JP2005522517A - 組み換えアデノ随伴ウイルスビリオンを使用したアミノ酸代謝に関与する酵素を搬送するための組成物、およびそのようなアデノ随伴ウイルスビリオンを用いてアミノ酸代謝疾患を治療するための使用方法 - Google Patents
組み換えアデノ随伴ウイルスビリオンを使用したアミノ酸代謝に関与する酵素を搬送するための組成物、およびそのようなアデノ随伴ウイルスビリオンを用いてアミノ酸代謝疾患を治療するための使用方法 Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
アデノ随伴ウイルスはデペンドウイルス(Dependovirus)属に属し、6つの既知の抗原型(AAV-1からAAV-6まで名付けられている)を有するパルボウイルスであり、他のウイルスには見られない魅力的な特徴を有している。例えばAAVは、非分裂細胞を含む広範囲の宿主細胞に感染できる。更にAAVは異なった種に由来する細胞に感染することができる。重要な事にAAVは如何なるヒト又は動物の疾患に関連しておらず、組み込みにより宿主細胞の生理学的な性質を変化させないようである。最後にAAVは、それ自身を産生、貯蔵、および輸送する要件へ導くことになる、広範囲の物理的及び化学的な条件において安定である。
本発明によると、代謝疾患を有している哺乳動物の被験体へ、遺伝子の使用および搬送のための方法とベクターが提供された。一つの態様においてその代謝疾患は、哺乳動物の被験体の血流中でのアミノ酸レベルが過剰となるアミノ酸代謝疾患である。他の態様においてそのアミノ酸代謝疾患により、哺乳動物被験体の尿中でアミノ酸またはアミノ酸代謝産物は過剰となる。好適な態様においてアミノ酸代謝疾患は芳香族アミノ酸代謝の異常から生じ、血中での芳香族アミノ酸レベルが過剰となる。他の態様において、過剰レベルの芳香族アミノ酸および/またはそれらの代謝物が哺乳動物被験体の尿中に存在する。特に好適な態様によると、芳香族アミノ酸代謝疾患は高フェニルアラニン血症、最も好適にはフェニルケトン尿症である。
i) アデノ随伴ウイルスベクターにより仲介された血液凝固因子IXの遺伝子輸送によるイヌ血友病Bの長期の修正。Herzog, R et al., Nature Medicine 5: 56-63, 1993.
ii) 非ヒト霊長類の筋肉への組み換えアデノ随伴ウイルス注入の急性および長期安全性。Favre, D et al. Molecular Therapy 4: 559-66, 2001.
iii) 技術評価:AAV因子IX遺伝子治療、Avigen Inc. Fabb, SA and Dickson, JG. Curr Opin Mol Ther 2: 601-6, 2000.
において議論されている。
本発明は、代謝経路に関与している蛋白質をコードしている遺伝子を代謝疾患を有する哺乳動物被験体へ搬送するために、組み換えアデノ随伴ウイルス(rAAV)ビリオンを使用する方法を与える。その遺伝子は一度送られると転写および翻訳され、その翻訳産物(即ち、蛋白質)は代謝疾患を有する哺乳動物被験体に治療効果を提供する。本発明との関連では、「蛋白質」という用語はポリペプチド、ペプチド、蛋白質およびペプチド輸送体、酵素、蛋白質複合体のポリペプチドサブユニット、蛋白質の機能的ドメインなどの全ての分類を含む。
マウスのフェニルアラニンヒドロキシラーゼ遺伝子を含む組み換えAAVビリオンは、米国特許番号6,01,650(上記参照)において述べられたトリプルトランスフェクションの手法を用いて調製された。
AAV pHLP19ヘルパー機能ベクター構築
AAV pHLP19ヘルパー機能ベクター通常の分子生物学的技術を用いて構築され;その構築は米国特許番号6,001,650(上記参照)において詳細に述べられている。
AAV pRepCap5ヘルパー機能ベクターは、AAV-5 repとcap遺伝子(GenBnak Accession Number Y18065)を、pUCプラスミド(Chiorini et al. (1999) J.Viol 73:1309-1319を見よ)のXbaI部位へ挿入することにより構築された。
