JP7497247B2 - 組換えアデノ随伴ウイルス9の髄腔内送達 - Google Patents
組換えアデノ随伴ウイルス9の髄腔内送達 Download PDFInfo
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- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000021542 voluntary musculoskeletal movement Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Description
この出願は、2012年8月1日に出願された米国仮出願第61/678,458号(これは、その全体が参考として本明細書に援用される)からの優先権を主張する。
本発明は、National Institutes of Health(NIH)によって付与されたRC2 NS69476-01の下、政府の支援を受けてなされた。政府は、本発明に一定の権利を有する。
本明細書と同時に提出されかつ以下:「47099PCT_SeqListing.txt」と称されるASCIIテキストファイル(8,954バイト、2013年7月31日作製)のとおりに識別されるコンピューター読み取り可能な形態での配列表は、その全体において本明細書に参考として援用される。
本発明は、ポリヌクレオチドの髄腔内送達(すなわち、脳もしくは脊髄のくも膜の下にある空間への送達)に有用なアデノ随伴ウイルス9型の方法および物質に関する。上記方法および物質の使用は、例えば、下位運動ニューロン疾患(例えば、SMAおよびALS)、ならびにポンペ病およびリソソーム蓄積症の処置に関して示される。
大型分子薬物は、血液脳関門(BBB)を横切らず、小型分子のうちの98%は、この関門を通過できず、それによって、多くのCNS障害の薬物開発の努力が制限されている[Pardridge, W.M. Nat Rev Drug Discov 1: 131-139 (2002)]。遺伝子送達は、BBBを迂回するための方法として近年提唱された[Kasparら、Science 301: 839-842 (2003)];しかし、脳および脊髄への広く行き渡る送達は、困難であった。運動ニューロン疾患に関する成功裡の遺伝子治療の開発は、脊髄および運動皮質内の広く行き渡る形質導入をおそらく必要とする。最も一般的な運動ニューロン疾患のうちの2つは、脊髄性筋萎縮症(SMA)および筋萎縮性側索硬化症(ALS)であり、これらはともに、それぞれ、小児および成人を衰弱させる障害であり、今までのところ有効な治療はない。SMAおよびALSの齧歯類モデルでの近年の研究は、筋肉内注射の後に逆行して輸送されるウイルスを使用する遺伝子送達を含む[Kasparら、Science 301: 839-842 (2003); Azzouzら、J Clin Invest 114: 1726-1731 (2004); Azzouzら、Nature 429: 413-417 (2004); Ralphら、Nat Med 11: 429-433 (2005)]。しかし、脊髄、脳幹および運動皮質全体にわたって神経変性が広く行き渡った領域を標的としてこれら疾患を有効に処置するために多くの注射が必要とされることを考慮すれば、臨床開発は困難であり得る。AAVベクターはまた、神経学的障害についての近年の多くの臨床試験で使用されてきており、持続する導入遺伝子発現、比較的安全なプロフィール、および有望な機能的応答を示すが、外科的な実質組織内注射(intraparenchymal injection)を要した[Kaplittら、Lancet 369: 2097-2105 (2007); Marksら、Lancet Neurol 7: 400-408 (2008); Worgallら、Hum Gene Ther (2008)]。
本発明は、組換えAAV9(rAAV9)をベクターとして使用する、中枢神経系へのポリヌクレオチドの髄腔内送達に有用な方法および物質を提供する。
特定の実施形態では、例えば以下が提供される:
(項目1)
ポリヌクレオチドの送達を必要とする患者の中枢神経系にポリヌクレオチドを送達する方法であって、該方法は、該患者へのrAAV9および非イオン性の低浸透性造影剤の髄腔内送達を包含し、ここで該rAAV9は、該ポリヌクレオチドを含む自己相補性ゲノムを含む、方法。
