JP2019521692A - アルデヒドデヒドロゲナーゼ欠損症の治療のための遺伝子治療 - Google Patents
アルデヒドデヒドロゲナーゼ欠損症の治療のための遺伝子治療 Download PDFInfo
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Abstract
Description
本特許出願は、2016年7月26日に出願された米国仮特許出願番号第62/367,012号(参照により本明細書に取り込まれる)についての利益を主張する。
本明細書と同時に提出され、以下の通り識別される、コンピューターで読み取り可能なヌクレオチド/アミノ酸の配列表は、参照により、その全体が本明細書に取り込まれる:2016年7月26日付作成の「725826_ST25.TXT」という名前の13,873バイトのASCII(テキスト)ファイル1件。
アルデヒドデヒドロゲナーゼ (ALDH)は、内在的及び外来の両方のソースのアルデヒドの代謝において重要な役割を果たす、酵素のスーパーファミリーに属する。生理学的及び毒物学的な機能を有する、19個の機能的なALDH遺伝子が、ヒトゲノムにおいて同定されている(Edenberg HJ, Alcohol Res Health 2007, 30(1):5-13;Steinmetz CGら、Structure 1997, 15:5(5):701-11)。アセトアルデヒドを酸化する重要な酵素である、アルデヒドデヒドロゲナーゼ2(ALDH2)は、アルコール代謝のために重要である。広範囲の民族グループの間で、ヒトALDH2の遺伝子多型が良く研究されている(Eriksson CJ, Alcohol Clin Exp Res 2001, 15S-32S;Yoshidaら、Proc. Natl. Acad. Sci 1984, 81(1):258-261)。最も現実問題となるALDH2変異体はALDH2*2アレルであり、東アジア人の約35〜45%において見出される(Yoshidaら、Proc. Natl. Acad. Sci 1984, 81(1):258-261;Li Hら、Ann Hum Genet 2009, 73:335-345)。世界人口のうち約5億6千万人(8%)は、この変異を有しており、それによりALDH2*2は、他の良く知られているヒトの酵素病やヘモグロビン異常を上回って、最もありふれたヒト酵素欠損症となっている(Brooks PJら、PLoS Med 2009, 6(3):e50;Chen CHら、Physiol Rev 2014, 94(1):1-34)。様々な研究によって、ALDH2機能障害が、気道消化器がん、心血管疾患、糖尿病及び神経変性疾患を含む複数のヒトの疾患と結びつけられている(Mandel Sら、Ann NY Acad Sci 2005, 1053:356-375;Kamino Kら、Biochem. Biophys. Res. Commun 2000, 273:192-96;Wang Bら、J. Neurol. Sci 2008, 268:172-75;Murata Cら、Alcohol. Clin. Exp Res 2000, 24:5S-11S;Xu Fら、Hypertens. Res 2010, 33:49-55;Yokoyama Aら、Cancer Epidemiol. Biomarkers Prev 1996, 5:99-102;Oze Iら、Jpn. J. Clin. Oncol 2011, 41:677-92;Takagi Sら、Hypertens. Res 2002, 25:677-81;Jo SAら、Clin. Chim. Acta 2007, 382:43-47;Xu Fら、J. Cell. Mol. Med 2011, 15:1955-62;Takeuchi Fら、Eur. J. Hum. Genet 2012, 20:333-40;Wang Qら、DNA Cell Biol 2013, 32:393-99;Asakage Tら、Carcinogenesis 2007, 28:865-874;Ding JH,ら、World J Gastroenterol 2009, 15:2395-2400;Cui Rら、Gastroenterology 2009, 137:1768-75;Li Yら、J Clin Invest 2006, 116:506-511;Chen Zら、Proc Natl Acad Sci 2005, 102:12159-12164;Mackenzie ISら、Arterioscler. Thromb. Vasc. Biol 2005, 25:1891-95;Kato Nら、Nat Genet 2011, 43:531-538;Chen CHら、Cardiovasc Res 2010, 88(1):51-7)。
