JP2011067212A - ハイブリッドウイルス粒子とその製造方法 - Google Patents
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Abstract
【解決手段】(a)AAVキャプシド;及び(b)該AAVキャプシドとは血清型が異なっていることを条件として、該AAVキャプシド内にパッケージングされるAAVゲノムを含むハイブリッドウイルス粒子を提供する。
【選択図】なし
Description
本出願は、本明細書中でそれらの全体が援用される1998年11月10日に出願された出願番号第60/107,840号及び1999年3月10日に出願された出願番号第60/123,651号の各々の仮出願の利益を請求するものである。
本発明は、一部は、国立衛生研究所からの第DK42701号及び第5−32938 0−110号の助成金のもと政府支援によりなされた。合衆国政府は本発明に対する一定の権利を有する。
本発明は、導入(すなわち、送達)及び、好ましくは、細胞へヌクレオチド配列を発現するためのパルボウイルスベクターを提供する。本発明は、一部は、現在のベクターと比較して独特な構造及び特徴を持つパルボウイルスベクターが、外来配列(すなわち、外来性アミノ酸配列)をパルボウイルスキャプシドへ置換又は挿入することで作成しうるという発見に基づく。本発明は、異なるパルボウイルスキャプシド内のパルボウイルスゲノム(好ましくは、AAVゲノム)を交差パッケージングすることにより生成される新規なベクターをさらに提供する。本発明は、現在のAAVベクターと比較して独特かつ有利な抗原特性、パッケージング能力、及び細胞向性を持ちうる新規なパルボウイルスベクターのレパートリーを提供する。
本発明は、in vitro及びin vivoでの核酸を細胞に送達するためのパルボウイルスベクターを提供する。あるいは、本発明は、例えば、ワクチンとして又は細胞に化合物を送達するための使用に新規なキャプシド構造物を提供する(例えば、Samulskiらに対する米国特許第5,863,541号に記載され、その開示の全体が本明細書中で援用される)。本発明のパルボウイルスベクターはAAVベクターの有利な特性を使用し、これらのベクターで遭遇する問題の一部を軽減することができる。特別な実施例において、パルボウイルスベクターは、抗原特性、パッケージング能力、及び/又は細胞向性を含むがこれらに限定されない、AAVベクターとは異なる又は変化した特徴を持ちうる。
本発明はさらに、独特の構造及び特徴をもつキメラパルボウイルスを構成しうる発見を提供する。上述した方法は、異なるパルボウイルス内のAAVゲノムを交差パッケージングすることによるAAVウイルスの構造及び機能を変化させることが焦点であった。ウイルス粒子における別の多様性は、異なる(すなわち別の又は異質の)パルボウイルスからのキャプシドの一部分でパルボウイルスキャプシドの一部分を置換することにより達成しうる。あるいは、一部分の異なるパルボウイルスキャプシドをパルボウイルスキャプシドへ挿入(すなわち置換ではなく)し、キメラパルボウイルスキャプシドを生成することができる。また、キメラパルボウイルス粒子を構成するためのベクター、パッケージング細胞、及び方法も開示される。本明細書中で開示されるキメラパルボウイルスは、新しい抗原特性、パッケージング能力、及び/又は細胞向性を持つ。本発明のキメラキャプシド及びウイルス粒子は、新規なキャプシド構造に対するキメラ特異的抗体を産生するために有用である。
本発明の別の態様は、外来性ターゲティング配列がパルボウイルスキャプシドへ挿入又は置換されている、パルボウイルスキャプシド及び組換えAAVゲノムを含むパルボウイルスベクターである。パルボウイルスベクターは、パルボウイルスキャプシドへの外来性ターゲティング配列の置換又は挿入によりターゲティングされている(すなわち、特定の細胞型又は複数の細胞型に方向づけられている)ことが好ましい。別の述べ方をすれば、外来性ターゲティング配列はパルボウイルスに対して変化した向性を与えることが好ましい。さらに別の述べ方をすれば、ターゲティング配列は細胞への標的ベクターの送達の効率を増大させる。
あるいは、外来性アミノ酸配列は、当業者に周知の他の血清型のAAVキャプシドにおける上述した相同部位に挿入する(例えば、Chioriniら、(1999)J. Virology 73:1309を参照)。AAVキャプシド内のアミノ酸は、AAV血清型間に高度に、しかも完全に保存されているように見える。したがって、特別な実施例において、外来性アミノ酸配列は、血清型2以外(例えば、血清型1、3、4、5又は6)のAAVにおける表2(次のアミノ酸で開始する新しい配列)に示したアミノ酸位置で置換される。
本発明の方法は、細胞の分割と非分割を含め、広範囲の宿主細胞へ異種核酸配列を送達する手段を提供する。本発明のベクターや他の試薬、方法や医薬組成物は、治療又はその他の方法として、それを必要とする対象に対しタンパク質又はペプチドを投与する方法においてさらに有用である。このようにして、タンパク質又はペプチドは対象のin vivoで得ることができる。対象は、その対象がタンパク質又はペプチドの欠損を有しているため、又は対象におけるタンパク質又はペプチドの産生が一部の治療的効果に影響するため、治療又はその他の手段として、またさらに以下で説明されるように、タンパク質又はペプチドの必要がある。
本発明は獣医用及び医療用に使用される。適切な対象として、トリ及び哺乳動物が挙げられ、哺乳動物であることが好ましい。本明細書中で用いられる「トリ」という用語は、ニワトリ、アヒル、ガチョウ、ウズラ、シチメンチョウ及びキジを含むがこれらに限定されない。本明細書中で用いられる「哺乳動物」という用語は、ヒト、ウシ、ヒツジ、ヤギ、ウマ、ネコ、イヌ、ウサギ、等を含むがこれらに限定されない。ヒト対象が最も好ましい。ヒト対象は新生児、乳児、小児、及び成人を含む。
AAVベクター
