JP2022065134A - 中枢神経系へのアデノ随伴ウイルスを介した遺伝子導入 - Google Patents
中枢神経系へのアデノ随伴ウイルスを介した遺伝子導入 Download PDFInfo
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Abstract
Description
本願は、2013年5月15日に出願された米国特許出願第61/823,757号の出願日の恩典を主張し、その開示は参照により本明細書に組み入れられる。
本発明は、米国国立衛生研究所によって交付されたHD032652およびDK094538の下に、政府の支援を受けて為された。米国政府は本発明に一定の権利を有する。
ムコ多糖症(MPS)は、グリコサミノグリカン(GAG)異化の乱れが引き起こす11の蓄積症の一群であり、リソソームにおけるGAGの蓄積をまねく(Muenzer, 2004、Munoz-Rojas et al., 2008)。さまざまな重症度の所見には、臓器肥大、骨格異形成、心閉塞および肺閉塞、ならびに神経機能低下が含まれる。イズロニダーゼ(IDUA)欠損症であるMPS Iの場合、重症度は、軽度(シェイエ症候群)から中等度(ハーラー・シェイエ)、さらには重度(ハーラー症候群)に及び、後者は神経学的不全と15歳までの死亡をもたらす(Muenzer, 2004、Munoz-Rojas et al., 2008)。MPSの治療法は大部分が対症療法であった。しかし、MPS疾患のなかには、ハーラー症候群を含めて、同種異系造血幹細胞移植(HSCT)が効力を呈したものもある(Krivit, 2004、Orchard et al., 2007、Peters et al., 2003)。加えて、酵素補充療法(ERT)が利用可能になりつつあるMPS疾患も、次第に増えている(Brady, 2006)。一般に、HSCTとERTは蓄積物質の除去と末梢状態の改善をもたらすが、いくつかの問題は処置後も残存する(骨格、心臓、角膜混濁)。これらの細胞療法および酵素療法における最も大きな問題は、神経所見の対処における有効性である。というのも、末梢に投与された酵素は血液脳関門を透過せず、HSCTは一部のMPSに有益であることは見いだされているが、全てのMPSに有益なわけではないからである。
[本発明1001]
中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記方法が、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量の組換えアデノ随伴ウイルス(rAAV)ベクターを含む組成物を、前記哺乳動物に髄腔内投与する工程を含み、前記rAAVがAAV-2ではないか、または前記哺乳動物に浸透促進薬が髄腔内投与される、方法。
[本発明1002]
中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記方法が、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量の組換えアデノ随伴ウイルス(rAAV)ベクターを含む組成物を、前記哺乳動物に脳室内投与する工程を含み、前記rAAVがAAV-8ではないか、または前記哺乳動物が成体である、方法。
[本発明1003]
中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物と、有効量の浸透促進薬とを、前記哺乳動物に血管内投与する工程を含む、方法。
[本発明1004]
組成物が浸透促進薬を含む、本発明1003の方法。
[本発明1005]
浸透促進薬が、マンニトール、グリココール酸ナトリウム、タウロコール酸ナトリウム、デオキシコール酸ナトリウム、サリチル酸ナトリウム、カプリル酸ナトリウム、カプリン酸ナトリウム、ラウリル硫酸ナトリウム、ポリオキシエチレン-9-ラウリルエーテル(polyoxyethylene-9-laurel ether)、またはEDTAを含む、本発明1001または1004の方法。
[本発明1006]
中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物と、免疫抑制薬とを、前記哺乳動物に投与する工程を含む、方法。
[本発明1007]
免疫抑制薬がシクロホスファミドを含む、本発明1006の方法。
[本発明1008]
免疫抑制薬が、グルココルチコイド、アルキル化剤を含む細胞分裂阻害剤、代謝拮抗物質、細胞傷害性抗生物質、抗体、またはイムノフィリンに対して活性な作用物質を含む、本発明1006の方法。
[本発明1009]
免疫抑制薬が、ナイトロジェンマスタード、ニトロソウレア、白金化合物、メトトレキサート、アザチオプリン、メルカプトプリン、フルオロウラシル、ダクチノマイシン、アントラサイクリン、マイトマイシンC、ブレオマイシン、ミトラマイシン、IL-2受容体(CD25)またはCD3に対する抗体、抗IL-2抗体、シクロスポリン、タクロリムス、シロリムス、IFN-β、IFN-γ、オピオイド、またはTNF-α(腫瘍壊死因子アルファ)結合剤を含む、本発明1007または1008の方法。
[本発明1010]
rAAVと免疫抑制薬とが同時投与されるか、または免疫抑制薬がrAAVの後に投与される、本発明1006~1009のいずれかの方法。
[本発明1011]
rAAVと免疫抑制薬とが髄腔内投与される、本発明1006~1010のいずれかの方法。
[本発明1012]
rAAVと免疫抑制薬とが脳室内投与される、本発明1006~1010のいずれかの方法。
[本発明1013]
中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記疾患に関連する遺伝子産物に対して免疫寛容化された哺乳動物を提供する工程;および、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物を、前記哺乳動物に投与する工程を含む、方法。
[本発明1014]
遺伝子産物が、哺乳動物において欠陥酵素であるかまたは欠損しており、それによって、リソソーム蓄積症をもたらしている、本発明1001~1013のいずれかの方法。
[本発明1015]
哺乳動物が免疫適格性の成体である、本発明1001~1014のいずれかの方法。
[本発明1016]
rAAVベクターが、rAAV-1ベクター、rAAV-3ベクター、rAAV-4ベクター、rAAV-5ベクター、rAAV rh10ベクター、またはrAAV-9ベクターである、本発明1001~1015のいずれかの方法。
[本発明1017]
遺伝子産物が、アルファ-L-イズロニダーゼ、イズロン酸-2-スルファターゼ、ヘパラン硫酸スルファターゼ、N-アセチル-アルファ-D-グルコサミニダーゼ、ベータ-ヘキソサミニダーゼ、アルファ-ガラクトシダーゼ、ベータガラクトシダーゼ、ベータ-グルクロニダーゼ、またはグルコセレブロシダーゼである、本発明1001~1016のいずれかの方法。
[本発明1018]
哺乳動物がヒトである、本発明1001~1017のいずれかの方法。
[本発明1019]
疾患がアルファ-L-イズロニダーゼ欠損症である、本発明1001~1018のいずれかの方法。
[本発明1020]
疾患が、ムコ多糖I型障害、ムコ多糖症II型障害、またはムコ多糖症VII型障害である、本発明1001~1018のいずれかの方法。
[本発明1021]
複数回の投与が行われる、本発明1001~1020のいずれかの方法。
[本発明1022]
組成物が週に1回投与される、本発明1001~1020のいずれかの方法。
[本発明1023]
投与によって神経変性が防止、阻害または処置される、本発明1001~1022のいずれかの方法。
[本発明1024]
組成物の投与前に、哺乳動物が遺伝子産物に対して免疫寛容化される、本発明1001~1012または本発明1014~1023のいずれかの方法。
定義
本明細書にいう(処置の対象などでの)「個体」とは哺乳動物を意味する。哺乳動物には、例えばヒト;非ヒト霊長類、例えば類人猿およびサル;および非霊長類、例えばイヌ、ネコ、ラット、マウス、ウシ、ウマ、ヒツジ、およびヤギが含まれる。非哺乳動物には、例えば魚および鳥が含まれる。
rAAVの調製には、どの血清型のアデノ随伴ウイルスでも適している。というのも、種々の血清型は機能的にも構造的にも、遺伝子レベルでさえ関連しているからである。全てのAAV血清型が、相同なrep遺伝子によって媒介される類似の複製特性を呈するようであり、また全ての血清型が、一般に、3つの関連キャプシドタンパク質、例えばAAV2において発現するものを持っている。その近縁度はさらに、ゲノムの全長にわたる血清型間の大規模なクロスハイブリダイゼーションを示すヘテロ二重鎖分析と、ITRに対応する末端の類似自己アニーリングセグメントの存在によっても示唆される。類似する感染性パターンも、各血清型における複製機能が類似する調節制御下にあることを示唆している。さまざまなAAV血清型のなかでAAV2が最もよく使用される。