下記のようにしてpLadeno5アクセサリー機能ベクターを構築した。精製したアデノウイルス抗原型-2 DNA(Gibco/BRLから入手)から単離されたE2a, E4およびVA RNA領域をコードするDNA断片を、pAmpscriptと呼ばれるプラスミドへ結合した。pAmpscriptプラスミドを以下のようにして組み立てた。オリゴヌクレオチド指向性の突然変異生成を用いて、ポリリンカーとpBSII s/k+(Strarageneから入手した)由来のアルファ相補性発現カセットを含む623塩基対領域を除去し、EcoRV部位と置換した。オリゴヌクレオチド指向性の突然変異生成性に使用された突然変異生成性オリゴの配列は、5’-CCGCTACAGGGCGCGATATCAGCTCACTCAA-3’ (配列番号9)であった。ポリリンカー(下記の制限部位を含む:BamHI; KpnI; SrfI; XbaI; ClaI; Bst1107I; SalI; PmeI;およびNdeI)を合成し、そのリンカーのBamHI部位が改変されたプラスミドのf1起点に近接するように上記で生成されたEcoRV部位へ挿入し、pAmpscriptプラスミドを提供した。ポリリンカーの配列は5’-GGATCCGGTACCGCCCGGGCTCTAGAATCGATGTATACGTCGACGTTTAAACCATATG-3’ (配列番号10)であった。
ヒトのサイトメガウイルス即時早期(immediate early)プロモーター/エンハンサー(CAG)、マウスのフェニルアラニンヒドロキシラーゼ遺伝子(mPAH)、およびシミアンウイルス40ポリアデニレーション(SV40polyA)配列(”rAAV2-CAG-mPHA-SV40polyA”)を備える組み換えアデノ随伴ウイルス抗原型2、またはCAGプロモーターの5’に設置されたラット胎盤のグルタチオンS-トランスフェラーゼエンハンサー(GSTE)を有する同じベクター(”rAAV2-CAG-mPHA-SV40polyA”)を、以下のように構築した:マウスフェニルアラニンラニンヒドロキシラーゼ配列をマウス肝臓mRNAからRT-PCRクローン化した。ベクタープラスミドの一つのシリーズにおいて、ヒトのサイトメガウイルスエンハンサー-アクチンプロモーター-グロビンイントロン(CAG)プロモーター(Niwa H. et al. (1991) Gene 108:193-199)がフェニルアラニンラニンPAH発現を駆動する。SV40後期(late)アデニレーションがマウスPAH遺伝子の3’末端に隣接する。他のシリーズのベクターは、ラット胎盤のグルタチオンS-トランスフェラーゼエンハンサー(GSTE)がCAGプロモーター配列の5’に設置されている以外には同一であった。CAG-mPHA-SV40polyAまたはGSTE-CAG-mPHA-SV40polyAカセットのいずれかを、AAV2またはAAV5の5’と3’ITR配列の間に挿入した。AAV-2の左ITRの配列はGenBnak No. K01624として公開され、AAV-2の右ITRの配列はGenBnak No. K01625として公開されている。AAV-5のITRを含んでいる組み換えAAVベクターも同じようにして構築した。2つのITRを含んでいるAAV-5の完全なゲノムは公開されている(Chiorini et al., 上記を見よ)。
AAVヘルパー機能ウイルスpHLP19ベクター(AAV-2 ITRsを含むrAAVベクターと共に使用した)またはAAV pRepCap5ヘルパー機能ベクター(AAV-5 ITRsを含むrAAVベクターと共に使用した)、アクセサリー機能ベクターpLadeno5、およびrAAV2-CAG-mPHA-SV40polyA、rAAV2-GSTE-CAG-mPHA-SV40polyA、rAAV5-CAG-mPHA-SV40polyAまたはrAAV5-GSTE-CAG-mPHA-SV40polyAベクターのいずれかを用いて、組み換えAAV-mPAH-sv40polyAビリオンを産生した。2つの完全なセットの組み換えベクターが作製され:1つのセットはAAV-2 ITRsを有し、1つのセットはAAV-5 ITRsを有していた。
Shedrovskyにおいて述べられた方法(Shedrovsky et al. (1993) Genetics 134: 1205-1210)に従って生殖細胞系列のエチルニトロソウレア(ENU)突然変異生成を行い、BTBR系列のマウスでPAHenu2と名付けたフェニルケトン尿症マウスモデルを確立した。PAHenu2マウスにおいて、PAH遺伝子のエキソン7におけるTからCへの転位はF263S変異を引き起こす結果となり、肝臓におけるPAH活性が低下した。影響を受けた同型のマウスは、血中フェニルアラニンの顕著な増加(フェニルアラニンは1000μM以上、または20 mg/dl以上)、過剰な色素沈着、および神経発達の欠損など、古典的なヒトPKUの表現型を示した。
