JP2019513389A - 筋ジストロフィーを治療するためのマイクロrna−29のアデノ随伴ウイルスベクター送達 - Google Patents
筋ジストロフィーを治療するためのマイクロrna−29のアデノ随伴ウイルスベクター送達 Download PDFInfo
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Abstract
Description
本発明は、マイクロRNA miR−29を発現するアデノ随伴ウイルス(AAV)ベクターなどの遺伝子治療ベクター、ならびにこれらのベクターを使用して、筋ジストロフィーに罹患している対象における線維症を低減および予防する方法、ならびに筋線維を損傷から保護し、筋肉強度を増加させる方法を提供する。
運動および呼吸等の日常活動、ならびに全身代謝のための筋肉量および強度の重要性は疑う余地がない。筋機能の障害は、筋肉の衰弱および消耗を特徴とし、生活の質に重大な影響を与える筋ジストロフィー(MD)を生じる。最もよく特徴付けられたMDは、ジストロフィン関連タンパク質複合体(DAPC)のメンバーをコードする遺伝子の突然変異から生じる。これらのMDは、DAPCによる筋鞘−細胞骨格テザリングの喪失に関連する膜の脆弱性に起因する。デュシェンヌ型筋ジストロフィー(DMD)は、5000人に1人の新生男児に影響を与える最も壊滅的な筋肉疾患の1つである。
複数の研究は、筋肉内での長期(1.5年超)の組換えAAV媒介タンパク質発現を実証している。Clark et al.,Hum Gene Ther,8:659−669(1997)、Kessler et al.,Proc Nat.Acad Sc.USA,93:14082−14087(1996)、及びXiao et al.,J Virol,70:8098−8108(1996)を参照されたい。Chao et al.,Mol Ther,2:619−623(2000)及びChao et al.,Mol Ther,4:217−222(2001)も参照されたい。さらに、筋肉が高度に血管新生されるため、組換えAAV形質導入により、Herzog et al.,Proc Natl Acad Sci USA,94:5804−5809(1997)及びMurphy et al.,Proc Natl Acad Sci USA,94:13921−13926(1997)に記載されるように、筋肉内注射後に体循環に導入遺伝子産物の出現がもたらされた。さらに、Lewis et al.,J Virol,76:8769−8775(2002)は、骨格筋線維が、正しい抗体グリコシル化、折り畳み、及び分泌に必要な細胞因子を有することを実証し、筋肉が分泌タンパク質治療薬を安定して発現することができることを示す。
DMDおよび他の筋ジストロフィーに苦しむ患者の機能改善には、遺伝子修復および線維症の減少の両方が必要である。DMDおよび他の筋ジストロフィーのより効果的な治療のための遺伝子回復法で修復され得る線維症を低減する方法が必要とされている。miR29は、筋線維症を低減するための潜在的な遺伝子調節因子であり、理想的な候補である。
本発明の組換えAAVゲノムは、本発明の核酸分子及び核酸分子に隣接する1つ以上のAAV ITRを含む。rAAVゲノム中のAAV DNAは、AAV血清型AAV−1、AAV−2、AAV−3、AAV−4、AAV−5、AAVを含むがこれらに限定されない組換えウイルスが誘導され得る任意のAAV血清型−6、AAV−7、AAV−8、AAV−9、AAV−10、AAV−11、AAV−12およびAAV−偽型rAAVの産生は、例えばWO 01/83692に開示されている。他のタイプのrAAV変異体、例えば、カプシド変異を有するrAAVも企図される。例えば、Marsic et al.,Molecular Therapy,22(11):1900−1909(2014)を参照されたい。上記の背景部分に記載されるように、様々なAAV血清型のゲノムのヌクレオチド配列が、当該技術分野において既知である。骨格筋特異的発現を促進するために、AAV1、AAV6、AAV8またはAAVrh.74を使用することができる。
デュシェンヌ型筋ジストロフィーモデルの確認
