JP6309373B2 - Aavベクターの末梢注入を使用する広範囲におよぶ運動ニューロンへの遺伝子の送達 - Google Patents
Aavベクターの末梢注入を使用する広範囲におよぶ運動ニューロンへの遺伝子の送達 Download PDFInfo
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- JP6309373B2 JP6309373B2 JP2014136031A JP2014136031A JP6309373B2 JP 6309373 B2 JP6309373 B2 JP 6309373B2 JP 2014136031 A JP2014136031 A JP 2014136031A JP 2014136031 A JP2014136031 A JP 2014136031A JP 6309373 B2 JP6309373 B2 JP 6309373B2
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Description
運動ニューロン(MN)疾病、例えば脊髄性筋萎縮症(SMA)、筋萎縮性側策硬化症(ALS)、又はケネディー病は、脊髄、脳幹、及び/又は運動皮質における運動ニューロンの選択的変性により特徴づけられる神経変性疾患である(Monani 2005;Pasinelli及びBrown 2006);(MacLean, Warne et al.1996)。これらの疾病の処置法はない。なぜなら殆どの場合、全身注入を介した運動ニューロンへの薬物送達は、「血液脳関門」(BBB)の存在により妨害されるためである。この解剖学的及び生理学的障壁は、中枢神経系(CNS)毛細血管の内皮細胞間の密接な接合により形成され、血液循環とCNSの間を分子が容易に通過することを防いでいる(Scherrmann 2002)。組換えタンパク質を有する運動ニューロンをCNS実質に直接注入し供給する代替的な方法も、手術手順の侵襲性のために困難であり、臨床適応の可能性を妨げている。
本発明は、組換えAAVベクターを使用して、CNSへ治療産物を送達するための新規な組成物及び方法に関する。より具体的には、本発明は、AAVベクターの末梢投与により、哺乳動物被験体の運動ニューロン又はグリア細胞に遺伝子を送達するための組成物及び方法に関する。
脊髄への広範囲におよぶ遺伝子送達は、運動ニューロン(MN)疾病、例えば脊髄筋硬化症(SMA)又は筋萎縮性側索硬化症(ALS)の処置に対する重要な挑戦である。本明細書において、我々は、1回の組換えAAVベクターの末梢注入後に効率的な運動ニューロン形質導入を可能とする、新規な遺伝子導入法を記載する。我々は、血清型1及び9の組換え一本鎖(ss)AAVベクター及び自己相補性(sc)AAVベクターを、新生仔又は成体マウスに腹腔内、筋肉内、又は静脈内(i.v.)注入し、中枢神経系(CNS)における導入遺伝子の発現を解析した。組換えss−及びscAAV9ベクターの両方が、神経細胞及び上皮脳細胞、重要なことには、脊髄における運動ニューロン及びグリア細胞をターゲティングすることが判明した。背側感覚神経線維及び後根神経節もまた高度に形質導入された。最も印象的な形質導入効率は、scAAV9ベクターの静脈内注入により得られた。我々は更に、ネコのSMAモデルにおいて静脈内注入されたscAAV9が血液脳関門を迂回し、下位運動ニューロンを形質導入することができることを確認した。この戦略は、脊髄への広範囲におよぶ導入遺伝子の送達を達成した最初の非侵襲的な手順を示し、運動ニューロン疾病の処置のための新規な手段を提供するものである。
本発明の内容において、用語「AAVベクター」は、AAVの成分を含むか、又はAAVの成分から得られ、そして哺乳動物細胞、好ましくはヒト細胞を感染するのに適切である、任意のベクターのことをいう。用語AAVベクターは、典型的には、治療タンパク質をコードする少なくとも1種類の核酸分子を含む、AAV型ウイルス粒子(又はビリオン)のことをいう。以下に考察されているように、AAVは、様々な血清型(血清型の組合せ(すなわち「偽型」AAV)を含む)、又は様々なゲノム(例えば一本鎖又は自己相補性)から得られる。更に、AAVベクターは、複製欠損でもよく、そして/又はターゲティングされていてもよい。