本発明は、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターを含むベクターを提供する。本発明はまた、哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症を治療するため、又は哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症によって特徴付けられる疾患若しくはその任意の症状を治療若しくは予防するためのベクターを含む組成物及び該ベクターの使用方法も提供する。
本発明は、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターを含む、本質的にそれからなる、又はそれからなるベクターを提供する。本発明のベクターが、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターから本質的になる場合、ベクターに物質的に影響しない追加の構成要素(例、例えば、ポリ(A)配列又はin vitroでのベクターの操作を促進する制限酵素部位等の遺伝的要素)が含められ得る。該ベクターが、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターからなる場合、該ベクターは、追加の構成要素(即ち、ベクターに内在しておらず、核酸配列の発現をもたらすため、それによってタンパク質を提供するために必要とされない構成要素)を何ら含まない。
本実施例は、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターを含むベクターの開発について実例で示す。
発現カセットは、AAV2逆位末端反復(ITR)、キャプシド化シグナル(encapsidation signal)(Ψ)、ヒトALDH2 cDNA配列に作動可能に連結されたサイトメガロウイルス(CMV)エンハンサー、ニワトリβ-アクチンプロモーター(CAGプロモーター)及びウサギβ-グロビンポリアデニル化シグナルからなる(図1A)。マウスALDH2タンパク質からADLH2 cDNAを識別するために、C末端にヘマグルチニン(HA)タグを有するALDH2 cDNA配列を構築した。mRNAの安定性を増大させるため、及び突然変異体mRNAによるトランス阻害の可能性を低減するために、ALDH2 cDNAを最適化した。ALDH2 cDNAを、ヒトにバイアスするコドンを使用し、以下:mRNA不安定化エレメント;低(<30%)又は高(>80%)GC領域;コード領域内の翻訳開始配列;及び潜在的スプライシングシグナルの除去により、配列を最適化した。最適なコザックコンセンサスにより、最適化したALDH2 cDNAを合成した。
最適化した完全長ALDH2 cDNA配列を合成し、CAGプロモーター調節下のpAAVプラスミドにクローニングした。AAV-hALDH2プラスミドは、ベクターの複製のために必要なAAV2由来のAAV Repタンパク質、生成したAAVベクターの血清型を定義するAAVrh.10ウイルス構造(Cap)タンパク質VP1、2及び3;並びにE2、E4及びVA RNAのアデノウイルスヘルパー機能を有するプラスミドと共に、pAAV プラスミドを、ヒト胎児腎293T細胞(HEK 293T;アメリカンタイプカルチャーコレクション)に共トランスフェクションすることによって生成した。AAV-hALDH2-HAベクター(「AAVrh.10hALDH2」として言及される)を、イオジキサノール勾配及びQHP陰イオン交換クロマトグラフィーによって精製した。定量的TaqManリアルタイムPCR分析によってベクターゲノム力価を決定した。無関係なタンパク質をコードするベクターを、特定の発現研究のための対照として使用した。
AAVr.10hALDH2に管理された(directed)in vitroでのヒトALDH2タンパク質の発現を評価するために、HEK293T細胞をAAV-hALDH2プラスミドを用いてトランスフェクトするか、又はモックのトランスフェクトを行い、上清を72時間後に回収した。上清中のヒトALDH2発現を、SDS-PAGE及び抗HA 抗体を用いたウェスタン分析によって評価した。図1Bに示すように、細胞の培養上清においてヒトALDH2を検出した。本実施例の結果は、AAVベクターに由来するALDH2の発現を示している。
AAVrh.10hALDH2に管理されたin vitroでのヒトALDH2タンパク質の発現に由来するALDH2のテトラマー形成を評価するために、HEK293T細胞を、AAVrh.10hALDH2ベクター又は対照のAAVrh.10-hα1ATベクターを用いて感染させ、上清を72時間後に回収した。上清中のヒトALDH2テトラマー形成を、SDS-PAGE及び抗HA 抗体を用いたウェスタン分析によって評価した。図1Cに示すように、細胞の培養上清においてヒトALDH2のテトラマーを検出した。本実施例の結果は、AAVベクターに由来するALDH2の発現により、ALDH2のテトラマーが形成されることを示している。
