JP2021526818A - 心筋症のためのaav心臓遺伝子治療 - Google Patents
心筋症のためのaav心臓遺伝子治療 Download PDFInfo
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Abstract
Description
本出願は、2018年6月8日に出願された米国仮出願第 62/682,772号および2019年3月21に出願された米国仮出願第 62/822,015号の出願日の利益を主張し、これらの各々の内容全体は、参照により援用される。
拡張型心筋症(DCM)は、イヌにおける心臓疾患の第二の最も一般的な原因であり、二次的兆候の医療管理は、唯一の治療選択肢である。罹患したイヌの予後は、疾患の段階および品種に依存する。ドーベルマン・ピンシェルは、一旦うっ血性心不全(CHF)が生じると、最大の生存が6か月未満で、具体的に迅速なおよび一様な進行を示す。拡張型心筋症(DCM)は、最も一般的なタイプのヒト心筋症であり、20〜60の成年者に発生する。それは、心臓の心室および心房、夫々、心臓の下方および上方の房(chamber)に影響する。
心筋症は、対象における心臓疾患の第二の最も一般的な原因であり、および、二次的な兆候の医療管理が唯一の治療選択肢である。罹患した対象の予後は、疾患の段階および品種に依存する。心臓機能は、カルシウム依存性のシグナリングに重大に依存している。心臓疾患の間、心細胞内のカルシウムチャネルの機能障害は、カルシウム循環の異常を促進し、さらに心臓機能を阻害する。カルシウム循環の異常を低減するための遺伝子導入ストラテジーは、小および大動物モデルならびにヒト臨床試験における心疾患を寛解させることが示されている。
以下の図面は、本願明細書の一部を形成し、および、本発明のある側面をさらに示すために包含される。本開示は、似たような参照数字が似たような要素を同定する、添付の図面と併せて、以下の記載を参照することによって、より良く理解され得る。
本発明は、対象における心臓疾患、例として心筋症についての心臓遺伝子治療の組成物および方法に関する。本発明の方法は、2つの導入遺伝子の同時送達および発現のための、組換えAAV(rAAV)粒子の使用に関する。本発明の導入遺伝子は、少なくとも2つのクラスのタンパク質を含み、各々が、心臓疾患の異なる側面に取り組むための特定の機能を有する。1つのクラスの導入遺伝子は、心筋細胞におけるカルシウムシグナリングを調節する(例として、S100ファミリータンパク質)。他のクラスの導入遺伝子は、アポトーシスリプレッサーを含む。いくつかの態様において、導入遺伝子は、心臓S100カルシウム結合タンパク質A1(cS100A1)またはそのバリアント、およびカスパーゼ動員ドメインを有する心臓アポトーシスリプレッサー(cARC)またはそのバリアントであり得る。
(NCBI参照配列: XM_005622816.2)
ATGGGCTCTGAGCTGGAGACAGCGATGGAGACTCTCATCAATGTGTTCCATGCCCACTCGGGCAAGGAGGGAAACAAGTACAAGCTGAGCAAGAAGGAGCTAAAGGAGCTGCTGCAGACTGAGCTCTCCGGCTTCCTGGACGCCCAGAAGGATGCGGATGCTGTGGACAAGGTGATGAAAGAGCTAGATGAGAATGGAGATGGGGAGGTGGACTTCCAGGAGTATGTGGTGCTGGTGGCTGCCCTCACAGTGGCCTGTAACAACTTCTTCTGGGAAAACAGTTGA (配列番号1)
(NCBI参照配列: XM_003999773.3)