mdxマウスは、DMD病因を研究するための便利であるがまだ不完全な動物モデルを提供する。このモデルは、mdxマウスとユートロフィン遺伝子のヘテロ接合型ノックアウトとの交配(mdx:utrn+/−)であり、増加した線維症を呈し、ヒトDMDの病理をより忠実に再現する。Mdxマウスは、比較的軽度の表現型およびほぼ正常な寿命をもたらすDMDのエクソン23にナンセンス変異を有する。3週齢までに、mdxマウスの横隔膜および四肢筋肉は、内腔内炎症の徴候を発現する。これらの症状は、マウスが成人期に達した後に四肢筋肉に陥り、一方、横隔膜筋肉の炎症は徐々に悪化し続ける。テロメラーゼを欠くmdxマウスでは、筋ジストロフィーは年齢と共に次第に悪化する。ユートロフィン(DKO)を欠くmdxマウスは、早期発症筋力低下、重度の線維症および早期死を伴うヒトDMDのより特徴的な表現型を有する。ジストロフィンの常染色体パラログであるウトロフィンは、二重KO(ジストロフィン+ユートロフィン)のmdxマウスにおけるジストロフィンの欠如を補う高度の配列相同性を共有する。早期死亡を伴う重度の表現型が観察される。DKOマウスの早すぎる死は炎症および線維症の進行を妨げるが、mdx:utrn+/−マウスは線維症の顕著な程度を示すヒト疾患と類似のモデルを提示し、DKOよりも生存期間が長く、より良い我々の提案する翻訳研究のためのモデル。最近の報告では、mdx:utrn+/−マウスの使用がDMDとの関連で線維症を研究する理想的なモデルであることが確認されています。本研究では、シリウスレッド染色で測定した線維化の増加は、コラーゲン転写産物レベルの増加およびmir29cレベルの減少を伴う。
DMDマウスへのmiR29の送達は線維症を低減する
予備研究は、ヒトDMD患者およびmdx/utrn+/−マウスにおいて、コラーゲンについてのシリウスレッド染色の有意な増加およびmiR−29cレベルの減少があることを実証している。筋肉特異的AAVベクターを用いたmiR−29の遺伝子送達は、潜在的に安全かつ効率的である。本明細書においてrAAVrh.74.CMV.miR29cと称するrAAVベクターを生成するために、22ヌクレオチドのmiR29c配列(標的鎖配列番号3およびガイド鎖配列番号4)を、miR−30スカフォールドにクローニングした。CMVプロモーター。発現カセット(配列番号2)を自己相補的AAVプラスミドにクローニングし、筋肉でよく発現することが知られている血清型AAVrh.74を用いてパッケージングした。miR−29c cDNAは、miR−30c標的(センス)鎖、miR−30ステムループおよびmiR−30cガイド(アンチセンス)鎖をmiR−30骨格に含むカスタムプライマーを用いて合成した。miR−29c配列の3つの塩基が改変された。次いで、この配列を、CMVプロモーターおよびポリA配列によって駆動される自己相補的AAV ITR含有プラスミドにクローニングした。
MiR−29cの注射はコラーゲンを減少させ、miR−29cを回復させる
rAAVrh.74.CMV.MiR−29cが線維症を減少させることができるかどうかを判定するために、12週齢のmdx/utrn+−マウスに、rAAVrh.74.CMV.MiR−29cを左腓腹筋に5×1011vgsで筋肉内注射した(GAS)筋肉。注射後12週目にマウスを分析した。ピクロシリウスレッド染色は、未治療反対側mdx/utrn+/−GAS筋と比較して、GAS筋(図2a)全体にわたるコラーゲン染色の有意な減少を明らかにした。picrosirius赤色染色の定量化は、治療された筋肉が未処理の筋肉(処置−23.3%±1.3対未処置−29.5%±0.7)と比較して、コラーゲンの18.3%の減少を有することを示す(図2b)。被治療筋肉におけるmiR−29cの過剰発現を確認するために、24週齢のWT、miR−29c治療マウス、およびmdx/utrn+/−マウスからのGAS筋から全RNAを抽出し、miR−29c発現についての定量逆転写PCR(qRT−PCR)分析に供した。結果は、未治療マウスと比較して、被治療マウスのGAS筋においてmiR−29cが有意に増加したことを示した(図2d)。
MiR−29cは絶対および比筋力を改善するが、収縮誘発性損傷に対して保護しない
線維化が筋肉機能に影響を与えることが分かっているので、我々は、MiR−29cの発現を増加させることによって線維化を減少させることにより、収縮誘発性損傷からmdx/utrn+/−筋肉を保護し、rAAVrh.74.CMV.MiR−29cで処置したmdx/utrn+/−マウスからの腓腹筋の機能特性を評価した。注射の12週間後、GASを単離してインビボ力測定を行った。