(項目2)
前記ポリヌクレオチドが、脳に送達される、項目1に記載の方法。
(項目3)
前記ポリヌクレオチドが、脊髄に送達される、項目1に記載の方法。
(項目4)
前記ポリヌクレオチドが、グリア細胞に送達される、項目1に記載の方法。
(項目5)
前記グリア細胞が、星状細胞である、項目4に記載の方法。
(項目6)
前記ポリヌクレオチドが、下位運動ニューロンに送達される、項目1に記載の方法。
(項目7)
前記非イオン性の低浸透性造影剤が、イオビトリドール、イオヘキソール、イオメプロール、イオパミドール、イオペントール、イオプロミド、イオベルソールもしくはイオキシランである、項目1に記載の方法。
(項目8)
前記非イオン性の低浸透性造影剤が、イオヘキソールである、項目7に記載の方法。
(項目9)
前記ポリヌクレオチドが、生存運動ニューロン(SMN)ポリヌクレオチドである、項目1に記載の方法。
(項目10)
神経学的疾患の処置を必要とする患者において神経学的疾患を処置する方法であって、該方法は、該患者へのrAAV9および非イオン性の低浸透性造影剤の髄腔内送達を包含し、ここで該rAAV9は、治療用ポリヌクレオチドを含む自己相補性ゲノムを含む、方法。
(項目11)
前記神経学的疾患が、レット症候群である、項目10に記載の方法。
(項目12)
前記神経学的疾患が、神経変性疾患である、項目10に記載の方法。
(項目13)
前記治療用ポリヌクレオチドが、生存運動ニューロン(SMN)ポリヌクレオチドである、項目12に記載の方法。
(項目14)
前記神経変性疾患が、脊髄性筋萎縮症である、項目12に記載の方法。
(項目15)
前記神経変性疾患が、筋萎縮性側索硬化症である、項目12に記載の方法。
(項目16)
前記ポリヌクレオチドが、脳に送達される、項目10に記載の方法。
(項目17)
前記ポリヌクレオチドが、脊髄に送達される、項目10に記載の方法。
(項目18)
前記ポリヌクレオチドが、グリア細胞に送達される、項目10に記載の方法。
(項目19)
前記グリア細胞が、星状細胞である、項目18に記載の方法。
(項目20)
前記ポリヌクレオチドが、下位運動ニューロンに送達される、項目10に記載の方法。
(項目21)
前記非イオン性の低浸透性造影剤が、イオビトリドール、イオヘキソール、イオメプロール、イオパミドール、イオペントール、イオプロミド、イオベルソールもしくはイオキシランである、項目10に記載の方法。
(項目22)
前記非イオン性の低浸透性造影剤が、イオヘキソールである、項目21に記載の方法。
(項目23)
前記患者が、前記rAAV9の髄腔内送達後に、トレンデレンブルグ体位に置かれる、項目1~22のいずれか1項に記載の方法。
従って、一局面において、本発明は、患者の中枢神経系へのポリヌクレオチドの髄腔内送達のための方法を提供し、上記方法は、上記ポリヌクレオチドを含むゲノムを有するrAAV9を投与する工程を包含する。いくつかの実施形態において、非イオン性の低浸透性造影剤はまた、上記患者に投与される。上記非イオン性の低浸透性造影剤は、上記患者の中枢神経系における標的細胞の形質導入を増大させる。いくつかの実施形態において、上記rAAV9ゲノムは、自己相補性ゲノムである。他の実施形態において、上記rAAV9ゲノムは、1本鎖ゲノムである。
rAAV9が中枢神経系を標的として、そこでタンパク質を発現する能力を、インビボモデル系で評価した。rAAVゲノムは、先にBevanら、Molecular Therapy, 19(11): 1971-1980 (2011)に記載されるように、順に、AAV2 ITR、ニワトリβ-アクチンプロモーターとサイトメガロウイルスエンハンサー、SV40イントロン、緑色蛍光タンパク質(GFP)DNA、ウシ成長ホルモン由来のポリアデニル化シグナル配列およびもう1つのAAV2 ITRを含んだ。
いくつかの神経学的障害は、遍在的に発現されるタンパク質の欠損によって引き起こされるものの、他の障害においては、CNSのみにおける遺伝子発現が実質的な影響を有し得る。本発明は、CSFへの遺伝子送達が脳脊髄軸に沿った形質導入と、必要とされる用量を潜在的に低下させるという付加的な利益を生じ得ることを企図する。従って、より局所化したCNS送達をもたらすために、5.2×1012 vg/kgのAAV9 GFPおよび非イオン性の低浸透性造影剤の、5日齢のブタ(各々n=3)への髄腔内注入および/もしくは槽内注入を行い、それらの脳および脊髄を、GFP発現について試験した。