ATGGGCTCAGAGCTGGAGACGGCGATGGAGACTCTCATCAACGTGTTCCACGCCCACTCGGGCAAGGAGGGAGACAAGTACAAGCTGAGCAAGAAGGAGCTAAAAGAGCTGCTGCAGACCGAGCTCTCTGGCTTCCTGGACGCCCAGAAGGATGCCGACGCTGTGGACAAGGTGATGAAAGAGCTAGACGAGAATGGAGATGGGGAGGTGGACTTCCAAGAGTATGTGGTGCTGGTGGCTGCCCTCACAGTGGCCTGTAACAACTTTTTCTGGGAGAACAGTTGA (配列番号2)
cARC cDNA配列の非制限例は、以下に列挙される。
(NCBI参照配列: NM_001048121.1)
ATGCAGGAAGCGCCAGCCGCGCTGCCCACGGAGCCGGGCCCCAGCCCCGTGCCTGCCTTCCTCGGCAAGCTGTGGGCGCTGGTGGGCGACCCGGGGACCGACCACCTCATCCGCTGGAGCCCGAGCGGGACCAGTTTCCTCGTCAGCGACCAGAGCCGCTTCGCCAAGGAAGTGCTGCCCCAGTACTTCAAGCACAGCAACATGGCGAGCTTCGTGCGGCAGCTCAACATGTACGGTTTTCGGAAGGTGGTGAGCATCGAGCAGGGCGGCCTGCTCAGGCCGGAGCGCGACCACGTCGAGTTCCAGCACCCGAGCTTCGTCCGCGGCCGAGAGCAACTCCTGGAGCGCGTGCGGCGCAAGGTGCCCGCGCTGCGCAGCGACGACGGCCGCTGGCGCCCCGAGGACCTGGGCCGGCTGCTGGGCGAGGTGCAGGCTTTGCGGGGAGTGCAGGAGATCACCGAGGCGCGGCTGCGGGAGCTCAGGCAGCAGAACGAGATCTTATGGAGGGAGGTGGTGACTCTGCGGCAGAGCCACGGTCAGCAGCATCGCGTCATTGGCAAGCTGATCCAGTGCCTCTTTGGGCCACTTCAGACAGGGTCCAGCGGCGCAGGAGCTAAGAGAAAGCTGTCTCTGATGCTGGATGAGGGGAGCTCATGCCCAACACCGGCCAAATTCAACACCTGTCCTTTACCTGGTGCCCTCTTGCAGGATCCCTACTTTATCCAGTCGCCCCTCCCAGAGACCACCTTGGGCCTCAGCAGCTCTCATAGGACCAGGGGCCCTATCATCTCTGACATCCATGAAGACTCTCCCTCCCCTGATGGGACCAGGCTTTCTCCTTCCAGTGGTGGCAGGAGGGAGAAGGGCCTGGCACTGCTCAAAGAAGAGCCGGCCAGCCCAGGGGGGGAAGGCGAGGCCGGGCTGGCCCTGGCCCCAAACGAGTGTGACTTCTGCGTGACAGCCCCCCCCCCACTGTCCGTGGCTGTGGTGCAGGCCATCCTGGAAGGGAAGGGGAACTTCAGCCCCGAGGGGCCCAGGAATGCCCAACAGCCTGAACCAAGGGGTCCCAGGGAGGTACCTGACAGGGGGACTCTGGGCCTGGACAGGGGGGCACGAAGCCCAGAGAATCTGCTGCCTCCCATGCTGCTTCGGGCCCCCCCTGAAAGTGTGGAGCCTGCAGGGCCCCTGGATGTGCTGGGCCCCAGCCATCAAGGGCGAGAATGGACCCTGATGGACTTGGACATGGAGCTGTCCCTGATGCAGCCCTTGGGTCCAGAGAGGAGTGAGACTGAGCTGGCGGTCAAGGGGTTAAATTCTCCGGGGCCAGGGAAGGACTCCACACTTGGGGCACCACTCCTGCTCGATGTCCAAGCGGCTTTGGGAGGCCCAGCTCTCAGCCTTCCTGGAGCTTTAACCATTTACAGCACCCCTGAGAGCCGAGCCAACTACCTAGGCCCAGGGGCCAATCCCTCCCCCTGA (配列番号3)