本発明は、運動ニューロン又はグリア細胞における遺伝子の効率的かつ広範囲におよぶ発現は、AAVベクターの末梢投与により、非侵襲的な技術を用いて達成することができるという予期せぬ発見に基づいている。このような末梢投与には、脳への直接注入を意味しない任意の投与経路が含まれるがそれらに限定されるわけではない。より特定すると、末梢投与には、全身注入、例えば筋肉内(i.m.)、静脈内(i.v.)、腹腔内(i.p.)、動脈内、皮下、又は経皮注入が含まれる。末梢投与には、AAVベクターの経口投与(国際公開公報第96/40954号)、インプラントを使用した送達(国際公開公報第01/91803号)、又は、例えばスプレー、エアゾール、もしくは任意の他の適切な製剤を使用した、呼吸器系を通した滴下による投与も含まれる。
本発明は、初めて、末梢に投与されたAAVベクターが血液脳関門を通過し、CNS細胞、特に脊髄全体におよぶ運動ニューロンへの実質的な感染を引き起こすことを示す。提示された結果により、感染が、脊髄の頸髄セグメントから腰髄セグメントまで効果を及ぼし、これにより運動ニューロンへの広範囲におよぶ遺伝子の送達がなされたことが示される。
材料及び方法
動物。妊娠した成体(6〜8週令の雌)のC57Bl/6マウスは、Charles River Laboratories(Les Oncins, France)から購入した。新生仔に誕生日(生後1日目、PN1)に注入した。SMAネコブリーダー(ヘテロ接合性で冒された動物)はFyfe博士(米国ミシガン州所在、Laboratory of Comparative Medical Genetics)から入手し、ナント(Nantes)獣医学校のCenter of Boisbonneで飼育した。SMA子ネコの遺伝子型同定は、以前に記載されているように実施した(Fyfe、Menotti-Raymond et al.2006)。実験は、地域倫理委員会(CREEA)により承認された。全ての動物実験は、人間による実験動物の世話及び使用に関する欧州ガイドラインに従って実施した。
偽型AAV2/1及びAAV2/9ベクターは、AAV2_をベースとした組換え一本鎖(ss)及び自己相補性(sc)ゲノムをAAV1及び9カプシドにパッケージングすることにより作製された。簡潔には、ベクターは、(1)アデノウイルスヘルパープラスミド、(2)rep2及びcap1もしくは9遺伝子をコードするAAVパッケージングプラスミド(AAV1ではpLTRC02、AAV9ではp5E18−VD2/9)、(3)ss又はscゲノムとしてmSEAP又はGFP(サイトメガロウイルス最初期(CMV IE)プロモーターの制御下)を含むAAV2ベクタープラスミド(Xiao,Li et al.1998)を用いて、HEK293細胞におけるヘルパーウイルスを含まない3種プラスミド同時トランスフェクションを使用して作製された。この後者のプラスミドは、逆位末端配列の1つから、D配列及び末端分離部位(trs)を欠失させることにより作製された。組換えベクターは、二回のCsCl超遠心分離にかけ、その後、リン酸緩衝食塩水に対して透析することにより精製した。物理的粒子は、マウスに注入されたベクターについてはリアルタイムPCRにより、ネコに注入されたベクターについてはドットブロットハイブリダイゼーションにより定量し、ベクター力価は、ウイルスゲノム/ml(vg/ml)として表現した。
新生仔マウスに、誕生日(生後1日目、PN1)に注入した。筋肉内注入では、mSeAP又はGFPをコードするAAVベクター溶液(ssAAV2/1(n=2)、ssAAV2/9(n=2)、scAAV2/1(n=2)、又はscAAV2/9(n=3))を、三頭筋及び腓腹筋の両方に注入した(1筋肉あたり1か所の注入部位、1回の注入につき5μl、マウス1匹あたり8×109〜2×1010個のウイルスゲノム)。腹腔内注入では、mSeAP又はGFPをコードするウイルス溶液(ssAAV2/1、n=2、ssAAV2/9、n=1、scAAV2/1、n=1、及びscAAV2/9、n=2)を、1日令のC57Bl/6マウスの腹腔に注入した(100μl、マウス1匹あたり3×1010〜1011個のウイルスゲノム)。静脈内注入では、1日令のC57Bl/6マウスの側頭静脈に、scAAV2/9−GFPベクターを注入した(50μl、マウス1匹あたり1.5×1010個のウイルスゲノム、n=3)。成体C57Bl/6マウスの尾静脈に、scAAV2/9−mSeAP又はscAAV2/9−GFPベクターを注入した(500μl、マウス1匹あたり3×1011個のウイルスゲノム)。生誕2日後、合計で1.5×1012個のベクターゲノムを含むscAAV9−CMV−eGFPの粒子を、1匹のSMA罹患ネコ及び1匹のSMAヘテロ接合性ネコの頸静脈に注入した。