脳脈管構造の巨大なネットワークにもかかわらず、中枢神経系(CNS)への治療薬の全身性送達は、小分子の98%超にとって、また大分子のほぼ100%にとって、有効でない(Partridge, 2005)。この有効性の欠如は、大半の異物を、多くの有益な治療薬でさえ、循環血から脳に進入しないようにする血液脳関門(BBB)の存在による。全身性に与えられた一定の小分子、ペプチド、およびタンパク質治療薬はBBBを横切ることによって脳実質に到達するが(Banks, 2008)、治療レベルを達成するには一般に高い全身用量が必要になり、それは身体に有害な作用をもたらしうる。治療薬は脳室内注射または実質内注射によってCNSに直接導入することができる。鼻腔内送達はBBBを迂回し、鼻道に神経分布する嗅神経および三叉神経に沿った経路を利用して、治療薬をCNSに直接向かわせる(Frey II, 2002、Thorne et al., 2004、Dhanda et al., 2005)。
ムコ多糖症I型のマウスモデルにおけるAAVベクターを介したイズロニダーゼ遺伝子送達: CNSへのさまざまな送達経路の比較
ムコ多糖症I型(MPS I)は、リソソーム酵素アルファ-L-イズロニダーゼ(IDUA)の欠損が引き起こす遺伝性代謝障害である。グリコサミノグリカンの全身性の異常な蓄積が、成長遅延、臓器肥大、骨格異形成、および心肺疾患と関連する。最も重症な形態の疾患(ハーラー症候群)を有する個体は、神経変性、精神遅滞、および早死を患う。現在行われているMPS Iの2種類の処置(造血幹細胞移植および酵素補充療法)は、全ての中枢神経系(CNS)所見を効果的に処置できるわけではない。
AAV9-IDUAの調製. AAV-IDUAベクターコンストラクト(MCI)は以前に記述されている(Wolf et al., 2011)(mCagsプロモーター)。AAV-IDUAプラスミドDNAは、フロリダ大学ベクターコアでAAV9ウイルス粒子にパッケージングされ、1ミリリットルあたり3×1013ベクターゲノムの力価を得た。
AAVを脳室内(ICV)投与または髄腔内(IT)投与したイズロニダーゼ-欠損マウスに関する結果を、図1に示す。免疫応答を防止するために、動物をシクロホスファミド(CP)で免疫抑制するか、ヒトイズロニダーゼタンパク質(aldurazyme)の静脈内投与によって出生時に免疫寛容化するか、またはイズロニダーゼ欠損性でもあるNOD-SCID免疫不全マウスに注射を行った。処置後の表示した時点で動物を屠殺し、脳を顕微解剖し、抽出物をイズロニダーゼ活性についてアッセイした。
これらの結果は、送達経路(ICVまたはIT)とは関係なく脳におけるIDUAの高く広範な分布を示している。ただし、IT注射した動物では、ICV注射した動物と比較して、線条体および海馬におけるIDUA発現は低かった。免疫不全マウスでは免疫適格マウスより発現レベルが高いので、免疫応答があると思われる。ICV注射に関して、CPを早期に中断した場合、IDUA発現は低い。加えて、免疫寛容化は高レベルの酵素活性を回復するのに有効であった。さらに、全ての処置実験マウス群において、GAGレベルが正常レベルまで回復した。
方法
AAV9IDUAの調製. AAV-IDUAプラスミドは、フロリダ大学ベクターコアまたはペンシルベニア大学ベクターコアでAAV9ウイルス粒子にパッケージングされ、1ミリリットルあたり1~3×1013ベクターゲノムの力価を得た。
図9に実験計画と実験群を図解する。動物に脳室内(ICV)注入または髄腔内(IT)注入のどちらかによってAAV9IDUAベクターを投与した。ベクター投与は、IDUA欠損性でもあるNOD-SCID免疫不全(ID)マウスで行うか、シクロホスファミド(CP)で免疫抑制したIDUA欠損マウスで行うか、またはヒトイズロニダーゼタンパク質(Aldurazyme)の1回または複数回の注射によって出生時に免疫寛容化したIDUA欠損マウスで行った。ベクターによる処置と屠殺の時点は図9に示すとおりである。全てのベクター投与を3~4.5ヶ月齢の範囲の成体動物で行った。動物には10μLのベクターを10マイクロリットルあたり3×1011ベクターゲノムの用量で注射した。
成体マウスにおける脳室内経路および髄腔内経路のAAV9IDUA投与後に脳の全ての領域において、高く広範な治療的レベルのIDUAが観察された。AAV-IDUAを髄腔内注入した免疫適格IDUA欠損動物では、酵素活性が野生型レベルかそれよりわずかに高いレベルまで回復した。IDUAタンパク質の投与を出生時から開始することによって免疫寛容化した動物では、どちらのベクター注射経路でも、有意に高いIDUA酵素レベルが観察された。
成体免疫適格IDUA欠損マウス(12週齢)をケタミン/キシラジンで麻酔した後、AAV9IDUAベクターの鼻腔内注入を行った。ベクターは各3μLの液滴をマイクロピペットで左右の鼻孔に交互に各適用間に2分の間隔を空けて8回鼻腔内適用することによって投与した。ベクターの供給源に依存して合計2.4~7×1011個のベクターゲノムが各成体動物に投与された。120mg/kgのシクロホスファミドをベクター投与の翌日から開始して週に1回投与することによって動物を免疫抑制した。ベクター注入の12週間後にマウスを屠殺し、動物を脳におけるIDUA酵素発現およびベクターコピー数についてアッセイした。
Claims (24)
- 中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記方法が、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量の組換えアデノ随伴ウイルス(rAAV)ベクターを含む組成物を、前記哺乳動物に髄腔内投与する工程を含み、前記rAAVがAAV-2ではないか、または前記哺乳動物に浸透促進薬が髄腔内投与される、方法。
- 中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記方法が、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量の組換えアデノ随伴ウイルス(rAAV)ベクターを含む組成物を、前記哺乳動物に脳室内投与する工程を含み、前記rAAVがAAV-8ではないか、または前記哺乳動物が成体である、方法。
- 中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物と、有効量の浸透促進薬とを、前記哺乳動物に血管内投与する工程を含む、方法。
- 組成物が浸透促進薬を含む、請求項3に記載の方法。
- 浸透促進薬が、マンニトール、グリココール酸ナトリウム、タウロコール酸ナトリウム、デオキシコール酸ナトリウム、サリチル酸ナトリウム、カプリル酸ナトリウム、カプリン酸ナトリウム、ラウリル硫酸ナトリウム、ポリオキシエチレン-9-ラウリルエーテル(polyoxyethylene-9-laurel ether)、またはEDTAを含む、請求項1または4に記載の方法。
- 中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物と、免疫抑制薬とを、前記哺乳動物に投与する工程を含む、方法。
- 免疫抑制薬がシクロホスファミドを含む、請求項6に記載の方法。
- 免疫抑制薬が、グルココルチコイド、アルキル化剤を含む細胞分裂阻害剤、代謝拮抗物質、細胞傷害性抗生物質、抗体、またはイムノフィリンに対して活性な作用物質を含む、請求項6に記載の方法。
- 免疫抑制薬が、ナイトロジェンマスタード、ニトロソウレア、白金化合物、メトトレキサート、アザチオプリン、メルカプトプリン、フルオロウラシル、ダクチノマイシン、アントラサイクリン、マイトマイシンC、ブレオマイシン、ミトラマイシン、IL-2受容体(CD25)またはCD3に対する抗体、抗IL-2抗体、シクロスポリン、タクロリムス、シロリムス、IFN-β、IFN-γ、オピオイド、またはTNF-α(腫瘍壊死因子アルファ)結合剤を含む、請求項7または8に記載の方法。
- rAAVと免疫抑制薬とが同時投与されるか、または免疫抑制薬がrAAVの後に投与される、請求項6~9のいずれか一項に記載の方法。
- rAAVと免疫抑制薬とが髄腔内投与される、請求項6~10のいずれか一項に記載の方法。
- rAAVと免疫抑制薬とが脳室内投与される、請求項6~10のいずれか一項に記載の方法。
- 中枢神経系の疾患に関連する1つまたは複数の症状の防止、阻害、または処置を、それを必要とする哺乳動物において行うための方法であって、前記疾患に関連する遺伝子産物に対して免疫寛容化された哺乳動物を提供する工程;および、前記哺乳動物における発現が前記1つまたは複数の症状を防止、阻害または処置する遺伝子産物をコードするオープンリーディングフレームを含む有効量のrAAVベクターを含む組成物を、前記哺乳動物に投与する工程を含む、方法。
- 遺伝子産物が、哺乳動物において欠陥酵素であるかまたは欠損しており、それによって、リソソーム蓄積症をもたらしている、請求項1~13のいずれか一項に記載の方法。