(NCBI参照配列: XM_006941587.2)
ATGGGCAATGCGCAGGAGCGGCCCTCAGAGACGATCGATCGCGAGCGGAAACGCCTAGTGGAGACGCTGCAGGACGACTCCGGGCTGCTGCTGGATGCACTGCTGGCGCGCGGCGTGCTCACCGGGCCTGAGTATGAGGCGTTGGACGCGCTGCCTGATGCCGAGCGCAGGGTGCGTCGCCTGCTGCTGCTGGTACAAAGCAAGGGCGAGGCCGCCTGCCAGGAGCTGCTGCACTGCGCCCAGCGTACTACGCGCGCGCCAGACCCGGCCTGGGACTGGCAGCACGTGGGCACTGGCTACCGGGAACGCAGCTACGACTCTCCATGCCCTGGCCACTGGACGCCTGAGGCACCTGACTTGAGGACCGCTTGCCCCGAAACGCCCAGAGCTTCAGACTGCGACGAGGCTGGGGTTTCAGGGGGCTCGGAGGCAGTATCCGGAACCCTCGAGGAACTCGATCCGGAAGTGGAAGCTGAAGTCTCTGAAGGGGCTGAGCCAGAGCCAGAGCCAGAGCCCGACTTTGAGGCGGGTGATGAGTCTGAAGATTCC (配列番号4)
本発明のいくつかの側面は、心臓疾患の遺伝子治療のために使用され得る組換えAAVベクターに関する。本明細書に使用されるとき、用語「ベクター」は、核酸ベクター(例として、プラスミドまたは組換えウイルスゲノム)、野生型AAVゲノム、またはウイルスゲノムを含むウイルスを指し得る。
さらに本明細書に提供されるのは、rAAV粒子またはかかる粒子を含有するrAAV調製物である。rAAV粒子は、本明細書に記載のウイルスカプシドおよびrAAVベクターを含み、これは、ウイルスカプシドによってカプシド化される。rAAV 粒子を生成する方法は、当該技術分野において知られており、および、市販されている(例として、Zolotukhin et al., Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28 (2002) 158-167;および米国特許出願公開番号US2007/0015238およびUS2012/0322861を参照のこと、これらは参照により本明細書に組み込まれる;ならびにプラスミドおよびキットは、ATCCおよびCell Biolabs, Inc.から入手可能である)。
本発明はまた、開示されたrAAV粒子または調製物の1以上を含む組成物に関する。いくつかの態様において、rAAV調製物は、第一の血清型(例として、AAV3、AAV5、AAV6、またはAAV9)のITRを含有するrAAVベクターおよびrAAVベクターをカプシド化するカプシドタンパク質を含むrAAV粒子を含む。いくつかの態様において、カプシドタンパク質は、第一の血清型(例として、AAV3、AAV5、AAV6、またはAAV9)のものである。いくつかの態様において、調製物は、AAV2 ITRを含有するrAAVベクターを使用して調製された調製物と比較して、(例として、Huh7などのヒト肝細胞がん細胞株において)、少なくとも4倍高い形質導入効率を有する。
いくつかの側面において、本発明は、1以上の心臓状態(例として、心筋症、肥大型 心筋症、拡張型心筋症、心不全、心臓疾患、等々)を処置する際に有用な組成物および方法を提供する。いくつかの態様において、本願によって提供される組成物は、心臓への複数回の直接注射を介して、対象に提供することができる。対象に提供することができる例示のAAV構築物は、図1に描写される。ある態様において、かかる例示の構築物は、組換えAAV(例として、AAV6)によってカプシド化され、および、1以上の心臓状態(例として、心筋症)の2つの別々の側面に取り組むために、S100カルシウム結合タンパク質A1(S100A1)およびカスパーゼ動員ドメインを有するアポトーシスリプレッサー(ARC)の種特異的コード配列を含む。図1における例示的な構築物の両方の導入遺伝子は、心臓TnTプロモーターによって駆動され、およびよって心筋細胞においてのみ発現するだろう。