本実施例は、ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターを含むベクターの長期間のin vivoでの発現について実証する。
AAVrh.10hALDH2ベクターを用いた単回での処置後、ヒトALDH2の長期間のin vivoでの血清中での発現を評価するために、約100μlの体積での静脈内注射により、1011ゲノムコピー(gc)のAAVrh.10hALDH2ベクター、AAVrh.10-hα1ATベクター(対照ベクター)又はリン酸緩衝生理食塩水(PBS)を、C57Bl/6雄性及び雌性マウスに投与した(1グループ当たりn=4)。ベクター投与の2週間後、肝臓のホモジェネートから全RNA及びタンパク質を単離し、qPCRによってhALDH2 mRNAの発現を分析し、抗HA抗体を使用したウェスタンによってタンパク質の発現を分析した。
図2A及び2Bに示すように、高レベルのhALDH2 mRNA(1μgの全RNA当たり、6.58±2.2×104(雄性)及び1.25±5.4×104(雌性)のmRNAコピー)、並びに高レベルのhALDH2タンパク質を、AAVrh.10hALDH2を受容した動物中において検出した。
これらのデータは、ALDH2のAAVベクター媒介性の発現により、単回での投与で長期間のALDH2の発現がもたらされること(that that)を実証する。
本実施例は、AAVrh.10hALDH2を、ALDH2欠損症のマウスモデルに投与することにより、エタノールが関連する毒性から保護されることについて実証する。
AAVrh.10hALDH2ベクターから発現したALDH2のin vivoでの活性を評価するために、ヒトALDH2*2アレルに相当するE487K変異を有するALDH2*2マウス(Zambelliら、Sci Trans Med., 6:251ra118 (2014);Jinら、PNAS, 112:9088-9093 (2015))に、1011 ゲノムコピー(gc)でのAAVrh.10hALDH2の単回の静脈内注射、又は1011 ゲノムコピーでのAAVrh.10-GFP(対照)の単回の静脈内注射を施した(1グループ当たりn=2、雄性1匹/雌性1匹)。
ベクター投与の2週間後、胃内強制飼養によって、エタノール(4 g/kg)をマウスに投与した。投与の6時間後、マウスは、高い血中アルコール含有量を示し、それは24時間までにバックグラウンド近傍にまで低下した(データ非表示)。平均台テスト(落下までの時間)(Carterら、Current Protocols Neuroscience, Chapter 8:Unit 8 (2001))によって、投与24時間後の行動を評価した。
図3に示すように、AAVrh.10hALDH2で処置した雄性及び雌性マウスは、割り当て時間(即ち、60秒)の間ずっと平均台上に残った一方で、対照ベクターを投与したマウスは、より早い時間で平均台から落下した。
これらのデータは、AAVrh.10hALDH2ベクターから発現したALDH2は、in vivoにおいて活性があり、エタノール関連の毒性に対して保護し得ることを実証する。
Claims (25)
- ヒトアルデヒドデヒドロゲナーゼをコードする核酸配列に作動可能に連結したプロモーターを含むベクター。
- 前記ベクターがアデノ随伴ウイルス(AAV)、アデノウイルス、レンチウイルス、レトロウイルス及びプラスミドからなる群から選択される、請求項1に記載のベクター。
- 前記ベクターがAAVベクターである、請求項2に記載のベクター。
- 前記AAVベクターが非ヒトアデノ随伴ウイルスである、請求項3に記載のベクター。
- 前記非ヒトアデノ随伴ウイルスがアカゲザル・アデノ随伴ウイルスである、請求項4に記載のベクター。
- 前記アカゲザル・アデノ随伴ウイルスがアデノ随伴ウイルス血清型rh.10である、請求項5に記載のベクター。
- 前記プロモーターが構成的に活性があるプロモーターである、請求項1に記載のベクター。
- 前記プロモーターが細胞の種類に特異的なプロモーターである、請求項1に記載のベクター。
- 前記プロモーターが誘導性プロモーターである、請求項1に記載のベクター。
- 前記構成的に活性があるプロモーターがニワトリベータアクチンプロモーターである、請求項7に記載のベクター。
- 前記ヒトアルデヒドデヒドロゲナーゼがヒトアルデヒドデヒドロゲナーゼ2(ALDH2)である、請求項1に記載のベクター。
- 前記ベクターが、ヒトアルデヒドデヒドロゲナーゼ配列をコードする核酸配列に作動可能に連結されたミトコンドリア局在配列をコードする核酸配列を更に含む、請求項1に記載のベクター。