筋肉、脳、及び脊髄を、新生仔マウスから注入の1日後(PN2)、3日後(PN4)、もしくは7日後(PN8)に、又は、成体マウスから注入の7日後及び35日後に取り出した。成体C57Bl6マウスを麻酔し(キシラジン10mg/kg、ケタミン100mg/kg)、0.1Mリン酸緩衝食塩水(PBS)で、次いでPBS中4%パラホルムアルデヒド(PFA)を用いて心内を灌流した。組織を取り出し、4時間、同溶液中で後固定し、その後、一晩4℃で脳及び筋肉については15%スクロースに移し、脊髄については30%スクロースに移した。新生仔を断頭し、組織を4%PFA中に4時間浸漬し、その後4℃で一晩凍結保護した。試料を冷イソペンタン(−50℃)中で凍結させ、連続切片をクリオスタットで切り出し、更なる解析のために−80℃で保存した。
mSeAP組織化学的検査では、新生仔マウスの筋肉、脳、及び脊髄を、注入から1日後、3日後、及び7日後に取り出し、冷イソペンタン(−50℃)中で凍結させ、即時使用のために−80℃で維持した。成体動物の脳及び脊髄は、注入から35日後に収集し、同条件下で処理した。脳及び脊髄では16μmの厚さの組織切片を、筋肉では8μmの厚さの組織切片をクリオスタットで作製し、その後、導入遺伝子発現のために加工した。該切片を、0.5%グルタルアルデヒドで固定し、PBSで洗浄し、内因性アルカリホスファターゼを30分間65℃で熱により失活させた。その後、切片を、一晩37℃で、0.165mg/mlの5−ブロモ−4−クロロ−3−インドリルホスフェート及び0.33mg/mlのニトロブルーテトラゾリウムの、100mMトリス−HCl、100mMのNaCl及び50mMのMgCl2溶液中でインキュベートし、ヘマトキシリン−エオシンで対比染色し、Eukitを用いてマウントした。
GFPの発現及び免疫細胞化学的検査は、488nm(緑)及び543nm(赤)でそれぞれ単色光線を放出するブルーアルゴンイオンレーザー及びヘリウムネオンレーザーを備えた、倒立ニコンTE−2000レーザー走査共焦点顕微鏡を用いて観察した。スライドを、油浸20倍の対物レンズを使用して連続的に走査した。各画像を別々のチャネルで記録し(GFPではチャネル緑で、ストレプトアビジン555ではチャネル赤)、同所に局在する蛍光シグナルの検出が可能となるように重層させた。
我々は初めに、血清型1及び9ss−又はscAAVベクターが、筋肉内注入後にCNS細胞を形質導入できるかについて評価した。サイトメガロウイルス(CMV)プロモーター下のマウス分泌アルカリホスファターゼ(mSEAP)をコードするssAAV1、ssAAV9、scAAV1、又はscAAV9を、1日令のC57Bl6マウスの三頭筋及び腓腹筋の両方に注入した(マウス1匹あたり8×109〜2×1010個のウイルスゲノム、1群あたり3匹のマウス)。注入された筋肉、脳、及び脊髄組織を、注入から1日後、3日後、又は7日後に取り出し、組織化学的検査を使用してmSEAP発現について解析した。
我々は、その後、ssAAV1、ssAAV9、scAAV1、及びscAAV9の、1日令のC57Bl6マウスの腹腔内への投与(100μl、マウス1匹あたり3×1010〜1×1011個のウイルスゲノム)により、注入から1日後、3日後、又は7日後にCNSにおいて導入遺伝子の発現が媒介され得るかどうかを解析した。
mSEAPは分泌されたタンパク質であるので、AAVの末梢注入後にCNSにおいて観察された導入遺伝子発現は、AAV細胞形質導入からではなくむしろ、タンパク質経細胞輸送から生じた可能性があった。それ故、我々は、分泌されないタンパク質を使用して類似の結果を得ることができるかどうかを確かめた。
組換えscAAV9ベクターは、筋肉内又は腹腔内送達後にCNS細胞形質導入を媒介する上で最も効率的なベクターであるように思われたので、我々は、静脈内投与経路を使用することによりこのベクターを改善することができるかどうかを評価した。
scAAV9で観察されたのと同じように、ssAAV9−GFPは、静脈内送達後にCNS細胞の形質導入を媒介することが判明したが、その効力は、scAAV9の効力よりも低かった。ここでも、脈絡叢及び上衣細胞が大量のGFPを発現し、脳室に近い多くの脳領域が形質導入されたことが判明した(図6a)。例えば、GFP陽性ニューロンは、海馬及び手綱核(図6a)並びに正中隆起(図6b)において検出された。興味深いことに、いくつかの運動ニューロン様細胞は、腹側脊髄においてGFPを発現することが判明した(図6c〜e)。数個のCNS細胞もまた、組換えssAAV9の筋肉内又は腹腔内送達後にGFPを発現することが判明した(データは提示せず)。