拡張型心筋症(DCM)は、イヌにおける後天性心臓疾患の第二の最も一般的な原因であり、最も一般的にはドーベルマン・ピンシェル、グレート・デーンおよびアイリッシュ・ウルフハウンドなどの大型犬種に影響する。この疾患に罹患したヒトにおいて、心臓移植および左心室補助デバイスなどの外科手術選択肢が存在する。しかしながら、獣医学において、唯一の治療的選択肢は、心不全に関連する兆候の医療管理である。罹患したイヌの予後は、疾患の段階および品種に依存する。例えば、ほとんどのドーベルマン・ピンシェルは、うっ血性心不全(CHF)の発症後6か月未満生存する。対照的にコッカー・スパニエルなどの他の品種は、それより長く生存する傾向がある。心臓疾患が進行するにつれて、心臓細胞内のカルシウム移動を調節するチャネルの機能障害は、カルシウム循環異常、さらに心臓の収縮および弛緩の機能障害を促進する。注目すべきことに、カルシウム輸送異常は、天然に存在するDCM5を有するイヌにおいて認識されており、および、多くの異なる病理学に続発する心不全とともに発生する。
S100A1/ARC自己相補的なベクターの心臓AAV遺伝子送達は、デュシェンヌ型筋ジストロフィー(ジストロフィン欠乏症)のマウスおよびイヌモデルにおいて査定された。以前には、AAV8(その複数のバリアントを包含する)、AAV9、およびAAVrh.10血清型は、イヌ心臓に感染するそれらの能力について比較され、およびAAVrh.10は、最も効率的であると見出された。この理由のために、AAVrh.10は、この例において記載されるすべての実験のために使用された。
2匹のドーベルマン・ピンシェル対象は、今日までに、AAVrh.10−S100A1/ARCで処置され、ここで、両方のイヌは、処置の時点で心不全を経験していた。最初のイヌは、処置の時点で死に近く、10%のみの心臓駆出率を呈した。処置後24時間以内に、駆出率は、25%まで改善した(データは示さず)。処置後4か月での、イヌの最初の経過観察訪問において、駆出率は、26%で着実に維持されていた。この対象は、処置後5か月でも依然として生存していた。
これらの予備知見に基づき、AAVrh.10−S100A1/ARC処置は、イヌにおける心臓機能を正常範囲まで回復することができる。
数個の本発明の態様が、本明細書に記載され、および、説明されているが、当業者は、本明細書に記載の、機能を実施するための、および/または、結果および/または1以上の利点を得るための、様々な他の手段および/または構造を容易に心に描くだろう。および、かかるバリエーションおよび/または改変の各々は、本明細書に記載の本発明の態様の範囲内であるとみなされる。より一般的には、当業者は、本明細書に記載のすべてのパラメータ、寸法、材料、および配置は、例示的であることを意味すること、および、実際のパラメータ、寸法、材料および/または配置は、本発明の教示が使用される特定の出願(単数または複数)に依存するだろうということを、容易に理解するだろう。
本明細書に開示の、すべての参考文献、特許および特許出願は、各々が引用される主題に関して、参考により援用され、いくつかのケースにおいて、文献全体を包含し得る。
不定冠詞「a」および「an」は、本明細書および請求項に使用されるとき、それとは反対であることが明確に表されない限り、「少なくとも1の」を意味すると理解されるべきである。
Claims (25)