- 前記ベクターが、配列番号1をコードする、請求項1に記載のベクター。
- 前記ベクターが、配列番号3をコードする、請求項12に記載のベクター。
- 請求項1〜14のいずれか一項に記載のベクター及び医薬的に許容される担体を含む組成物。
- 哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症を治療する方法、又は哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症によって特徴付けられる疾患若しくはその任意の症状を治療若しくは予防する方法であって、前記方法が、請求項1〜14のいずれかに記載のベクターを哺乳動物に投与することを含む、方法。
- 前記哺乳動物がヒトである、請求項16に記載の方法。
- 前記哺乳動物がALDH2*2アレルに関してヘテロ接合性又はホモ接合性である、請求項17に記載の方法。
- 前記哺乳動物が、エタノール毒性、上部呼吸器/消化管のがん、骨粗鬆症、扁平上皮がん、ファンコニ貧血、パーキンソン病、アルツハイマー病、脳卒中、高血圧、心不整脈、心筋梗塞及びニトログリセリン不耐症からなる群から選択される、アルデヒドデヒドロゲナーゼの欠損症によって特徴付けられる疾患を患っている、請求項16〜18のいずれかに記載の方法。
- 前記ベクターが、約30日以内に1回以下で哺乳動物に投与される、請求項16〜19のいずれかに記載の方法。
- 前記ベクターが、口腔内、筋肉内、経皮、静脈内、動脈内、皮下、皮内又は腹腔内投与により投与される、請求項16〜20のいずれか一項に記載の方法。
- 哺乳動物のアミノ酸配列又は核酸配列を分析すること、及び哺乳動物におけるALDH2タンパク質の残基487がグルタミンでない場合に哺乳動物を治療のために選択することを更に含む、請求項16〜21のいずれかに記載の方法。
- 残基487のアミノ酸がリジンである場合に、被検体が治療のために選択される、請求項22に記載の方法。
- 哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症を治療するための、又は哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症によって特徴付けられる疾患若しくはその任意の症状を治療若しくは予防するための、請求項1〜14のいずれかに記載のベクター又は請求項15に記載の組成物。
- 哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症を治療するための医薬、又は哺乳動物におけるアルデヒドデヒドロゲナーゼ欠損症によって特徴付けられる疾患若しくはその任意の症状を治療若しくは予防するための医薬を調製するための、請求項1〜14のいずれかに記載のベクター又は請求項15に記載の組成物の使用。
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WO2017106354A1 (en) * | 2015-12-14 | 2017-06-22 | The Trustees Of The University Of Pennsylvania | Adeno-associated viral vectors useful in treatment of spinal muscular atropy |
CN109069668B (zh) * | 2015-12-14 | 2023-04-18 | 宾夕法尼亚州大学信托人 | 用于眼病的基因疗法 |
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WO2018022783A1 (en) | 2018-02-01 |
EP3490613A1 (en) | 2019-06-05 |
JP2022116045A (ja) | 2022-08-09 |
AU2017301819A1 (en) | 2019-02-07 |
CN109952114A (zh) | 2019-06-28 |
US20190160187A1 (en) | 2019-05-30 |
KR20190038583A (ko) | 2019-04-08 |
SG10202100632WA (en) | 2021-03-30 |
EP3490613A4 (en) | 2020-03-04 |
JP7165357B2 (ja) | 2022-11-04 |
SG11201900543SA (en) | 2019-02-27 |
KR102621134B1 (ko) | 2024-01-04 |
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