組み換えAAVビリオンをリン酸緩衝生理食塩水中で再懸濁した。本技術分野でよく知られている方法に従ったイソフルラン麻酔下で、上腸間膜静脈を介してオスのPAHenu2マウスに種々の用量のビリオン(表1に見られる通り)を300μLの溶液で与えた。血中フェニルアランンレベルを、Enzaplate PKU-R(バイエル薬品、東京、日本)を用いた酵素的な微蛍光測定法により測定した。テイルクリッピングによりマウスを出血させ、マススクリーンググレードの紙フィルター(#545、アドバンテック東京、東京、日本、より提供された)上に血液をスポットした。直径3mmのディスクを血液スポットから打ち抜き、96穴プレート上に設置した。フェニルアラニンをディスクから溶出し、NAD依存性酵素であるフェニルアラニンデヒドロゲナーゼおよびレサズリン(resazurin)と共にインキュベートした。酵素反応によりNADPHを産生し、その代わりにジアフォラーゼの助けでレサズリンはレソルフィンへ変換する。得られたレソルフィンを、フルオロスキャン・アセント(ラボシステム、ヘルシンキ、フィンランド)および544nm/590nmの励起/放射フィルターセットにより測定した。
フェニルケトン尿症のマウス(PAHenu2マウス)へ、250μLのrAAV2-CAG-hPAH-SV40polyA, rAAV2-GSTE-CAG-hPAH-SV40polyA, rAAV5-CAG-hPAH-SV40polyAまたはrAAV5-GSTE-CAG-hPAH-SV40polyAビリオンを、肝管への逆行性管投与を介して注入した。マウスを麻酔し、胆嚢管へ接近するために手術用顕微鏡の下で正中腹部切開を行った。前部肝鎌状間膜(falciform ligamentum anterior)を分離し、中肝葉(median lober lobe)を移動させて、胆嚢、胆嚢管、肝管および総胆管を露出させた。脾管との接合部の上で総胆管をクランプし、ベクターの十二指腸への順行性の流れと脾臓への逆行性の流れを防止した。しかし、総胆管のクランプするのに先立って総胆管に生理食塩水を流した。絹の縫合糸を胆嚢に隣接した部位の周囲へ緩く置き、胆嚢管にカニューレを挿入した。組み換えAAVビリオンをカニューレへゆっくりと注入した。各用量群あたり6匹のマウスで3つの用量群を確立し、低用量群には1×1012のrAAV-CAG-hPAH-SV40polyAまたはrAAV2-GSTE-CAG-hPAH-SV40polyAウイルスゲノムを投与し、中間用量群には5×1012ウイルスゲノムを投与し、高用量群には1×1013ウイルスゲノムを投与した。注入の後、ポリエチレンチューブの遠位端を固め、全ての鉤とキシフォイド(xyphoid)クランプを取り除き、腸管をその元の位置に戻した。rAAVビリオンを注入して1時間後、総胆管からクランプを除去することにより、胆管から十二指腸への順行性の流れを回復した。その後、腹部を2層で閉じた。血漿フェニルアラニンレベルを実施例3と同様に測定した。
組み換えAAVビリオンをリン酸緩衝生理食塩水溶液中に再懸濁した。本技術分野で良く知られている手法に従い、オスPAHenu2マウスにrAAVビリオンを前脛骨筋への注入を介して投与した。前脛骨筋上で皮膚を切除して筋膜を同定した。露出させた脛骨筋の中へ組み換えAAVビリオンを直接注入した。一回のrAAVビリオンの注入はrAAV-mAPHからなる。各用量群あたり6匹のマウスで3つの用量群を確立し、低用量群には1×1012のrAAV-CAG-hPAH-SV40polyAまたはrAAV2-GSTE-CAG-hPAH-SV40polyAウイルスゲノムを投与し、中間用量群には5×1012ウイルスゲノムを投与し、高用量群には1×1013ウイルスゲノムを投与した。血液フェニルアラニンレベルを実施例3で述べた手法と同様に測定した。
Claims (30)
- 哺乳動物被験体に蛋白質を搬送するための組み換えビリオン組成物であって、該組成物は組み換えアデノ随伴ウイルス(rAAV)ビリオンを備え、前記rAAVビリオンはアミノ酸代謝に関与している代謝蛋白質をコードしている異種の遺伝子を備える、上記組成物。
- 前記代謝蛋白質は芳香族アミノ酸代謝において有用である、請求項1記載の組成物。
- 前記代謝蛋白質はフェニルアラニンヒドロキシラーゼである、請求項2記載の組成物。
- 前記代謝蛋白質はチロシンヒドロキシラーゼである、請求項2記載の組成物。
- 前記代謝蛋白質はグアノシントリフォスフェートシクロヒドロラーゼIである、請求項2記載の組成物。
- 前記代謝蛋白質はジヒドロ葉酸レダクターゼである、請求項2記載の組成物。
- 前記代謝蛋白質は6-ピルボイル-テトラヒドロプテリン合成酵素である、請求項2記載の組成物。
- 前記哺乳動物被験体はヒト被験体であり、前記rAAVはヒト被験体に対して治療上有効な量で含まれている、請求項1記載の組成物。