- 哺乳動物が免疫適格性の成体である、請求項1~14のいずれか一項に記載の方法。
- rAAVベクターが、rAAV-1ベクター、rAAV-3ベクター、rAAV-4ベクター、rAAV-5ベクター、rAAV rh10ベクター、またはrAAV-9ベクターである、請求項1~15のいずれか一項に記載の方法。
- 遺伝子産物が、アルファ-L-イズロニダーゼ、イズロン酸-2-スルファターゼ、ヘパラン硫酸スルファターゼ、N-アセチル-アルファ-D-グルコサミニダーゼ、ベータ-ヘキソサミニダーゼ、アルファ-ガラクトシダーゼ、ベータガラクトシダーゼ、ベータ-グルクロニダーゼ、またはグルコセレブロシダーゼである、請求項1~16のいずれか一項に記載の方法。
- 哺乳動物がヒトである、請求項1~17のいずれか一項に記載の方法。
- 疾患がアルファ-L-イズロニダーゼ欠損症である、請求項1~18のいずれか一項に記載の方法。
- 疾患が、ムコ多糖I型障害、ムコ多糖症II型障害、またはムコ多糖症VII型障害である、請求項1~18のいずれか一項に記載の方法。
- 複数回の投与が行われる、請求項1~20のいずれか一項に記載の方法。
- 組成物が週に1回投与される、請求項1~20のいずれか一項に記載の方法。
- 投与によって神経変性が防止、阻害または処置される、請求項1~22のいずれか一項に記載の方法。
- 組成物の投与前に、哺乳動物が遺伝子産物に対して免疫寛容化される、請求項1~12または請求項14~23のいずれか一項に記載の方法。
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Families Citing this family (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2015012739A (es) | 2013-03-15 | 2016-02-19 | Univ Pennsylvania | Composiciones y metodos para tratar la mucopolisacaridosis tipo 1. |
CN105377039A (zh) * | 2013-05-15 | 2016-03-02 | 明尼苏达大学董事会 | 腺相关病毒介导的基因向中枢神经系统转移 |
WO2015191508A1 (en) | 2014-06-09 | 2015-12-17 | Voyager Therapeutics, Inc. | Chimeric capsids |
CN107106689A (zh) | 2014-11-05 | 2017-08-29 | 沃雅戈治疗公司 | 用于治疗帕金森病的aadc多核苷酸 |
SG11201703419UA (en) | 2014-11-14 | 2017-05-30 | Voyager Therapeutics Inc | Modulatory polynucleotides |
MX2017006216A (es) | 2014-11-14 | 2018-08-29 | Voyager Therapeutics Inc | Composiciones y métodos para tratar la esclerosis lateral amiotrófica (ela). |
EP3230441A4 (en) | 2014-12-12 | 2018-10-03 | Voyager Therapeutics, Inc. | Compositions and methods for the production of scaav |
EP3632923A1 (en) * | 2015-01-16 | 2020-04-08 | Voyager Therapeutics, Inc. | Central nervous system targeting polynucleotides |
EP3285788A4 (en) | 2015-04-23 | 2018-12-05 | University of Massachusetts | Modulation of aav vector transgene expression |
GB201508025D0 (en) | 2015-05-11 | 2015-06-24 | Ucl Business Plc | Fabry disease gene therapy |
US20180289839A1 (en) * | 2015-05-15 | 2018-10-11 | Regents Of The University Of Minnesota | Intranasal therapeutic delivery of adeno-associated virus to central nervous system |
US11027024B2 (en) | 2015-05-29 | 2021-06-08 | University Of Iowa Research Foundation | Methods of delivery of transgenes for treating brain diseases |
AU2016341428B2 (en) | 2015-10-23 | 2021-12-02 | University Of Iowa Research Foundation | Methods for treating neurodegenerative diseases using gene therapy to delay disease onset and progression while providing cognitive protection |
CA3003747A1 (en) * | 2015-11-05 | 2017-05-11 | The General Hospital Corporation | Intrathecal delivery of nucleic acid sequences encoding abcd1 for treatment of adrenomyeloneuropathy |
JP6930052B2 (ja) | 2016-01-15 | 2021-09-01 | サンガモ セラピューティクス, インコーポレイテッド | 神経性疾患の処置のための方法および組成物 |
JP7360241B2 (ja) * | 2016-02-03 | 2023-10-12 | ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア | ムコ多糖症i型を治療するための遺伝子治療 |
RU2018132517A (ru) * | 2016-02-22 | 2020-03-24 | Дзе Юниверсити Оф Норт Каролина Эт Чепел Хилл | Aav-idua вектор для лечения ассоциированной с mps i слепоты |
US11185555B2 (en) | 2016-04-11 | 2021-11-30 | Noah James Harrison | Method to kill pathogenic microbes in a patient |
EP3452104A1 (en) * | 2016-04-15 | 2019-03-13 | The Trustees of The University of Pennsylvania | Gene therapy for treating mucopolysaccharidosis type ii |
US11299751B2 (en) | 2016-04-29 | 2022-04-12 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
SG11201809643UA (en) | 2016-05-18 | 2018-12-28 | Voyager Therapeutics Inc | Compositions and methods of treating huntington's disease |
KR102392236B1 (ko) | 2016-05-18 | 2022-05-03 | 보이저 테라퓨틱스, 인크. | 조절성 폴리뉴클레오티드 |
AU2017313917B2 (en) | 2016-08-18 | 2023-12-21 | The Regents Of The University Of California | CRISPR-Cas genome engineering via a modular AAV delivery system |
EP3831281A1 (en) | 2016-08-30 | 2021-06-09 | The Regents of The University of California | Methods for biomedical targeting and delivery and devices and systems for practicing the same |