BBBは新生仔マウスにおいて不完全に形成されているので、我々は、AAV9ベクターが新生仔マウスの神経細胞を形質導入する能力が、成体マウスでも保存されているかどうかを評価した。mSEAPをコードするss及びscAAVベクター(マウス1匹あたり、3×1011個又は1×1012個のウイルスゲノム)を成体マウスの尾静脈に注入し、CNSにおける導入遺伝子の発現を、その4週間後に解析した。scAAV9−mSEAPの静脈内送達後、導入遺伝子の発現持続が、多くの脳領域、例えば正中隆起(図7f)、海馬(図7g)、又は脳梁(図7h)において見られた。
大型動物モデルにおけるこの新規なCNS遺伝子導入戦略の検証は、ヒトへの臨床応用に必須である。我々は、組換えscAAV9ベクターの静脈内送達後に、LIX−1ネコの脊髄における導入遺伝子の発現を評価した。2日令のネコ(1匹はホモ接合型、1匹はヘテロ接合型)の頸静脈に、GFP発現scAAV9を注入した。10日後、脊髄組織切片を、レーザー走査共焦点顕微鏡を使用してGFP発現について解析した。強力なGFPシグナルが、脊髄に沿って頸部から馬尾までの灰白質及び白質の両方において観察され、発現パターンは、ヘテロ接合型動物及び罹患動物の両方において類似していたようであった。薄束及び楔状背側感覚路の神経線維は、高レベルのGFPを発現していた(図9a)。更に、GFP発現は、GFPの蛍光(図9a、c)及び免疫組織化学的解析(図9b〜d)の両方の観察後に、腹側脊髄の多くの細胞体で検出された。GFPに対する抗体及びコリンアセチルトランスフェラーゼ(ChAT)を使用した二重免疫染色解析により、SMA罹患ネコ及び非罹患ネコの両方において、GFP陽性部分のかなりの部分が、運動ニューロンであることが示された(図10)。
Claims (16)
- 被験体へのAAV9ベクターの末梢注入により対象の遺伝子を運動ニューロン又はグリア細胞に送達するための医薬品の製造のための該遺伝子を含む、一本鎖AAV9ベクターの使用。
- 被験体へのAAV9ベクターの末梢注入により対象の遺伝子を脊髄に送達するための医薬品の製造のための該遺伝子を含む、一本鎖AAV9ベクターの使用。
- 被験体における運動ニューロン障害を処置するための医薬品の製造のための治療遺伝子を含む、一本鎖AAV9ベクターの使用であって、該AAV9ベクターは、該被験体への末梢注入により投与され、該投与により、運動ニューロン又はグリア細胞の感染と、運動ニューロン又はグリア細胞における該遺伝子の発現が引き起こされる、該使用。
- 一本鎖AAV9ベクターを末梢注入することにより被験体の運動ニューロンにおいて治療タンパク質又はRNAを産生するための医薬品の製造のための該AAV9ベクターの使用。
- 対象の遺伝子が、治療遺伝子である、請求項1又は2記載の使用。
- 医薬が、運動ニューロンへの送達用である、請求項1〜5のいずれか1項記載の使用。
- 医薬が、脊髄運動ニューロンへの送達用である、請求項1〜6のいずれか1項記載の使用。
- 末梢注入には、腹腔内(i.p.)、筋肉内(i.m.)又は静脈内(i.v.)注入が含まれる、請求項1〜7のいずれか1項記載の使用。
- 末梢注入が、静脈内注入である、請求項8記載の使用。
- AAV9ベクターが、偽型AAV9ベクターである、請求項1〜9のいずれか1項記載の使用。
- 偽型AAV9ベクターが、AAV2/9ベクターである、請求項10記載の使用。
- AAV9ベクターが、機能的Rep及びCapコードウイルス配列を欠損した複製欠損AAVゲノムを含む、請求項1〜11のいずれか1項記載の使用。
- 遺伝子が、治療RNA、又は、成長因子、サイトカイン、ホルモン、神経伝達物質、酵素、抗アポトーシス因子、血管新生因子、及び「運動ニューロンの生存」タンパク質(SMN)から選択された治療タンパク質をコードする、請求項1〜10のいずれか1項記載の使用。
- ベクターが、神経変性疾病、神経筋疾病、疼痛、リソソーム病、外傷、骨髄損傷、神経系の癌、脱髄疾病、神経系の自己免疫疾病、神経毒性症候群、及び睡眠障害から選択される疾患のために用いられる、請求項3〜13のいずれか1項記載の使用。
- ベクターにおける治療タンパク質の発現が、遍在的な、調節された、及び/又は組織特異的なプロモーターにより制御される、請求項13記載の使用。
- AAV9が、SMNタンパク質をコードする治療遺伝子を含み、対象における運動ニューロン疾患の処置のための医薬の製造のためであり、該疾患が、脊髄性筋萎縮症(SMA)である、請求項13記載の使用。
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