- 組み換えビリオン組成物であって、該組成物は組み換えアデノ随伴ウイルス(rAAV)ビリオンを備え、前記rAAVビリオンはアミノ酸代謝に関与している代謝蛋白質をコードしている異種の遺伝子を備え、且つ、そのrAAVは哺乳動物被験体に投与されたときに異種の該遺伝子を発現させるのに十分な量で存在し、発現により治療効果を発揮する、上記組成物。
- 前記治療効果は好ましくはフェニルアラニンの血中濃度の低下である、請求項9記載の組成物。
- フェニルアラニンの血中濃度がおよそ1000マイクロモル以下へ低下する、請求項9記載の組成物。
- 組み換えビリオン組成物であって、該組成物は組み換えアデノ随伴ウイルス(rAAV)ビリオンを備え、前記rAAVビリオンはアミノ酸代謝に関与している代謝蛋白質をコードしている異種の遺伝子を備え、且つ、異種の該遺伝子は、哺乳動物被験体の標的細胞内における該遺伝子の発現に影響することが可能な異種のプロモーターと動作が可能なように結合している、上記組成物。
- 組み換えビリオン組成物であって、該組成物は組み換えアデノ随伴ウイルス(rAAV)ビリオンを備え、前記rAAVビリオンはアミノ酸代謝に関与している代謝蛋白質をコードしている異種の遺伝子を備え、rAAVは哺乳動物被験体あたり少なくとも5×1012ウイルスゲノムの量で存在している、上記組成物。
- 哺乳動物被験体においてアミノ酸病を治療するために有用な組成物を作製するための方法であって、:
組み換えアデノ随伴ウイルス(rAAV)ビリオンを提供する工程であって、該rAAVビリオンはアミノ酸代謝に関与している代謝蛋白質をコードする核酸分子を有するrAAVベクターを備え、該核酸分子は、宿主細胞内に存在するときに該核酸分子の転写に影響する制御配列と動作が可能なように結合している上記工程、および
該組み換えrAAVビリオンを薬学的に需要可能なベヒクルと組み合わせる工程、
の上記工程からなる上記方法。 - 前記代謝蛋白質は芳香族アミノ酸代謝において有用である、請求項14記載の方法。
- 前記代謝蛋白質はフェニルアラニンヒドロキシラーゼである、請求項15記載の方法。
- 前記代謝蛋白質はチロシンヒドロキシラーゼである、請求項15記載の方法。
- 前記代謝蛋白質はグアノシントリフォスフェートシクロヒドロラーゼIである、請求項15記載の方法。
- 前記代謝蛋白質はジヒドロ葉酸レダクターゼである、請求項15記載の方法。
- 前記代謝蛋白質は6-ピルボイル-テトラヒドロプテリン合成酵素である、請求項15記載の方法。
- 前記哺乳動物被験体はヒト被験体であり、前記rAAVはヒト被験体に対して治療上有効な量で含まれている、請求項14記載の方法。
- アミノ酸病を有する哺乳動物被験体へ組み換えアデノ随伴ウイルス(rAAV)ビリオンを搬送するための薬剤の製造におけるrAAVビリオンの使用方法であって、該rAAVビリオンは核酸分子を備え、該核酸分子は、アミノ酸代謝に関与している代謝蛋白質をコードしている遺伝子を備え、インビボで該遺伝子の転写に影響することができる制御配列と動作が可能なように結合している、上記使用方法。
- 前記rAAVは前記代謝蛋白質を哺乳動物被験体へ搬送することが可能である、請求項22記載の使用方法。
- 前記代謝蛋白質は芳香族アミノ酸代謝において有用である、請求項22記載の使用方法。
- 前記代謝蛋白質はフェニルアラニンヒドロキシラーゼである、請求項24記載の使用方法。
- 前記代謝蛋白質はチロシンヒドロキシラーゼである、請求項24記載の使用方法。
- 前記代謝蛋白質はグアノシントリフォスフェートシクロヒドロラーゼIである、請求項24記載の使用方法。
- 前記代謝蛋白質はジヒドロ葉酸レダクターゼである、請求項24記載の使用方法。
- 前記代謝蛋白質は6-ピルボイル-テトラヒドロプテリン合成酵素である、請求項24記載の使用方法。
- 前記哺乳動物被験体はヒト被験体であり、前記rAAVはヒト被験体に対して治療上有効な量で含まれている、請求項22記載の使用方法。
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DE (1) | DE60315009T8 (ja) |
ES (1) | ES2290447T3 (ja) |
WO (1) | WO2003087383A1 (ja) |
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DE69841982D1 (de) * | 1997-03-14 | 2010-12-16 | Philadelphia Children Hospital | Zusammensetzungen zum einsatz in einer gentherapie zur behandlung von hämophilie |