MX2019003567A (es) | 2016-09-28 | 2019-12-02 | Cohbar Inc | Peptidos terapeuticos relacionados con mots-c. |
CA3049915A1 (en) * | 2017-01-31 | 2018-08-09 | Stephen YOO | Treatment of mucopolysaccharidosis i with fully-human glycosylated human alpha-l-iduronidase (idua) |
US11117930B2 (en) | 2017-02-23 | 2021-09-14 | Adrx, Inc. | Peptide inhibitors of transcription factor aggregation |
WO2018187363A1 (en) | 2017-04-03 | 2018-10-11 | Encoded Therapeutics, Inc. | Tissue selective transgene expression |
IL269892B2 (en) * | 2017-04-14 | 2024-04-01 | Regenxbio Inc | Treatment for mucopolysaccharidosis 2 with the help of recombinant human iduronate-2 suplatase (ids) produced by human neuron or glial cells |
CA3061652A1 (en) | 2017-05-05 | 2018-11-08 | Voyager Therapeutics, Inc. | Compositions and methods of treating amyotrophic lateral sclerosis (als) |
EP3619308A4 (en) | 2017-05-05 | 2021-01-27 | Voyager Therapeutics, Inc. | COMPOSITIONS AND METHODS OF TREATMENT FOR HUNTINGTON'S MORBUS |
AU2018281280A1 (en) | 2017-06-07 | 2020-01-16 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for internalizing enzymes |
WO2018226992A1 (en) | 2017-06-07 | 2018-12-13 | Adrx, Inc. | Tau aggregation inhibitors |
JOP20190269A1 (ar) | 2017-06-15 | 2019-11-20 | Voyager Therapeutics Inc | بولي نوكليوتيدات aadc لعلاج مرض باركنسون |
KR20240063170A (ko) | 2017-07-06 | 2024-05-09 | 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 | I형 점액다당류증을 치료하기 위한 유전자 요법 |
JP7229989B2 (ja) | 2017-07-17 | 2023-02-28 | ボイジャー セラピューティクス インコーポレイテッド | 軌道アレイガイドシステム |
KR20200044793A (ko) | 2017-08-03 | 2020-04-29 | 보이저 테라퓨틱스, 인크. | Aav의 전달을 위한 조성물 및 방법 |
EP3684938A1 (en) | 2017-09-22 | 2020-07-29 | The Trustees of the University of Pennsylvania | Gene therapy for treating mucopolysaccharidosis type ii |
CN112481269A (zh) | 2017-10-03 | 2021-03-12 | 普利维尔治疗公司 | 用于溶酶体障碍的基因疗法 |
KR102693318B1 (ko) | 2017-10-03 | 2024-08-07 | 프리베일 테라퓨틱스, 인크. | 리소좀 장애를 위한 유전자 요법 |
CN112501208A (zh) | 2017-10-03 | 2021-03-16 | 普利维尔治疗公司 | 用于溶酶体障碍的基因疗法 |
WO2019079242A1 (en) | 2017-10-16 | 2019-04-25 | Voyager Therapeutics, Inc. | TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS (ALS) |
JP7502991B2 (ja) | 2017-10-16 | 2024-06-19 | ボイジャー セラピューティクス インコーポレイテッド | 筋萎縮性側索硬化症(als)の治療 |
WO2019109051A1 (en) | 2017-12-01 | 2019-06-06 | Encoded Therapeutics, Inc. | Engineered dna binding proteins |
WO2019132624A1 (ko) | 2017-12-29 | 2019-07-04 | 주식회사 헬릭스미스 | 하이브리드 hgf 유전자가 도입된 aav(아데노-연관 바이러스) 벡터 |
CN112739419A (zh) * | 2018-05-22 | 2021-04-30 | 布里格姆妇女医院 | 用于阿尔茨海默症的基因治疗 |
CA3114199A1 (en) | 2018-09-26 | 2020-04-02 | California Institute Of Technology | Adeno-associated virus compositions for targeted gene therapy |
CN113518784A (zh) | 2019-01-28 | 2021-10-19 | 科巴公司 | 治疗性肽 |
CN114025806A (zh) * | 2019-04-10 | 2022-02-08 | 普利维尔治疗公司 | 用于溶酶体障碍的基因疗法 |
KR20220006527A (ko) | 2019-04-10 | 2022-01-17 | 프리베일 테라퓨틱스, 인크. | 리소좀 장애에 대한 유전자 요법 |
WO2020210615A1 (en) * | 2019-04-10 | 2020-10-15 | Prevail Therapeutics, Inc. | Gene therapies for lysosomal disorders |
WO2020210698A1 (en) | 2019-04-10 | 2020-10-15 | Prevail Therapeutics, Inc. | Gene therapies for lysosomal disorders |
US11981912B2 (en) | 2019-12-10 | 2024-05-14 | Takeda Pharma ceutical Company Limited | Adeno associated virus vectors for the treatment of hunter disease |
EP4118219A4 (en) * | 2020-03-11 | 2024-04-17 | Shanghai Belief-Delivery Biomed Co., Ltd. | NOVEL USE OF AN ASPIRIN COMPOUND TO INCREASE NUCLEIC ACID EXPRESSION |
US20230414659A1 (en) * | 2020-10-30 | 2023-12-28 | Immusoft Corporation | Methods of administering genetically modified b cells for in vivo delivery of therapeutic agents |
AU2022214429A1 (en) | 2021-02-01 | 2023-09-14 | Regenxbio Inc. | Gene therapy for neuronal ceroid lipofuscinoses |
WO2022170082A1 (en) * | 2021-02-05 | 2022-08-11 | Regents Of The University Of Minnesota | Methods for preventing cardiac or skeletal defects in diseases including mucopolysaccharidoses |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5929648A (ja) * | 1982-08-10 | 1984-02-16 | Mitsubishi Chem Ind Ltd | ペプチド類 |