これらの研究で使用されるAAVベクターのすべての製造では、Ferrariら、(1997)Nature Med. 3:1295及びXiaoら、(1998)J. Virology 72:2224に記載されたベクター製造スキームが利用される。一過性形質移入法を利用することにより、アデノウィルスを欠くrAAVが生成されている。同上。このプロトコールでは、ウイルス複製及び後期遺伝子発現のために無能力化されているアデノウィルスDNAゲノムを利用する。複製及び子孫の産生が不可能であるミニAdプラスミドは、293細胞におけるアデノウィルス遺伝子発現では生存可能である。この作生物を用いて、新しいAAVヘルパープラスミド(pAAV/Ad ACG)及びAAVベクターDNA(sub201)に関与したAAVパッケージング法が有効に補完されている(Samulskiら、(1989)J of Virology 63:3822)。この新しい作成物は典型的に293細胞の107〜109/10cm皿のrAAVを生成する(Xiaoら、(1998)J.Virology 72:2224)。Adの完全非存在下のこれらのベクターについて効率的な遺伝子送達が筋、脳及び肝において観察された。
細胞及びウイルス
ヒト293細胞及びHeLa細胞をストレプトマイシン及びペニシリン(Lieneberger包括的癌センター、Capel Hill、NC)とともに、Dulbeccoの改変Ragles培地(Gibco BRL)中に10%ウシ血清(Hyclone)中5%CO2飽和で37℃下に維持した。4x106293細胞を形質移入の前日に10cmプレート上にプレーティングした。製造元の規格に従い、細胞をリン酸カルシウム(Gibco BRL)又はSuperfection(Qiagene)の両方で形質移入した。以下に述べる挿入変異体パッケージングプラスミドを核局在化シグナルによりCMV駆動Lac Z遺伝子を含有するぱB11とともに形質移入した。各々の形質移入について、同じ量のパッケージングプラスミド(12μg)及びぱpAB11(8μg)を各々の10cmプレートに用いた。各々の形質移入について、変換効率を評価するためのみの導入遺伝子プラスミドを含有する追加のプレートを用いた。形質移入後、細胞を5のMOlでヘルパーウイルスAd5 dl309を感染させ、48時間後に細胞を溶解し、ウイルスを精製した。
AAVパッケージングプラスミドの構成
Hind IIIを用いてpAAV/Adのキャプシド領域をPBS+(Stratagene)へクローン化し、pAV2Capを得た。制限酵素Hae III、Nla、IV、及びRsa Iを用いたpAV2Capの部分消化及び単位長DNA断片のゲル精製により、クローン化の開始材料を得た。SaIIで消化したpUC4K(Pharmacia)のカナマイシン耐性(Kanr)を付与したアミノグリコシド3’−ホスホとランスフェラーゼ遺伝子をNaeI及びEco RV部位、一端でオーバーハングしたSaII、他の一端でオーバーハングしたEco RI(上部5’− AATTCGCCGGCGATATC−3’、SEQ ID NO:6、下部5’− TCGAGATATCGCCGGC−3’、SEQ ID NO:7)を含有するリンカーでフランキングした。この断片をpBIuescript SK+(Stratagene)のEco Rl部位へクローン化した。Naeによる消化はKanr遺伝子を放出し、この断片をpAV2Cap部分へ結合した。こうして得られたプラスミドをキャプシド領域への挿入についてスクリーニングし、次いでEco RVで消化し、キャプシド領域へ12塩基対の挿入5’−GGCGATATCGCC−3’(SEQ ID NO: 8)を残したKanr遺伝子を除去した。複数の酵素消化及びDNA塩基配列決定法を用いて、キャプシドコード領域内の12bp挿入の位置を判定した。酵素消化としてEco RVIBanII、Eco RVIBst NI、Eco RVIPstII及びEco RVIHind IIIが挙げられる。得られたプラスミドのキャプシド領域はAsp718で消化し、3’−Asp718部位を重複した1つのNIaIVを除き、pACG2パッケージングプラスミド(Liら、1997 J. Virology 71:5236)へサブクローン化した。この挿入変異体をHind III/Nsi I消化を用いてpAAV/Adへクローン化した。
ウエスタンブロット分析
凍結溶解及び超音波処理後の細胞ライセートを遠心分離し、大きな細胞片を除去した。20マイクロリットルの上清を直ちにジチオスレイトール含有2xSDSゲル添加液20μlに添加し、5分間煮沸した。タンパク質をSDSポリアクリルアミドゲル電気泳動により分析し、電気泳動によりニトロセルロースへ移した。ニトロセルロース膜を抗Vp3モノクロナール抗体B1(Jurgen A. Kleinschmidtより寄贈)を用いて免疫ブロットした。各々の挿入変異体を少なくとも2回、ウエスタンブロット分析で試験した。二次抗マウス西洋わさびペルオキシダーゼIgGを用いて強化化学発光(ECL-Amersham)によりタンパク質を間接的に視覚化した。ウエスタンブロットを強化化学発光から走査露光BioMaxフィルム(Kodak)からAdobe PhotoShopへ、ImageQuaNTソフトウエア(Molecular Dynamics Inc.)により分析した。
組換えウイルスの力価
CsCl勾配からのフラクションを針吸引により得た。屈折計(Leica MarkII)を用いて屈折率を得、その屈折率を用いてフラクションの密度を測定した。1.36g/ml〜1.45g/mlのフラクションから10μlのアリコートをドットブロットハイブリッド形成による保護粒子の存在について試験した。アリコートをウイルス希釈緩衝液(50mM Tris HCl、1mM MgCl2、1mM CaCl2 10μg/ml RNase、10μg/ml DNae)中に1:40で希釈し、37℃下30分間インキュべートした。サルコシン(最終濃度0.5%)及びEDTA(最終10mM)を試料に添加し、70℃下10分間インキュべートした。プロテイナーゼK(Boehringer Mannheim)を最終濃度1mg/mlになるまで添加し、試料を37℃下2時間インキュべートした。このインキュべションの後、NaOH(350mM最終)及びEDTA(25mM最終)中で試料を変性させた。ドットブロットマニフォールド(Manifold I、schleicher and Schuell)を用いて平衡nytran(Gene Screen Plus、NEN Life Science Products)に試料をかけた。膜をランダム開始(Boehringer Mannheim)32P−dCTP標識Lac Z DNA断片でプローブした。膜をフィルム(BioMax MR、Kodak)又は蛍光体イメージングスクリーン(Molecular Dynamics)に露光し、密度推計をImageQuantソフトウェア(Molecular Dynamics)を用いて行った。次いでウイルスのピークフラクションを形質導入の力価のために1xPBS中で透析した。