マイクロジストロフィンとの同時送達は線維症をさらに低減する
miR−29c/マイクロジストロフィン併用遺伝子治療アプローチが線維症を減少させる上でより有益であるかどうかを決定するために、12週齢のmdx/utrn+/−マウスは、rAAVrh.74.CMV.MiR−29cを5x1011で筋肉内注射した左腓腹筋のVGS。以下の遺伝子治療ベクターを、3ヶ月齢のmdx/utrn+/−マウス、DMDマウスモデル:scAAVrh.74.CMV.miR−29c単独の左腓腹筋(GAS)筋肉への筋肉内注射(IM)によって投与したrAAVrh.74.MCK.micro−ジストロフィンおよびrAAVrh.74.MCK.micro−ジストロフィン単独で送達される。
絶対力のさらなる増加および収縮誘発性損傷からの保護の追加
miR−29で処理された筋肉が絶対力および比重の中程度ではあるが有意な増加を有することを知って、miR−29cの過剰発現および筋ジストロフィン遺伝子置換の筋肉機能への影響を調べた。注射から12週間後、インビボでの力測定を行ったGASを単離した。実施例2で上記したrAAVrh.74.MiR−29cベクターとrAAV
併用療法は筋肥大および過形成を増加させる
マイクロジストロフィンと同時送達されたMiR−29cは、3ヶ月齢で単独で注射されたいずれか一方と比較して、被注射腓腹筋の全重量を増加させた(図8、図9a)。筋肉量の増加の原因を調べるために、筋線維直径を測定する。miR−29c/μ−dys併用治療は、平均線維サイズの増加を示した。mdx/utrn+/−対照をmiR−29c/μ−dys治療mdx/utrn+/−と比較して、平均直径は25.96〜30.97μmに増加した(図9b)。同時送達は野生型線維サイズ分布へのシフトをもたらした(図9c)。平均繊維サイズが増加しても、総筋肉重量の約30%の増加は説明されない。筋肉の全断面積も測定した。すべての群からのガストロム筋肉をフルスライドスキャンし、総面積を測定した。マイクロジス/miR−29cで併用治療された筋肉は、未治療およびいずれかの単剤治療と比較して断面積の有意な増加を有した(未注射:24.6対miR−29c:26.3対マイクロジス:26.6対マイクロジス/miR−29c:33.1)(図8、図9d)。
早期併用治療は線維症を予防する
DMDの予防的治療としてのコンビナトリアルmiR−29cおよびマイクロジストロフィンの潜在的重要性を考慮して、より若いmdx/utrn+/−マウスのコホートを4週齢で処置した。本明細書に記載の他の群と同じパラダイムを用いて、以下の処置をGASの筋肉内注射による線維症予防の有効性について比較した:scAAVrh.74.CMV.miR−29c単独、ssAAVrh74.MCK.micro−ジストロフィン+ scAAVrh。同じ用量で74.CMV.miR−29c併用療法、またはssAAVrh74.MCK.micro−ジストロフィン単独で投与した。注射の12週間後にマウスを剖検した。未治療反対側mdx/utrn+/−GAS筋と比較して、すべての被治療群においてGAS筋全体にわたるコラーゲン染色の有意な減少が観察された(図10A)。ピクロシリウスレッド染色の定量化は、マイクロジストロフィン/miR−29cで併用治療された筋肉が未治療筋肉と比較してコラーゲンの51%減少を有したことを示し(被治療−11.32%±1.18対未治療−23.15%±0.90)(p<0.0001)(図10)、pRT−PCRは、コンビナトリアル療法後にCol1A、Col3A、Fbn、およびTGF−β1の減少を確認した(図10DおよびE)。
早期併用療法は後期治療よりも良好に力を回復し、収縮誘発性損傷から保護する
インビボ力測定を、実施例8に記載されているように併用療法で早期に治療されたマウスのGASについて行った。4週齢のmdx/utrn+/−マウスにおいて、miR−29c /マイクロジストロフィンを用いた併用療法は、未処理のmdx/utrn+/−マウスと比較した場合、絶対的な力において有意な改善を示し、野生型との差はなかった(共処理:2908±129.5mN対未処理:1639.4±116.9mN対野生型:3369.73±154.1mN)。比力もまた、コンビナトリアル療法後に野生型レベルまで正常化した(併用治療338.9±22.34mN/mm2対未治療184.3±13.42mN/mm2対WT364.3±7.79mN/mm2)(図11AおよびBならびに12)。