JP2006503847A (ja) * | 2002-09-27 | 2006-02-02 | チルドレンズ メディカル センター コーポレーション | 神経疾患の治療のための方法および組成物 |
JP2016523835A (ja) * | 2013-05-15 | 2016-08-12 | リージェンツ オブ ザ ユニバーシティ オブ ミネソタ | 中枢神経系へのアデノ随伴ウイルスを介した遺伝子導入 |
Family Cites Families (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US200901A (en) * | 1878-03-05 | Improvement in machines for compressing and purifying air | ||
US6407061B1 (en) | 1989-12-05 | 2002-06-18 | Chiron Corporation | Method for administering insulin-like growth factor to the brain |
AU6909091A (en) | 1989-12-05 | 1991-06-26 | Ramsey Foundation | Neurologic agents for nasal administration to the brain |
US5624898A (en) | 1989-12-05 | 1997-04-29 | Ramsey Foundation | Method for administering neurologic agents to the brain |
US5478745A (en) | 1992-12-04 | 1995-12-26 | University Of Pittsburgh | Recombinant viral vector system |
JP3952312B2 (ja) | 1993-11-09 | 2007-08-01 | メディカル カレッジ オブ オハイオ | アデノ関連ウイルス複製遺伝子を発現可能な安定な細胞株 |
PT733103E (pt) | 1993-11-09 | 2004-07-30 | Targeted Genetics Corp | Criacao de elevados titulos de vectores de aav recombinantes |
WO1996017947A1 (en) | 1994-12-06 | 1996-06-13 | Targeted Genetics Corporation | Packaging cell lines for generation of high titers of recombinant aav vectors |
US5656785A (en) | 1995-08-07 | 1997-08-12 | The Charles Stark Draper Laboratory, Inc. | Micromechanical contact load force sensor for sensing magnitude and distribution of loads and tool employing micromechanical contact load force sensor |
US6190659B1 (en) * | 1996-09-17 | 2001-02-20 | The Rockefeller University | Bacterial plasmin binding protein and methods of use thereof |
DE69737424T2 (de) | 1996-11-19 | 2007-06-21 | Surgx Corp., Fremont | Schutzvorrichtung gegen transiente spannungen und verfahren zu deren herstellung |
WO1998027204A2 (en) | 1996-12-18 | 1998-06-25 | Targeted Genetics Corporation | Aav split-packaging genes and cell lines comprising such genes for use in the production of recombinant aav vectors |
AU8672198A (en) * | 1997-07-31 | 1999-02-22 | Chiron Corporation | Method enabling readministration of aav vector via immunosuppression of host |
EP1658857A1 (en) * | 1997-10-29 | 2006-05-24 | Genzyme Corporation | Compositions and methods for treating lysosomal storage disease |
CA2329259C (en) | 1998-05-27 | 2003-08-05 | Avigen, Inc. | Convection-enhanced delivery of aav vectors |
EP1135105B1 (en) | 1998-12-09 | 2005-03-02 | Chiron Corporation | Use of a neurologic agent for the manufacture of a medicament for the treatment of a central nervous system disorder |
EP1137401B1 (en) | 1998-12-09 | 2005-11-23 | Chiron Corporation | Administration of neurotrophic agents to the central nervous system |
US7273618B2 (en) | 1998-12-09 | 2007-09-25 | Chiron Corporation | Method for administering agents to the central nervous system |
US20050032841A1 (en) * | 1999-04-20 | 2005-02-10 | Steven Walkley | Therapeutic compositions and methods of treating glycolipid storage related disorders |
US6585971B1 (en) | 1999-11-12 | 2003-07-01 | Harbor-Ucla Research And Education Institute | Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating disease caused by deficiencies thereof |
US6569661B1 (en) | 1999-11-12 | 2003-05-27 | Biomarin Pharmaceutical Inc. | Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof |
US6582692B1 (en) * | 1999-11-17 | 2003-06-24 | Avigen, Inc. | Recombinant adeno-associated virus virions for the treatment of lysosomal disorders |
IL150109A0 (en) | 1999-12-09 | 2002-12-01 | Chiron Corp | Method for administering a cytokine to the central nervous system and the lymphatic system |
US7084126B1 (en) | 2000-05-01 | 2006-08-01 | Healthpartners Research Foundation | Methods and compositions for enhancing cellular function through protection of tissue components |