電子顕微鏡観察
野生型ビリオン又は変異誘発ビリオンを有するrAAVのピークフラクションを0.5x0.5mM MgCl2含有PBS中で透析した。10μl滴のウイルスを反転させることにより400メッシュのグロー放電した炭素グリッド上にウイルスを室温で10分間配置した。その後、各1分間3回1xPBS洗浄した。ウイルスを1%リンタングステン酸中で1分間染色した。Zeiss EM910電子顕微鏡を用いて試料を視覚化した。
へパリンアガロース結合アッセイ
野生型キャプシド又はキャプシドへ挿入を含有する組換えウイルスを0.5x0.5mM MgCl2含有PBSに対して透析した。100マイクロリットルの各ウイルスを100μlのへパリンアガロース1型(0.5x0.5mM MgCl2含有PBS20容積中に前平衡したH−6508 Sigma)に1.5mlミクロチューブ中に室温下1時間、結合した。各ステップ後、結合洗浄及び溶出試料を2000rpm(Sorvall MC 12V)で2分間遠心分離し、上清を採集した。試料を0.5x0.5mM MgCl2含有PBS0.5mlで6回洗浄し、上清を採集した。0.5x0.5mM MgCl2含有PBS中に0.5、1.0及び1.5M NaClを含有する100μl容積の3つのステップ中に溶出して上清を採集した。各ステップからの上清20μlの各サンプルを用いてドットブロットハイブリッド形成を行った。100%結合対照をドットブロットで使用した各入力ウイルスの5分の1に相当する内規準とした。へパリンアガロースウイルス混合液を容積0.5x0.5mM MgCl2含有PBSで6回洗浄し、1:15625の希釈を得た。
rAAVにおける挿入突然変異の構成
アセンブリー及び感染力におけるAAV構造タンパク質の役割を評価するために、われわれはキャプシドリンカー挿入変異体を生成した。AAV2のキャプシド領域の配列コードを含有するpAAV/Adの2.8kb Hind III断片(Samulskiら、(1989)J. Virology 63: 3822)をpBS+へサブクローニングした。このプラスミド、pAV2CapをHae III、Na IV、及びRsa Iで部分消化し、キャプシド特異的挿入の基質を生成した(図1)。これら3つのDNA制限酵素は、4つのみが重複するAAV−2キャプシドコード配列上にまたがる43の部位を構成する。挿入を含有するクローンを効率的に確認するために、新規のオリゴ(Nae IIEcoR V)によりフランキングされたカナマイシン耐性遺伝子(Kanr)を部分消化、全長、直線化したpAV2Capと結合した(実施例3及び図1を参照)。E.coliにおけるアンピシリン及びカナマイシン選択を用いて、挿入変異体を確認し、Kanr遺伝子をEco RV部位の入れ子状の対で消化及び再結合することでキャプシドコード領域から移動させた(実施例3を参照)。これにより、キャプシドコード配列における独特なEco RV部位の単一コピーを保有する12の塩基対(bp)の特異的なリンカー挿入が得られた。リンカー挿入の正確な位置をさらに制限酵素消化により、及び6カセット配列決定で精製した(データは示さず)。挿入変異体の位置は、部分消化で用いた酵素の最初の文字で確認され、その後にAAV2ゲノムにおける制限部位のヌクレオチド位置が確認され、例えばNla IV4160はN4160となる。
実施例9
キャプシドタンパク質の分析
相補性アッセイにおいて変異体キャプシド作成物を用いたベクター産生の検定のために、各挿入変異体の形質移入後の293細胞におけるキャプシドサブユニットの発現について試験した。正常な化学量論でのVp1、Vp2、及びVp3産生能は、リンカー挿入がキャプシドタンパク質発現、又は安定性を変化させなかったことを示すであろう。リンカーは終止コドンを導入しなかった、各挿入は3つのすべてのキャプシドを精製すると予想された。形質移入の48時間後、細胞ライセートをAAVについてウエスタンブロット分析で分析した。図2のウエスタンブロット分析は、細胞ライセートにおける挿入変異体キャプシド発現を表わす。H2634(図2レーン2)を除き、3つのキャプシドサブユニットの化学量論は野生型の対照と大きな違いはないように思われる(図2のレーン1、3〜7乃至8を比較)。このアッセイにより、挿入変異体H2634はVp3サブユニットを生成するのみであると思われる(図2;レーン2)。長い曝露では、図4レーン5及び6の副キャプシドサブユニットが明らかであった(データは示さず)。
変異体キャプシドの安定なビリオンの産生能
DNase消化からベクターゲノムを保護する安定なビリオンの産生について試験するために、われわれは細胞ライセートを塩化セシウム(CsCl)勾配遠心分離にかけた。ウイルス密度を屈折計により測定し、適切なフラクションからのアクリオートをドットブロットハイブリッド形成にかけた(図3a)。この分析に基づき、完全な組換えゲノムをパッケージングする粒子は、野生型と同様の浮遊密度を示し、野生型よりもわずかに高い浮遊密度を有するH2944を除き、NNase処置に対して耐性であるはずである。このアッセイの結果、挿入変異体が2つのクラスに分けられた。クラスI変異体はウイルスゲノムの保護に対して陰性であったが、クラスII変異体はベクター基質のパッケージング及び保護に対して正常であるように思われた(表I)。