miR−29およびマイクロジストロフィンの筋特異的発現による治療は線維症およびECM発現を減少させた
miR29c配列および筋肉特異的プロモーターMCKを含むAAVベクターも生成し、マイクロジストロフィンを発現するAAVベクターとの併用療法として試験した。rAAV.MCK.miR29cと呼ばれるrAAVベクターを作製するために、22ヌクレオチドのmiR29c配列(標的鎖配列番号3およびガイド鎖配列番号4)を、MCKによって駆動されるmiR−30足場にクローニングしたプロモーター(配列番号11)。発現カセット(配列番号12)を一本鎖AAVプラスミドにクローニングし、筋肉でよく発現することが知られている血清型AAVrh74を用いてパッケージングした。miR−29c cDNAは、miR−30c標的(センス)鎖、miR−30ステムループおよびmiR−30cガイド(アンチセンス)鎖をmiR−30骨格に含むカスタムプライマーを用いて合成した。miR−29c配列の3つの塩基が改変された。次いで、この配列を、MCKプロモーターおよびポリA配列によって駆動されるプラスミドを含む一本鎖AAV ITRにクローニングした。
早期併用療法は後期治療よりも良好に力を回復し、収縮誘発性損傷から保護する
インビボ力測定を、実施例8および9に記載されているように、miR−29およびマイクロジストロフィンの筋特異的発現で早期に治療されたマウスのGASについて行った。4週齢のmdx/utrn+/−マウスにおいて、rAAV.MCK.miR−29c/およびマイクロジストロフィンを発現するrAAVを用いた併用療法は、未治療mdx/utrn+/−マウスと比較した場合、絶対力の有意な改善を示し、野生型との差はなかった(図15a)。比力もまた、併用療法後に野生型レベルまで正常化した(図15b)。
早期併用治療は筋肥大および過形成を増加させる
rAAVを発現するマイクロジストロフィンとrAAV.MCK.miR−29との同時送達は、注射後3ヶ月で単独で注射されたもの(図17a)と比較して、注射されたガストグの全体重量を増加させなかった。筋線維直径も測定した。miR−29c/マイクロジストロフィン併用治療は、平均線維サイズの増加を示した。mdx/utrn+/−対照とmiR−29c/マイクロジストロフィン処理mdx/utrn+/−を比較すると、平均直径は28.96から36.03μmに増加した(図17b)。同時送達は野生型線維サイズ分布へのシフトをもたらした(図17c)。miR−29c/マイクロジストロフィン併用治療における1mm2当たりの筋線維の数は、未治療マウスおよび野生型より有意に少なかった(図17d、***p<0.01、****p<0.0001)。
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Claims (32)
- miR−29cを発現する組換えAAVベクター。
- a)配列番号3および配列番号4のヌクレオチド配列、
b)配列番号2のヌクレオチド配列、
c)配列番号1のヌクレオチド配列、または
d)配列番号12のヌクレオチド配列を含む、請求項1に記載の組換えAAVベクター。 - 前記ベクターが、血清型AAV1、AAV2、AAV4、AAV5、AAV6、AAV7、AAVrh74、AAV8、AAV9、AAV10、AAV11、AAV12、またはAAV13である、請求項1または2に記載の組換えAAVベクター。
- 前記ポリヌクレオチド配列が、筋特異的制御要素に作動可能に連結される、請求項1〜3のいずれか1項に記載の組換えAAVベクター。
- 前記筋特異的制御要素が、サイトメガロウイルス(CMV)プロモーター、ヒト骨格アクチン遺伝子要素、心臓アクチン遺伝子要素、筋細胞特異的エンハンサー結合因子mef、筋クレアチンキナーゼ(MCK)、短縮MCK(tMCK)、ミオシン重鎖(MHC)、MHCK7、C5−12、マウスクレアチンキナーゼエンハンサー要素、骨格速筋トロポニンC遺伝子要素、遅筋心臓トロポニンC遺伝子要素、遅筋トロポニンI遺伝子要素、低酸素誘発性核因子、ステロイド誘発性要素、またはグルココルチコイド応答要素(gre)である、請求項4に記載の組換えAAVベクター。
- 前記筋特異的制御要素が、配列番号10、配列番号11または配列番号13のヌクレオチド配列を含む、請求項4または5に記載の組換えAAVベクター。