US20040204379A1 (en) | 2000-06-19 | 2004-10-14 | Cheng Seng H. | Combination enzyme replacement, gene therapy and small molecule therapy for lysosomal storage diseases |
AU2001271941B2 (en) * | 2000-07-18 | 2007-03-01 | Duke University | Treatment of glycogen storage disease type II |
US20020014242A1 (en) * | 2000-07-31 | 2002-02-07 | Abraham Scaria | Use of rapamycin to inhibit immune response and induce tolerance to gene therapy vector and encoded transgene products |
US20020082215A1 (en) | 2000-10-13 | 2002-06-27 | Chiron Corporation | Method for treating ischemic events affecting the central nervous system |
US20020169102A1 (en) | 2001-04-03 | 2002-11-14 | Frey William H. | Intranasal delivery of agents for regulating development of implanted cells in the CNS |
WO2002086105A1 (en) | 2001-04-20 | 2002-10-31 | Chiron Corporation | Delivery of polynucleotide agents to the central nervous sysstem |
US20030229025A1 (en) | 2002-02-25 | 2003-12-11 | Chiron Corporation | Intranasal administration of MC4-R agonists |
US7485314B2 (en) * | 2002-05-06 | 2009-02-03 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Induction of antigen specific immunologic tolerance |
AU2003302724A1 (en) * | 2002-08-13 | 2004-07-09 | Mcivor, Scott, R. | Methods of using vectors to treat metabolic disorders |
US7446098B2 (en) * | 2003-02-18 | 2008-11-04 | Mount Sinai School Of Medicine Of New York University | Combination therapy for treating protein deficiencies |
US20050026823A1 (en) * | 2003-06-20 | 2005-02-03 | Biomarin Pharmaceutical Inc. | Use of the chaperone receptor-associated protein (RAP) for the delivery of therapeutic compounds to the brain and other tissues |
US7442372B2 (en) * | 2003-08-29 | 2008-10-28 | Biomarin Pharmaceutical Inc. | Delivery of therapeutic compounds to the brain and other tissues |
WO2005062881A2 (en) * | 2003-12-24 | 2005-07-14 | Transgenrx, Inc. | Gene therapy using transposon-based vectors |
US7776312B2 (en) | 2004-08-13 | 2010-08-17 | Healthpartners Research Foundation | Method of treating Alzheimer's disease comprising administering deferoxamine (DFO) to the upper one-third of the nasal cavity |
US7618615B2 (en) | 2004-08-13 | 2009-11-17 | Healthpartners Research Foundation | Methods for providing neuroprotection for the animal central nervous system against neurodegeneration caused by ischemia |
NZ581205A (en) | 2005-02-23 | 2011-06-30 | Alza Corp | Intranasal administration of active agents to the central nervous system |
US20090136505A1 (en) | 2005-02-23 | 2009-05-28 | Johanna Bentz | Intranasal Administration of Active Agents to the Central Nervous System |
US20070093420A1 (en) | 2005-08-26 | 2007-04-26 | Yeomans David C | Therapy procedure for drug delivery for trigeminal pain |
US20100221235A1 (en) * | 2006-02-08 | 2010-09-02 | Diatos | Compositions and Methods for Treating Lysosomal Storage Diseases |
LT1986661T (lt) * | 2006-02-08 | 2018-12-10 | Genzyme Corporation | Nimano-piko a tipo ligos genų terapija |
JP2009526066A (ja) * | 2006-02-09 | 2009-07-16 | ジェンザイム・コーポレーション | 遅速性脳室内送達 |
WO2007127163A2 (en) | 2006-04-24 | 2007-11-08 | Geron Corporation | Cns-tumor treatment method and composition |
EP1915986A1 (en) | 2006-10-23 | 2008-04-30 | BIOPHARM GESELLSCHAFT ZUR BIOTECHNOLOGISCHEN ENTWICKLUNG VON PHARMAKA mbH | Lipid growth factor formulations |
US20100221225A1 (en) * | 2007-02-23 | 2010-09-02 | University Of Florida Research Foundation, Inc | Compositions and methods for treating glycogen storage diseases |
PT2158322T (pt) * | 2007-06-06 | 2017-08-09 | Genzyme Corp | Terapia genética para doenças do armazenamento lisossomal |
JP2011504163A (ja) | 2007-06-08 | 2011-02-03 | ヘルスパートナーズ リサーチ ファウンデーション | 中枢神経系への治療化合物の標的化を高めるための薬学的組成物および方法 |
US8283160B2 (en) | 2007-09-11 | 2012-10-09 | Frey Ii William H | Methods, pharmaceutical compositions and articles of manufacture for administering therapeutic cells to the animal central nervous system |