クラスII挿入変異体の感染力
相補性アッセイにおける挿入変異体により生成されるビリオンの感受性について、ヒト細胞におけるLac受容体遺伝子の形質導入をモニタリングすることで試験した。ドットブロッドハイブリッド形成から得られたウイルス力価を用いて、HeLa細胞を同じ粒子数での変異体ウイルスストックに感染させた。
クラスII及びクラスIII変異体の電子顕微鏡観察
生物学的な違いについてクラスII及びIIIのrAAV2挿入変異体をさらに特徴づけるために、われわれは電子顕微鏡観察(EM)により変異体粒子を視覚化した。EM分析は感染性クラスIIIウイルスの全体の形態のみを示し、これらは野性型ビリオンと区別不可能であった(図4aと4b、cを比較)。しかし、野生型ビリオン(図4a及び4f−下の4パネル)と比較するとクラスII/III変異体ウイルスH3595間に明確な違いが観察された。H3595のEM像はわずかに大きな粗い五角形の輪郭を示したが、野性型ウイルスはサイズが不均一であり、六角形であった。興味深いことに、クラスII変異体H2634は、ウエスタンブロットではVp1又はVp2に対して陰性であったが(図2レーン2)、EM分析(図4d)による形態は正常に見えた。この分析に基づき、ビリオンの形態のみがクラスII変異体をクラスIIIと区別するのに不十分であり、それはキャプシド内の小さな挿入により非検出可能である(図4b、c、d、e)か、ビリオン構造(図4f−下の4パネル)の変化が注目すべきあったかのいずれかのためである。しかし、この方法ではこれらのリンカー挿入変異体のわれわれの特徴づけに追加のデータを提供することはできなかった(図4、a乃至fを比較)。
クラスIIとクラスIIIのビリオンのキャプシド比
Roseら(1971)は、AAV2粒子が1:1:20の比でVp1、Vp2、Vp3からなることを証明した(Roseら、(1971)J. Virology 8:766)。クラスIIとクラスIIIの変異体ビリオンがこの比を維持したかどうかを判定する努力において、塩化セシウム精製ウイルスでウエスタンブロット分析を実施した。ウエスタンブロット分析により分析された精製ウイルスは、サンプリングしたすべての変異体でほぼ同じ量のVp3を示し、1x109〜2.5x109ウイルス粒子を各試料に用いた。Vp2とVp1の量も、副キャプシド成分が確認されなかったH2634を除くすべての被験試料でほぼ同じであった(図5レーン5)。H2634の副キャプシド成分の欠如は、細胞ライセートからのウエスタンの結果と一致している(図2)。この分析における検出限界では、クラスIIの挿入変異体H2634は、Vp1及びVp2のないAAVビリオンを構築するように見えるが、EM分析では、この変異体は正常な形態を有することを示している(図4d)。
クラスIとクラスIIIの変異体のへパリン結合
最近われわれの実験室では、AAV−2は感染力の一次受容体としてへパラン硫酸プロテオグリカンを使用することを証明した(SummerfordとSamulski、(1998)J. Virology 72:1438)。へパリン結合がクラスII粒子の細胞感染能がない点、及びクラスIIIウイルスのへパリンアガロースとの結合能の点でどのような役割があるかを判定するために、へパリンバッチ結合実験を実施した。クラスIIIのすべての変異体がへパリンに対して陽性であり、大多数のウイルスが1M Nacl2段階に溶出した(データは示さず)ことは意外ではない。クラスII変異体ウイルスの感染力の喪失がへパリン結合の欠如と関連があったかどうかを判定するために、バッチ結合実験をドットブロットハイブリッド形成により分析した(図6)。試験した各々のウィルス試料について、100%結合を判定する内部対照をへパリン結合とは無関係にフィルター上にスポットした(図6;100%結合)。これにより、われわれは、へパリン精製の各段階で保持されたウイルスのパーセントを判定することができた。へパリンアガロースとの結合後、試料を洗浄し、塩濃度を増大させることで溶出した(実施例7を参照)。野性型ビリオンのシェルを有する組換えAAV2は90%の結合を示し、洗浄で10%放出後、溶出液中で60%回復し、へパリンアガロースとの結合して20%残った(図6、レーン1)。クラスII変異体H2285、H2426、及びH2634は同様の結合及び溶出プロフィールを示した(図6、レーン2〜4)。しかし、クラスII変異体H3761は、そのへパリンアガロース結合プロフィールが異なり、大多数のビリオンが結合緩衝液及び洗浄に認められた(図6、レーン5)。このバッチアッセイにおけるへパリン結合の欠如の理由を判定するには、さらに分析が必要である。
リンカー挿入変異体
ポリ−リシン、ポリ−ヒスチジン、RGDモチーフ、又はブラジキニンをコード化する挿入配列を表1に記載したリンカー変異体に挿入した。われわれは、AAV2キャプシド遺伝子のコード領域への異なるリンカーの挿入を確認するPCRベースの方法を開発した。簡単に言えば、キャプシドコード領域の外側及びリンカーに正確に対応するリンカーをそれぞれ1つ用いた。リンカーが正しい配向にある場合は、PCR産物の大きさは挿入変異体の位置によって決まる。
3900bp
1121bp
1112bp
445bp −H2944シフト
347bb −H2634、H2690シフト
253bp −H3595シフト
215bp −R22356、H2416シフト
121bp
111bp
64bp
63bp −H2285シフト
33bp −H2591シフト
13bp
9bp
異なる挿入変異体によるバンドシフトも指示される。
1421bp
168bp
843bp −H4047シフト
835bp
734bp −H2634シフト
464bp
223bp
218bp
211bp
50bp
各々の挿入は最初の12塩基対のEco RV部位を含有する。また、各々のリンカーは以下の塚の塩基対を付加する:
・RGB=36bp+12=単一挿入で48bp。
枠1:
上部プライマー48mer(SEQ ID NO:9):
5’−GCT AGC GGC GGA CAC CAT CAC CAC CAC CAT CAC GGC GGA AGC GCT−3’