- 請求項1〜6のいずれか1項に記載の組換えAAVベクターを含む、組成物。
- 治療有効量の請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物を投与することを含む、筋ジストロフィーを治療する方法。
- 治療有効量の請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物を投与することを含む、筋ジストロフィーに罹患している対象における線維症を低減または予防する方法。
- 治療有効量の請求項1〜5のいずれか1項に記載の組換えAAVベクターまたは請求項6に記載の組成物を投与することを含む、筋ジストロフィーに罹患している患者における線維症を予防する方法。
- 治療有効量の請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物を投与することを含む、筋ジストロフィーに罹患している対象における筋力または筋肉量を増加させる方法。
- 前記筋ジストロフィーが、デュシェンヌ型筋ジストロフィーまたは肢帯型筋ジストロフィーである、請求項8〜11のいずれか1項に記載の方法。
- 前記組換えAAVベクターまたは前記組成物が、筋肉内注射により投与される、請求項8〜12のいずれか1項に記載の方法。
- 前記組換えAAVベクターまたは前記組成物が、全身投与される、請求項8〜12のいずれか1項に記載の方法。
- 前記組換えAAVベクターまたは前記組成物が、注射、注入、または移植によって非経口投与される、請求項14に記載の方法。
- 前記組成物の組換えAAVベクターが、前記対象において線維症が観察される前に、または前記対象において筋力が減少する前に、または前記対象において筋肉量が減少する前に投与される、請求項8〜15のいずれか1項に記載の方法。
- 筋ジストロフィーの治療のための、請求項1〜6のいずれか1項に記載の組換えAAVベクターを含む組成物。
- 筋ジストロフィーに罹患している対象における線維症を低減または予防するための、請求項1〜6のいずれか1項に記載の組換えAAVベクターを含む組成物。
- 筋ジストロフィーに罹患している対象における筋力を増加させるための、請求項1〜6のいずれか1項に記載の組換えAAVベクターを含む組成物。
- 静脈内注射用に製剤化される、請求項17〜19のいずれか1項に記載の組成物。
- 全身投与用に製剤化される、請求項17〜19のいずれか1項に記載の組成物。
- 注射、注入または移植による非経口投与のために製剤される、請求項21に記載の組成物。
- 前記組成物が、前記対象において線維症が観察される前に、または前記対象において筋力が減少する前に、または前記対象において筋肉量が減少する前に投与される、請求項17〜22のいずれか1項に記載の組成物。
- 筋ジストロフィーの治療用の薬剤の調製のための、請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物の使用。
- 必要がある対象における線維症の低減または予防用の薬剤の調製のための、請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物の使用。
- 筋ジストロフィーに罹患している対象における筋力または筋肉量の増加用の薬剤の調製のための、請求項1〜6のいずれか1項に記載の組換えAAVベクターまたは請求項7に記載の組成物の使用。
- 筋ジストロフィーがデュシェンヌ型筋ジストロフィーである、24〜26のいずれか1項に記載の使用。
- 前記薬剤が、筋肉内投与用に製剤化される、請求項24〜27のいずれか1項に記載の使用。
- 前記薬剤が、全身投与用に製剤化される、請求項24〜27のいずれか1項に記載の使用。
- 前記薬剤が、注射、注入または移植用に製剤化される、請求項29に記載の使用。
- 前記薬剤が、前記対象において線維症が観察される前に、または前記対象において筋力が減少する前に、または前記対象において筋肉量が減少する前に投与される、請求項24〜30のいずれか1項に記載の使用。
- 宿主細胞を請求項1〜6のいずれか1項に記載の組換えAAVベクターで感染させることと、前記宿主細胞において成熟miR−29ポリヌクレオチドを発現させることとを含む、成熟miR−29ポリヌクレオチド配列の産生方法。
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