EP2058401A1 (en) * | 2007-10-05 | 2009-05-13 | Genethon | Widespread gene delivery to motor neurons using peripheral injection of AAV vectors |
WO2009075815A1 (en) * | 2007-12-07 | 2009-06-18 | Duke University | Immunomodulating gene therapy |
WO2009120978A2 (en) * | 2008-03-27 | 2009-10-01 | The Ohio State University | Treatment of metabolic-related disorders using hypothalamic gene transfer of bdnf and compositions therfor |
US11219696B2 (en) * | 2008-12-19 | 2022-01-11 | Nationwide Children's Hospital | Delivery of polynucleotides using recombinant AAV9 |
US9415121B2 (en) * | 2008-12-19 | 2016-08-16 | Nationwide Children's Hospital | Delivery of MECP2 polynucleotide using recombinant AAV9 |
WO2010071832A1 (en) * | 2008-12-19 | 2010-06-24 | Nationwide Children's Hospital | Delivery of polynucleotides across the blood brain barrier using recombinant aav9 |
US7989502B2 (en) | 2009-02-06 | 2011-08-02 | Sri International | Intranasal delivery of modafinil |
WO2010093784A2 (en) * | 2009-02-11 | 2010-08-19 | The University Of North Carolina At Chapel Hill | Modified virus vectors and methods of making and using the same |
US20110070241A1 (en) * | 2009-06-30 | 2011-03-24 | Duke University | Methods for modulating immune responses to aav gene therapy vectors |
US8622993B2 (en) | 2009-12-18 | 2014-01-07 | Healthpartners Research Foundation | Device and method for delivering therapeutic substances to the maxillary sinus of a patient |
EP2826860B1 (en) * | 2010-04-23 | 2018-08-22 | University of Massachusetts | CNS targeting AAV vectors and methods of use thereof |
EP2394667A1 (en) * | 2010-06-10 | 2011-12-14 | Laboratorios Del Dr. Esteve, S.A. | Vectors and sequences for the treatment of diseases |
KR102537084B1 (ko) * | 2010-06-25 | 2023-05-26 | 샤이어 휴먼 지네틱 테라피즈 인크. | 아릴설파타제 a의 cns 전달을 위한 방법들 및 조성물들 |
LT2588130T (lt) * | 2010-06-25 | 2016-12-12 | Shire Human Genetic Therapies, Inc. | Terapinės priemonės pristatymas cns |
CN103260637B (zh) * | 2010-06-25 | 2016-04-06 | 夏尔人类遗传性治疗公司 | 乙酰肝素n-硫酸酯酶cns递送的方法和组合物 |
EP2593131B1 (en) * | 2010-06-25 | 2019-08-21 | Shire Human Genetic Therapies, Inc. | Methods and compositions for cns delivery of iduronate-2-sulfatase |
ES2895655T3 (es) * | 2010-06-25 | 2022-02-22 | Shire Human Genetic Therapies | Métodos y composiciones para la administración al SNC de iduronato-2-sulfatasa |
AR082319A1 (es) * | 2010-07-22 | 2012-11-28 | Biomarin Pharm Inc | Produccion de una n-acetilgalactosamina-6-sulfatasa humana activa altamente fosforilada y sus usos |
EP4234571A3 (en) * | 2011-02-10 | 2023-09-27 | The University of North Carolina at Chapel Hill | Viral vectors with modified transduction profiles and methods of making and using the same |
EP2691529B1 (en) | 2011-03-31 | 2019-06-12 | University of Iowa Research Foundation | AAV2 particle comprising an AAV2 capsid protein and a vector comprising a nucleic acid encoding a tripeptidyl peptidase 1 (TPP1) for use in treating late infantile ceroid lipofuscinosis (LINCL) in a non-rodent mammal by intraventricular injection or ICV delivery. |
WO2012145597A2 (en) * | 2011-04-21 | 2012-10-26 | Nationwide Children's Hospital, Inc. | Recombinant virus products and methods for inhibition of expression of myotilin |
US10196636B2 (en) * | 2011-04-21 | 2019-02-05 | Nationwide Children's Hospital, Inc. | Recombinant virus products and methods for inhibition of expression of myotilin |
US8609088B2 (en) * | 2011-05-10 | 2013-12-17 | Regents Of The University Of Minnesota | Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases |
US10227387B2 (en) * | 2011-05-18 | 2019-03-12 | Children's Hospital Medical Center | Targeted delivery of proteins across the blood-brain barrier |
US20130039888A1 (en) * | 2011-06-08 | 2013-02-14 | Nationwide Children's Hospital Inc. | Products and methods for delivery of polynucleotides by adeno-associated virus for lysosomal storage disorders |
CA3106285A1 (en) * | 2011-07-25 | 2013-01-31 | Nationwide Children's Hospital, Inc. | Recombinant virus products and methods for inhibition of expression of dux4 |