下部プライマー48mer(SEQ ID NO:10):
5’−AGC GCT GCC GTG GTG ATG GTG GTG GTG ATG GTG TCC GGC GCT AGC−3’
枠2:
上部プライマー51mer(SEQ ID NO:11):
5’−AC GCT AGC GGC GGA CAC CAT CAC CAC CAC CAT CAC CAC GGC GGA AGC GCT T−3’
下部プライマー51mer(SEQ ID NO:12):
5’−A AGC GCT TCC GCC GTG GTG ATG GTG GTG GTG ATG GTG TCC GCC GCT AGC GT−3’
枠3:
上部プライマー51mer(SEQ ID NO:13):
5’−G GGT TCC GGA CAC CAC CAT CAC CAC CAC CAT CAC GGA GGC GCC AGC GA−3’
下部プライマー51mer(SEQ ID NO:14):
5’−TC GCT GGC TCC GTG ATG GTG GTG GTGATG GTG GTG CCC TCC GGA ACC C−3’
ブラジキニンプライマー対:
枠1:
上部プライマー60mer(SEQ ID NO:15):
5’−GCC GGA TCC GGC GGC GGC TCC AGA CCC CCC GGC TTC AGC CCC TTC AGA TCC GGC GGC GCC−3’
下部プライマー60mer(SEQ ID NO:16):
5’−GGC GCC GCC GGA TCT GAA GGG GCT GAA GCC GGG GGG TCT GGA GCC GCC GCC GGA TCC GGC−3’
フレーム2:
上部プライマー69mer(SEQ ID NO:17):
5’−GA GGT TCA TGT GAC TGC GGG GGA AGA CCC CCT GGC TTC AGC CCA TTC AGA GGT GGCTGC TTC TGT GGC G−3’
下部プライマー69mer(SEQ ID NO:18)
5’−C GCC ACA GAA GCA GCC ACC TCT GAA TGG GCT GAA GCC AGG GGG TCT TCC CCC GCA GTC ACA TGA ACC TC−3’
枠3:
上部プライマー60mer(SEQ ID NO:19):
5’−A GGT TCA TGT GAC TGC GGG GGA AGA CCC CCT GGC TTC AGC CCA TTC AGA GGT GGC TGC TTC TGT GGC GG−3’
下部プライマー60mer(SEQ ID NO:20):
5’−CC GCC ACA GAA GCA GCC ACC TCT GAA TGG GCT GAA GCC AGG GGG TCT TCC CCC GCA GTC ACA TGA ACC T−3’
RGDプライマー対:
枠1:
上部プライマー36mer(SEQ ID NO:21):
5’−GGA TCC GAC TGC AGG GGC GAT TGT TTC TGC GGC−3’
下部プライマー36mer(SEQ ID NO:22):
5’−GCC GCA GAA ACA ATC GCC CCT GCA GTC GCA GGA TCC−3’
枠2:
上部プライマー36mer(SEQ ID NO:23):
5’−GA TCC TCG GAC TGC AGG GGC GAT TGTTTC TGC GGC G−3’
下部プライマー36mer(SEQ ID NO:24):
5’−C GCC GCA GAA ACA ATC GCC CCT GCA GTC GCA GGA TC−3’
枠3:
上部プライマー36mer(SEQ ID NO:25):
5’−A GGA TCC TGC GAC TGC AGG GGC GAT TGT TTC TGC GG−3’
下部プライマー36mer(SEQ ID NO:26):
5’−CC GCA GAA ACA ATC GCC CCT GCA GTCGCA GGA TCC T−3’
ポリリシンプライマー対:
注:3プライマー対の枠のみが作成された。
5’−A GGT TCA TGT GAC TGC GGG GGA AAG AAG AAG AAG AAG AAG AAG GGC GGC TGC TTC TGT GGC GG−3’
下部プライマー63mer(SEQ ID NO:28):
5’−CC GCC ACA GAA GCA GCC GCC CTT CTT CTT CTT CTT CTT TCC CCC GCA GTC ACA TGA ACC T−3’
外部プライマーAAV2/4 5’上部プライマー(SEQ ID NO:29):
5’−TGC CGA GCC ATC GAC GTC AGA CGC G−3’
RGDリンカーは、表1のH2285、R2356、H2591、H2634、H2690、H/N3761、及びH/N4947変異体に挿入された。
挿入変異体の特徴づけ
部位H2690での挿入変異体はすべて最初の12bp挿入と力価がほぼ同じである。ELISAアッセイ及び抗ヒスチジン抗体を用いて、この部位へのポリHis挿入がビリオンの表面上に表示されることが示された。
独特の制限部位の変異体
AAV2型のキャプシド内の独特の制限部位を作成し、挿入変異体の生成を促進した。部位は、キャプシドのヌクレオチド配列に導入される変異体が保存的であるよう、すなわち、ミスセンス変異体ではなく、又は終止コドンを来たさないように選択した。アミノ酸位置586、529、595、及び517(アミノ酸#1としてVP1メチオニン)を選択した。529を除き、これらの位置すべてについて、独特のHpaI部位を操作した。アミノ酸529での位置では、独特のEco RV部位を操作した。これらの制限部位の各々により、インフレームの平滑断端した消化産物が得られる。そこで枠1リンカーを用いてこれらの部位に挿入した。重複プライマーを用いて独特の部位を生成し、外部プライマーを用いて挿入の右及び左のフラグメントを生成した。
595上部プライマー(SEQ ID NO:30):