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2002
- 2002-04-16 US US10/124,749 patent/US20030198620A1/en not_active Abandoned
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2003
- 2003-04-16 AU AU2003222451A patent/AU2003222451A1/en not_active Abandoned
- 2003-04-16 AT AT03717600T patent/ATE367446T1/de not_active IP Right Cessation
- 2003-04-16 DE DE60315009T patent/DE60315009T8/de not_active Expired - Fee Related
- 2003-04-16 EP EP03717600A patent/EP1497436B1/en not_active Expired - Lifetime
- 2003-04-16 CA CA002479996A patent/CA2479996A1/en not_active Abandoned
- 2003-04-16 WO PCT/JP2003/004856 patent/WO2003087383A1/en active IP Right Grant
- 2003-04-16 ES ES03717600T patent/ES2290447T3/es not_active Expired - Lifetime
- 2003-04-16 EP EP07013616A patent/EP1847614A1/en not_active Withdrawn
- 2003-04-16 JP JP2003584322A patent/JP2005522517A/ja active Pending
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- 2004-11-18 US US10/992,346 patent/US20050147592A1/en not_active Abandoned
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JP2020068734A (ja) * | 2018-11-01 | 2020-05-07 | 国立大学法人東京工業大学 | Sprをコードするポリヌクレオチドを含む組換えベクター、及びそれを含む組成物 |
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WO2021256579A1 (ko) * | 2020-06-16 | 2021-12-23 | 노벨파마 주식회사 | 글루타르산뇨증 치료용 조성물 및 이의 투여방법 |
JP2023529686A (ja) * | 2020-06-16 | 2023-07-11 | ノベルファーマ株式会社 | グルタル酸尿症治療用組成物及びこの投与方法 |
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DE60315009T2 (de) | 2008-04-03 |
DE60315009D1 (de) | 2007-08-30 |
EP1497436A1 (en) | 2005-01-19 |
DE60315009T8 (de) | 2009-02-05 |
ATE367446T1 (de) | 2007-08-15 |
WO2003087383A1 (en) | 2003-10-23 |
US20050147592A1 (en) | 2005-07-07 |
AU2003222451A1 (en) | 2003-10-27 |
ES2290447T3 (es) | 2008-02-16 |
US20030198620A1 (en) | 2003-10-23 |
CA2479996A1 (en) | 2003-10-23 |
EP1497436B1 (en) | 2007-07-18 |
EP1847614A1 (en) | 2007-10-24 |
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