやすいAAV9血清型を用いて膠細胞に特異的にターゲッティングするNurr1及びFoxa2遺伝子導入システムを構築した。Nurr1及びFoxa2遺伝子発現のためにCMV又はGFAPプロモーターが使用された。Nurr1+Foxa2-AAV9ウイルスの注入は、タウオパチーの一種であるアルツハイマー病の病変部位である海馬(Hippocampus)と脳室(Intracerebroventricle,ICV)に行われた。
タウオパチーの一種であるアルツハイマー病の治療に、膠細胞のNurr1及びFoxa2発現が与える効果を検討した。3種の遺伝子であるAPP、PS1、及びtauを変異させてアルツハイマー病を誘発した15~18月齢の3xFADマウスの海馬及び脳室の膠細胞に特異的にNurr1及びFoxa2発現を起こした。15~18月齢は、マウスの平均寿命が約24ヶ月であることからして、かなり高齢である。アルツハイマー病モデルマウスにNurr1及びFoxa2遺伝子を導入し、遺伝子導入3ヶ月後に、当該マウスの認知能力分析を行った。
Nurr1及びFoxa2遺伝子導入により、リン酸化されたタウタンパク質の形成を抑制できるかどうか、をさらに確認した。
Claims (29)
- Nurr1及びFoxa2遺伝子が搭載されたベクターを含む、タウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項1に記載のタウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- Nurr1遺伝子が搭載されたベクターを含む、タウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項3に記載のタウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- Nurr1及びFoxa2遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項5に記載のタウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- Nurr1遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項7に記載のタウタンパク質蓄積、凝集又はタングル形成抑制用組成物。
- Nurr1及びFoxa2遺伝子が搭載されたベクターを含む、タウタンパク質リン酸化抑制用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項9に記載のタウタンパク質リン酸化抑制用組成物。
- Nurr1遺伝子が搭載されたベクターを含む、タウタンパク質リン酸化抑制用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項11に記載のタウタンパク質リン酸化抑制用組成物。
- Nurr1及びFoxa2遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質リン酸化抑制用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項13に記載のタウタンパク質リン酸化抑制用組成物。
- Nurr1遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質リン酸化抑制用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項15に記載のタウタンパク質リン酸化抑制用組成物。
- Nurr1及びFoxa2遺伝子が搭載されたベクターを含む、タウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項17に記載のタウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- Nurr1遺伝子が搭載されたベクターを含む、タウタンパク質蓄積、凝集、又はタングルによって発病する疾患の予防又は治療用組成物。
- 前記ベクターが、ウイルスベクター又は非ウイルスベクターである、請求項19に記載のタウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- Nurr1及びFoxa2遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項21に記載のタウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- Nurr1遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- 前記膠細胞(glia)が、星状細胞(astrocyte)又は小膠細胞(microglia)である、請求項23に記載のタウタンパク質蓄積、凝集又はタングルによって発病する疾患の予防又は治療用組成物。
- Nurr1及びFoxa2遺伝子が搭載されたベクターを含む、タウオパチー予防又は治療用薬剤学的組成物。
- Nurr1遺伝子が搭載されたベクターを含む、タウオパチー予防又は治療用薬剤学的組成物。
- Nurr1及びFoxa2遺伝子が導入された神経細胞(neurons)又は膠細胞(glia)を含む、タウオパチー予防又は治療用薬剤学的組成物。
- Nurr1遺伝子が搭載されたベクターを含む、タウオパチー予防又は治療用薬剤学的組成物。
- 前記タウオパチーが、タウ陽性アルツハイマー病(Tau-positive Alzheimer’s disease)、レビー小体型認知症(Dementia with Lewy Bodies)、前頭側頭型認知症(Frototemporal dementia,FTD)、多発梗塞性認知症(Multi-Infarct Dementia,MID)、前頭側頭葉変性症(frontotemporal lobar degeneration,FTLD)、進行性核上麻痺(Progressive cupranuclear palsy,PSP)、ピック病(Pick’s disease)、慢性外傷性脳症(Chronic traumatic encephalopathy,CTE)、大脳皮質基底核変性症(Corticobasal degeneration,CBD)、球状神経膠タウオパチー(Globular glial tauopathy)、ハンチントン病(Huntington’s disease)、神経節細胞膠腫(ganglioglioma)、神経節細胞腫(gangliocytoma)、原発性加齢性タウオパチー(primary age-related tauopathy:PART)、嗜銀顆粒病(argyrophilic grain disease)、鉛毒性脳症(lead encephalopathy)、リポフスチン沈着症(lipofuscinosis)、リティコ-ボディグ病(Lytico-Bodig disease)、髓膜血管腫症(meningioangiomatosis)からなる群から選ばれる疾患である、請求項25~28のいずれかに記載のタウオパチー予防又は治療用薬剤学的組成物。
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