5’−GCA GAT GTT AAC ACA CAA GGC GTT CTT CCA−3’
595下部プライマー(SEQ ID NO:31):
5’−TTG TGT GTT AAC ATC TGC GGT AGC TGC TTG−3’
586上部プライマー(SEQ ID NO:32):
5’−CAG AGA GTT AAC AGA CAA GCA GCT ACC GC−3’
586下部プライマー(SEQ ID NO:33):
5’−GTC TGT TAA CTC TCT GGA GGT TGG TAG ATA−3’
注:この構成物によりグリシンのバリンへのミスセンス変異が生じる。
5’−ACA AAT GTT AAC ATT GAA AAG GTC ATG ATT−3’
552下部プライマー(SEQ ID NO:35):
5’−TTC AAT GTT AAC ATT TGT TTT CTC TGA GCC−3’
529上部プライマー(SEQ ID NO:36):
5’−GGA CGA TAT CGA AAA GTT TTT TCC TCA G−3’
529下部プライマー(SEQ ID NO:37):5’−ACT TTT CGA TAT CGT CCT TGT GGC TTGC−3’
注:この構成物によりグルタミン酸からイソロイシンへのミスセンス変異が生じる。
5’−TCT CTG GTT AAC CCG GGC CCG GCC ATG GCA−3’
517下部プライマー(SEQ ID NO:39):
5’−GCC CGG GTT AAC CAG AGA GTC TCT GCC GCC ATT−3’
外部プライマーは以下の通りであった:
5’−(SEQ ID NO:40):
5’−TGC GCA GCC ATC GAC GTC AGA CGC G−3’
3’プライマー(SEQ ID NO:41):
5’−CAT GAT GCA TCA AAG TTC AAC TGA AAC GAA T−3’
529Eco RV部位に挿入されたRGD及び8Hisリンカー(実施例15)によって4つのクローンも生成された。5つの8Hisリンカー及び1つのRGDリンカー挿入変異体が586Hpa I部位に生成された。
二重変異体
単一変異体H3761(表1)をテンプレートとして用いて二重変異体を生成した。H3761挿入変異体は、バッチ及びカラム結合実験の両方で評価されたようにへパリン硫酸と結合することはない。この変異体は、試験した限りではどの細胞系にも感染しないが、電子顕微鏡観察ではこのウイルスが正常なパルボウイルスシェルを形成し、ドットブロットによりこのウイルスがウィルスゲノムを効率的にパッケージングすることを示しているという点で興味深い。
MSH−ターゲティングAAVベクター
本発明の1実施例では、メラニン細胞刺激ホルモン(MSH)が、MSH受容体を発現する細胞にAAVベクターをターゲティングするために使用される。研究によって、このペプチドがリガンド随伴複合体が特異的にメラニン細胞NEL−M1細胞へ方向づけ(Murphyら、(986)Proc. Nat. Acad. Sci USA 82:8258)、便利な試験系を提供することがわかっている。例えば、MSHリガンドをコード化する12残基ペプチドに繋がれたジフテリア毒素が、MSH受容体発現細胞のみを殺傷することにおいて効率的であった(Morandiniら、(1994)Internat. J. Ca. 56:129)。細胞死は特異的リガンド送達の受容体介在性エンドサイトーシスに起因した。
ループ3 5’上部プライマー(SEQ ID NO:42):
5−’GATACTTAAGATCTAGTGGAACCACCACCACGCACTCAAGGCTT−3’
cttaagはAfl II部位であり、agatctはBgl II部位である。これら2つの部位は2つの塩基対により重複する。AAV配列との相同性は位置3556で開始、3583で終わる。
5−’CTAGCTTAAGCATGCATACACAGGTACTGGTCGATGAGAGGATT−3’
gcatgcはSphl部位であり、cttaagはAfl II部位である。これら2つの部位は1つの塩基対により重複する。AAV配列との相同性は位置3505で開始、3531で終わる(これは下部鎖であることに注意)。
キメラAAV2/4ウイルス−キャプシドタンパク質置換
AAV血清型のビリオンが、3つのタンパク質サブユニットVP1VP2及びVp3で作り上げられる。VP3は最も豊富なサブユニットであり、ビリオンを作り上げる60のサブユニットの80から90%を代表し、VP1及びVP2は各々5〜10%のビリオンを作り上げる。これらのサブユニットは重複転写から翻訳され、VP3配列はVP2とVP1の両方の内部にあり、VP2配列はVP1内部にある。
5’−TGC CGA GCC ATC GAC GTC AGA CGC G−3
AAV2及びAAV4下部プライマー(SEQ ID NO:45):
5’−CAT GAT GCA TCA AAG TTC AAC TGA AAC GAA T−3’
AAV2 VP3上部プライマー(SEQ ID NO:46):
5’−CGA GCT CTT CGA TGG CTA CAG GCA GTG GCG CAC−3’
AAV2 VP3下部プライマー(SEQ ID NO:47):
5’−AGC GCT CTT CCC ATC GTA TTA GTT CCC AGA CCA GAG−3’
AAV2 VP2上部プライマー(SEQ ID NO:48):
5’−CGA GCT CTT CGA CGG CTC CGG GAA AAA AGA GGC−3’
AAV2 VP2下部プライマー(SEQ ID NO:49):
5’−AGC GCT CTT CCC GTC TTA ACA GGT TCC TCA ACC AGG−3’
AAV4 VP3上部プライマー(SEQ ID NO:50):
5’−CGA GCT CTT CGA TGC GTG CAG CAG CTG GAG GAG CTG−3’
AAV4 VP3下部プライマー(SEQ ID NO:51):