- 対象の心臓に2以上の導入遺伝子を送達するための組換えアデノ随伴ウイルス(rAAV)核酸ベクターであって、該ベクターは、5’から3’の順に、第一のアデノ随伴ウイルス(AAV)逆方向末端反復(ITR)配列、2以上の導入遺伝子および2以上の導入遺伝子に操作可能に連結されたプロモーター、ポリアデニル化シグナル、および第二のAAV逆方向末端反復(ITR)配列を含み、ここで2以上の導入遺伝子は、S100ファミリータンパク質およびアポトーシスインヒビターを含む、前記組換えアデノ随伴ウイルス(rAAV)核酸ベクター。
- S100ファミリータンパク質が、心臓S100カルシウム結合タンパク質A1 (cS100A1)またはそのバリアントである、請求項1に記載のrAAVベクター。
- アポトーシスインヒビターが、カスパーゼ動員ドメインを有する心臓アポトーシスリプレッサー(cARC)またはそのバリアントである、請求項1または2に記載のrAAVベクター。
- 配列内リポソーム進入部位(IRES)が、cS100A1導入遺伝子とcARC 導入遺伝子との間に存在する、請求項2または3に記載のrAAVベクター。
- 導入遺伝子が、種特異的である、請求項1〜4のいずれか一項に記載のrAAVベクター。
- プロモーターが、心臓に限局的なプロモーターである、請求項1〜5のいずれか一項に記載のrAAVベクター。
- 心臓に限局的なプロモーターが、α−ミオシン重鎖遺伝子、6−ミオシン重鎖遺伝子、ミオシン軽鎖2v遺伝子、ミオシン軽鎖2a遺伝子、CARP遺伝子、心臓α−アクチン遺伝子、心臓m2ムスカリン性アセチルコリン遺伝子、ANF、心臓トロポニンC、心臓トロポニンI、心臓トロポニンT(cTnT)、心筋小胞体Ca−ATPアーゼ遺伝子、および骨格筋α−アクチンからなる遺伝子の群、およびMLC−2v遺伝子に由来する人工心臓プロモーターから選択される、請求項6に記載のrAAVベクター。
- 心臓に限局的なプロモーターが、cTnTである、請求項6または7に記載のrAAVベクター。
- AAVカプシド中にカプシド化された、請求項1〜8のいずれか一項に記載のrAAVベクターを含むrAAV粒子。
- AAVカプシドが、AAV1、AAV2、AAV3、AAV6、AAV8、またはAAV9血清型に由来するカプシドタンパク質を含む、請求項9に記載のrAAV粒子。
- AAVカプシドが、AAVrh.10血清型に由来するカプシドタンパク質を含む、請求項9に記載のrAAV粒子。
- 請求項9〜11のいずれか一項に記載のrAAV粒子を含む組成物。
- 請求項12に記載の組成物または請求項9〜11のいずれか一項に記載のrAAV粒子を対象に投与することを含む、心臓疾患を患う対象の処置の方法。
- 心臓疾患が、対象において心不全を引き起こすものである、請求項13に記載の方法。
- 心臓疾患が、心筋症である、請求項13または14に記載の方法。
- 心臓疾患が、肥大型心筋症または拡張型心筋症である、請求項13〜15のいずれか一項に記載の方法。
- 心臓疾患が、急性虚血である、請求項13または14に記載の方法。
- 組成物が、対象の心臓に注射を介して投与される、請求項13〜17のいずれか一項に記載の方法。
- 組成物の投与が、対象の心臓における2以上の導入遺伝子の発現を結果として生じる、請求項13〜18のいずれか一項に記載の方法。
- 対象が、哺乳動物である、請求項13〜19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20に記載の方法。
- 哺乳動物が、伴侶動物である、請求項20に記載の方法。
- 伴侶動物が、イヌまたはネコである、請求項22に記載の方法。
- S100ファミリータンパク質を含む導入遺伝子が、アポトーシスインヒビターを含む導入遺伝子の5’側に位置する、請求項1〜8のいずれか一項に記載のrAAVベクター。
- アポトーシスインヒビターを含む導入遺伝子が、S100ファミリータンパク質を含む導入遺伝子の5’側に位置する、請求項1〜8のいずれか一項に記載のrAAVベクター。
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