US9579366B2 (en) * | 2011-10-12 | 2017-02-28 | Alexion Pharmaceuticals, Inc. | Recombinant human NaGlu protein and uses thereof |
US9821149B2 (en) | 2011-10-14 | 2017-11-21 | Healthpartners Research & Education | Methods for using ultrasound for enhancing efficiency and targeting of intranasal administration of therapeutic compounds to the central nervous system |
JP6266529B2 (ja) * | 2011-12-02 | 2018-01-24 | アーマジェン・インコーポレイテッドArmagen, Inc. | Cnsにおけるアリールスルファターゼa活性を増加するための方法および組成物 |
CN107982548A (zh) * | 2012-02-07 | 2018-05-04 | 全球生物疗法有限公司 | 核酸输送的区室化方法及其组合物和应用 |
EP3818991A3 (en) * | 2012-06-19 | 2021-07-14 | University of Florida Research Foundation, Inc. | Compositions and methods for treating diseases |
WO2013190059A1 (en) * | 2012-06-21 | 2013-12-27 | Association Institut De Myologie | Widespread gene delivery of gene therapy vectors |
BR112015002168A2 (pt) * | 2012-08-01 | 2017-11-07 | Nationwide Childrens Hospital | liberação intratecal de vírus 9 adeno-associado recombinante |
WO2014043480A1 (en) * | 2012-09-13 | 2014-03-20 | Crystal Ronald G | Treatment of brain cancers using central nervous system mediated gene transfer of monoclonal antibodies |
TWI711632B (zh) * | 2012-11-27 | 2020-12-01 | 美商拜奧馬林製藥公司 | 靶向治療性溶小體酶融合蛋白及其用途 |
KR102413498B1 (ko) * | 2013-04-20 | 2022-06-24 | 더 리서치 인스티튜트 앳 네이션와이드 칠드런스 하스피탈 | 엑손 2-표적 U7snRNA 폴리뉴클레오티드 작제물의 재조합형 아데노 부속 바이러스 전달 |
MX2016001026A (es) | 2013-07-26 | 2016-08-03 | Univ Iowa Res Found | Metodos y composiciones para tratar enfermedades del cerebro. |
EP4219727A3 (en) * | 2013-08-27 | 2023-09-06 | Research Institute at Nationwide Children's Hospital | Products and methods for treatment of amyotrophic lateral sclerosis |
EA036394B1 (ru) * | 2013-10-24 | 2020-11-05 | ЮНИКЬЮРЕ АйПи Б.В. | Псевдотипированный вектор на основе аденоассоциированного вируса aav-5 для генной терапии неврологических заболеваний |
EP3134113A4 (en) * | 2014-04-25 | 2017-11-29 | University of Florida Research Foundation, Inc. | Methods of permitting a subject to receive multiple doses of recombinant adeno-associated virus |
EP3137497B1 (en) * | 2014-05-02 | 2021-04-07 | Genzyme Corporation | Aav vectors for retinal and cns gene therapy |
US20180289839A1 (en) * | 2015-05-15 | 2018-10-11 | Regents Of The University Of Minnesota | Intranasal therapeutic delivery of adeno-associated virus to central nervous system |
US10166255B2 (en) * | 2015-07-31 | 2019-01-01 | Regents Of The University Of Minnesota | Intracellular genomic transplant and methods of therapy |
AU2017333336B2 (en) * | 2016-09-30 | 2023-11-09 | Esteve Pharmaceuticals, S.A. | Adenoassociated virus vectors for the treatment of mucopolysaccharidoses |
JP2020500928A (ja) * | 2016-11-15 | 2020-01-16 | リジェネクスバイオ インコーポレイテッド | Mpsiおよびmpsiiならびに他の神経障害において神経機能を改善するための方法 |
WO2018136435A1 (en) * | 2017-01-17 | 2018-07-26 | Children's Medical Center Corporation | Compositions and methods for treating lysosomal storage diseases and disorders |
KR20240028976A (ko) * | 2021-04-13 | 2024-03-05 | 캡시다, 인크. | 뇌에서 높은 발현 수준을 갖는 aav 조성물 |
-
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- 2014-05-15 CN CN201480027622.1A patent/CN105377039A/zh active Pending
- 2014-05-15 KR KR1020247017529A patent/KR20240093939A/ko unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5929648A (ja) * | 1982-08-10 | 1984-02-16 | Mitsubishi Chem Ind Ltd | ペプチド類 |
JP2006503847A (ja) * | 2002-09-27 | 2006-02-02 | チルドレンズ メディカル センター コーポレーション | 神経疾患の治療のための方法および組成物 |
JP2016523835A (ja) * | 2013-05-15 | 2016-08-12 | リージェンツ オブ ザ ユニバーシティ オブ ミネソタ | 中枢神経系へのアデノ随伴ウイルスを介した遺伝子導入 |
JP2020073559A (ja) * | 2013-05-15 | 2020-05-14 | リージェンツ オブ ザ ユニバーシティ オブ ミネソタ | 中枢神経系へのアデノ随伴ウイルスを介した遺伝子導入 |
Non-Patent Citations (1)
Title |
---|
MOLECULAR THERAPY, MAY 01 2013, VOLUME 21, SUPPLEMENT 1, S140, ABSTRACT NO. 364, JPN6021041692, ISSN: 0004772052 * |
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