5’−AGC GCT CTT CGC ATC TCA CTG TCA TCA GAC GAG TCG−3’
AAV4 VP2上部プライマー(SEQ ID NO:52):
5’−CGA GCT CTT CGA CGG CTC CTG GAA AGA AGA GAC−3’
AAV4 VP2下部プライマー(SEQ ID NO:53):
5’−AGC GCT CTT CCC GTC TCA CCC GCT TGC TCA ACC AGA−3’
これらのプライマーにより図7に示されているサブユニットの交換が生じる。AAV Vp2が置換されたキメラAAV2キャプシドの代表的な配列を付録2(SEQ ID NO:2)に示す。この配列はAAVrepコード配列を含有し、ほとんどのAAV Vp1及びVp3コード配列、及び全体のAAV Vp2コード配列及び一部のAAV Vp1とVp3コード配列がpBluescriptバックボーンにある。
B19/AAV−2キメラベクターの構成
Dongら、(1996)Human Gene Therapy 7:2101による研究では、rAAVを用いてパッケージングの限界が明らかにされている。stufferDNAの挿入を増大した組換えAAV DNAを用いることにより、DongらはrAAVベクターのパッケージング能が、104%乃至108%wt(それぞれ4883に対して5083ヌクレオチド)で劇的に低下することを測定した。このパッケージング制限は、ミニ筋ジストロフィー遺伝子及びプロモーター制御嚢胞性線維症配列を含め、重要な遺伝の使用を妨げる。
キメラウイルスの製造
pAAV/B19ヘルパー作成物を実施例1に記載した一時的なパッケージング系において用いた。簡単に言えば、ヘルパープラスミドAd及びぱB11(CMV早期プロモーターの制御下AAV末端反復及びβ−ガラクトシダーゼ遺伝子を含有)をリン酸カリウムにより293細胞へ同時形質移入した。形質移入の24時間後、培地を変更し、アデノウィルスdl309(MOI−5)を添加した。48時間後に細胞を遠心分離して上清を捨てた。細胞ペレットのフラクションをHIRTアッセイで用いた。細胞ペレットを塩化セシウム(1.39g/ml)中で溶解し、超音波処理し、41,000rpm下72時間遠心分離した。セシウム勾配からのフラクションを回収し、各々の試料をドットブロットハイブリッド形成に用いてウイルスの粒子数を試験した。ドットブロットをβ−ガラクトシダーゼ遺伝子でプローブし、対照量のβ−ガラクトシダーゼ遺伝子により粒子数を測定した。ウイルスを含有するピークフラクションをPBS、20%グリセロールに対して透析した。
キメラウイルスとの細胞の感染
形質移入後48時間に、細胞ライセートを生成し、各種標的細胞への形質移入について試験した。2x106の形質移入力価を生成した。各種量のウイルスを少量の倍地中の293、RT−2ラット神経膠腫、U87神経膠腫のほか、2つの原発性ヒトグリア芽細胞腫細胞系に添加した。エリスロポエチン(EPO)の存在下数種間インキュべートしてあったUT7巨核球にもウイルスを添加した。EPOへのUT7細胞の曝露は、これらの細胞にB19感染に対して許容的にさせることが知られている。
B19/AAVキメラの特徴づけ
実施例23の結果は、形質移入キメラウイルスが有効に生成されたことを示している。キメラウイルスをさらに総粒子収量及び完全性について評価した。ベクター標本の残りを勾配精製し、キメラウイルスをドットブロット分析で分析し、1x108の粒子力価を測定、EM分析(実施例6を参照)で正確な正二十面体の構造が形成されているかどうかを判定した(図9)。この分析より、生成されたキメラウイルスが典型的なパルボウイルス構造を保持し、超音波処理やCsCl2勾配遠心分離など物理的な精製ステップに対して安定であることが確認された。これはほとんどのパルボウイルスが熱安定(65度まで耐性)であり、洗剤(0.5%SDS)に対して耐性であり、極度なpH変化(pH2.0〜11で変動)に耐えることができるため重要な所見である。
B19/AAV−キメラのパッケージング能
実施例21からのキメラウイルスのパッケージング能を定量化するために、Dongと共同研究者(1996)Human Gene Therapy 7:2101により開発された一連のベクターを、745乃至1811塩基(最大総ゲノムサイズ6.4kb)に挿入を有するサイズを連続的に増大したゲノムが利用される。小規模生産のキメラ組換えウイルスを用いて、Hirtアッセイを用いたウイルスのDNA含量を試験するとともに、クロラムフェニコールアセチルトランスフェラーゼ(CAT)レポーターアッセイによりパッケージング効率を検定した。
他のB19/AAVキメラの構成
他のキメラB19/AAVキャプシドが実施例21におけるように生成され(例えば、AAV Vp1又はVp2をB19 Vp1で交換)、上記の実施例22〜25の通り特徴づけられる。特に、B19 Vp1とVp2はAAV Vp1キメラへ置換され、AAV Vp1及びB19 Vp1とVp2を含有する新規なキメラキャプシドを生成する。
AAV血清型間のループ交換
ヘルパーベクターpACG2におけるAAV2のキャプシド遺伝子wp酵素Asp718及びBsi Wlで消化した。Bsi Wlは位置3254bpでのAAV2ゲノムの独得な部位を有し、Asp718は1906及び4158bps(AAV配列数)で2回消化する。AAV2のキャプシドコード領域は部分的にAsp718で消化され、全長(単一切断)断片を分離した。次いでこの断片をBsi Wlで消化し、7272bp断片を分離した。この断片は、VP3ループ2、3、及び4領域のコード領域を含む904bp断片を除去した。
ハイブリッドウイルス
プライマーを作り、AAV2におけるHind III部位を重複するAAV4rep遺伝子における独得なHind III部位を作成した。また、repコード配列の3’末端で、独得なNotI部位がポリアデニル化部位の3’末端で作成された。アメリカン・タイプ・カルチャー・コレクション(ATCC)から購入したウイルスをPCRのテンプレートとした。
AAV 3’Not Iプライマー(SEQ ID NO:58):
5’−AAG CGC CGC GGC CGC TGC TTA TGT ACG CA−3’
AAV 5’Hind IIIプライマー(SEQ ID NO:59):
5’−GAC GCG GAA GCT TCG GTG GAC TAC GCG −3’
このクローニング法により、AAV2及びAAV4rep遺伝子のハイブリッドであり、AAV4cap遺伝子を含有するヘルパープラスミドが得られる。このヘルパーはHind III部位までAAV2rep遺伝子及びここから配列がAAV4から由来するポリアデニル化部位を含む。
Claims (21)
- (a)アデノ随伴ウイルス(AAV)キャプシド;及び
(b)該AAVキャプシドとは血清型が異なっていることを条件として、該AAVキャプシド内にパッケージングされるAAVゲノム
を含むハイブリッドウイルス粒子。 - 前記AAVゲノムが少なくとも1つのAAV逆方向末端反復を含む、請求項1のウイルス粒子。
- 前記AAVゲノムが少なくとも1つの異種核酸配列を含む、請求項1又は請求項2のウイルス粒子。
- 前記少なくとも1つの異種核酸配列がペプチド又はタンパク質をコード化する、請求項3のウイルス粒子。
- 前記ペプチド又はタンパク質が治療的タンパク質又はペプチドである、請求項4のウイルス粒子。
- 前記少なくとも1つの異種核酸配列が、嚢胞性線維症膜コンダクタンス制御因子、ジストロフィン、ミニジストロフィン、ウトロフィン、IX因子を含む凝固因子、エリトロポエチン、LDL受容体、リポタンパク質リパーゼ、オルニチントランスカルバモイラーゼ、β−グロビン、α−グロビン、スペクトリン、α−アンチトリプシン、アデノシンデアミナーゼ、ヒポキサンチングアニンホスホリボシルトランスフェラーゼ、β−グルコセレブロシダーゼ、スフィンゴミエリナーゼ、リソソームヘキソサミニダーゼ、分枝鎖ケト酸デヒドロゲナーゼ、ホルモン、成長因子、β−インターフェロンを含むサイトカイン、自殺遺伝子生成物腫瘍抑制遺伝子生成物からなる群より選択される治療的タンパク質又はペプチドをコード化する、請求項5のウイルス粒子。
- 前記ペプチド又はタンパク質が免疫原性ペプチド又はタンパク質である、請求項4のウイルス粒子。
- 前記少なくとも1つの異種核酸配列が非翻訳RNAをコード化する、請求項3のウイルス粒子。
- 前記AAVゲノムがAAV血清型1、2、3、4、5及び6からなる群より選択されるAAVから由来する、請求項1−8のいずれかのウイルス粒子。
- 前記AAVキャプシドがAAV血清型1、2、3、4、5及び6からなる群より選択されるAAVから由来する、請求項1−9のいずれかのウイルス粒子。
- 薬学的に許容される担体における請求項1−10のいずれかのウイルス粒子を含む医薬組成物。
- 以下の群:嚢胞性線維症、血友病A、血友病B、サラセミア、AIDS、アルツハイマー病、パーキンソン氏病、筋萎縮性側索硬化症、癲癇、癌、真性糖尿病、筋ジストロフィー、ゴーシュ病、フルラー病、アデノシンデアミナーゼ欠損症、糖原貯蔵症、及び網膜変性疾患から選択される疾患の治療のための医薬品の製造のための請求項1−10のいずれかに記載のウイルス粒子の使用。
- ワクチン組成物としての請求項7に記載のウイルス粒子。
- 請求項1のハイブリッドウイルス粒子を製造するための分離核酸であって、前記分離核酸が、前記AAVcap遺伝子と前記AAVrep遺伝子とは血清型が異なることを条件として、AAVcap遺伝子及びAAVrep遺伝子を含む、分離核酸。
- 前記AAVcap遺伝子が操作可能に標準AAVポロモーターと随伴している、請求項14の分離核酸。
- 請求項14又は請求項15の分離核酸を含むベクター。
- 請求項16のベクターを含む細胞。
- 請求項14又は請求項15の分離核酸を含む細胞であって、当該分離核酸が当該細胞のゲノムへ安定に組み込まれることを特徴とする細胞。
- ハイブリッドウイルス粒子を製造する方法であって、
増殖性AAV感染を生成するためのアデノ随伴ウイルス(AAV)rep遺伝子、AAVcap遺伝子、AAVゲノム、及びヘルパー機能を、前記AAVrep遺伝子及び前記AAVcap遺伝子の血清型が異なることを条件として、細胞に供給し;
ハイブリッドウイルス粒子の集合を可能にすることを含む方法。 - 細胞に核酸配列を送達するインビトロの方法であって、
請求項3−8のいずれかに記載のハイブリッドウイルス粒子又は請求項11に記載の医薬組成物を細胞へ導入することを含む方法。 - 細胞が神経細胞、肺細胞、網膜細胞、上皮細胞、筋細胞、膵細胞、肝細胞、心筋細胞、骨細胞、脾細胞、ケラチン生成細胞、線維芽細胞、内皮細胞、前立腺細胞、胚細胞、前駆細胞、及び幹細胞からなる群より選択される、請求項20の方法。
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US6491907B1 (en) | 2002-12-10 |
CA2348382A1 (en) | 2000-05-18 |
CA2348382C (en) | 2013-09-17 |
AU780231B2 (en) | 2005-03-10 |
AU1911100A (en) | 2000-05-29 |
JP2002538770A (ja) | 2002-11-19 |
WO2000028004A1 (en) | 2000-05-18 |
EP1135468A4 (en) | 2003-07-02 |
EP1135468B1 (en) | 2010-01-06 |
EP1135468A1 (en) | 2001-09-26 |
US20060188483A1 (en) | 2006-08-24 |
US20030053990A1 (en) | 2003-03-20 |
ATE454445T1 (de) | 2010-01-15 |
ES2340230T3 (es) | 2010-05-31 |
US7172893B2 (en) | 2007-02-06 |
DE69941905D1 (de) | 2010-02-25 |
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