SMN変異体マウスの脳脊髄液(CSF)へのrAAV9 SMN[Foustら、Nature Biotechnology 28(3): 271-274 (2010)および本明細書中上記の説明を参照のこと。ここでベクターゲノム挿入物の配列は、配列番号1のヌクレオチド980~3336として示される)]および造影剤のインビボ送達の効果を試験した。
3匹の1歳のカニクイザルに、1×1013 vg/KgのshRNAおよびGFPをコードするrAAV9の髄腔内注入を受けさせた。上記注入を、腰椎髄腔(lumbar thecal sac)のくも膜下腔への腰椎穿刺によって行った。上記rAAV9を、オムニパーク(イオヘキソール)(臨床状況で慣用的に使用されるヨウ素化化合物)とともに再懸濁した。イオヘキソールを、くも膜下腔カニューレ挿入が成功したことを確認するために使用し、用量100mg/Kgを投与した。被験体を側臥位に配置し、ほぼL4/5レベルの後正中線注入部位(脊髄円錐の下)を確認した。滅菌条件下で、スタイレット付きの脊髄穿刺針(spinal needle)を挿入し、くも膜下カニューレ挿入を針から透明なCSFが流れ出てくることで確認した。くも膜下腔での圧力を減らすために、0.8mlのCSFを排出し、直後に2.1mLのウイルスと混合した0.7mL イオヘキソール(300mg/ml 処方物)を含む混合物(合計2.8ml)を注入した。上記ウイルスの吻側流動分布が頸部領域の細胞形質導入を改善し得るか否かを調査するために、ある被験体を側臥位で回復させ、第2の被験体および第3の被験体を、トレンデレンブルグ体位(頭を低くした姿勢)にて傾けた。これは、ヒト被験体でCTミエログラムを行う場合の慣用的手順である。
Claims (31)
- 配列番号1のヌクレオチド980~3336を含むポリヌクレオチド。
- 請求項1に記載のポリヌクレオチドを含む、組換えアデノ随伴ウイルス(rAAV)ベクター。
- 血清型9キャプシドを含む、請求項2に記載のrAAVベクター。
- 自己相補性rAAVゲノムを含む、請求項2または3に記載のrAAVベクター。
- 請求項1に記載のポリヌクレオチドを含むDNAプラスミド。
- 選択マーカーをさらに含む、請求項5に記載のDNAプラスミド。
- 配列番号1を含む、請求項5に記載のDNAプラスミド。
- 請求項1~4のいずれか一項に記載のrAAVベクターと薬学的に受容可能なキャリアとを含む組成物。
- 非イオン性の低浸透性造影剤をさらに含む、請求項8に記載の組成物。
- 前記非イオン性の低浸透性造影剤が、イオビトリドール、イオヘキソール、イオメプロール、イオパミドール、イオペントール、イオプロミド、イオベルソール、またはイオキシランである、請求項9に記載の組成物。
- 前記非イオン性の低浸透性造影剤がイオヘキソールである、請求項9に記載の組成物。
- 前記組成物が、髄腔内投与に適する、請求項8~11のいずれか一項に記載の組成物。
- 必要とする患者の中枢神経系に配列番号1のヌクレオチド980~3336を含むポリヌクレオチドを送達するための、請求項8~12のいずれか一項に記載の組成物であって、髄腔内投与されることを特徴とする、組成物。
- 必要とする患者の神経学的疾患を処置するための、請求項2~4のいずれか一項に記載のrAAVベクターを含む組成物であって、髄腔内投与されることを特徴とする、組成物。
- 必要とする患者の神経学的疾患を処置する方法において使用するための、請求項2~4のいずれか一項に記載のrAAVベクターを含む組成物であって、前記方法が、前記組成物を提供する工程と、非イオン性の低浸透性造影剤と組み合わせて前記組成物を髄腔内投与するための指示を提供する工程とを含む、組成物。
- 前記ポリヌクレオチドが脳に送達されることを特徴とする、請求項13に記載の組成物。
- 前記ポリヌクレオチドが脊髄に送達されることを特徴とする、請求項13に記載の組成物。
- 前記ポリヌクレオチドがグリア細胞に送達されることを特徴とする、請求項13に記載の組成物。
- 前記グリア細胞が星状細胞である、請求項18に記載の組成物。
- 前記ポリヌクレオチドが下位運動ニューロンに送達されることを特徴とする、請求項13に記載の組成物。
- 前記患者が、前記rAAVの髄腔内投与後に、トレンデレンブルグ体位に置かれる、請求項14または15に記載の組成物。
- 前記神経学的疾患が神経変性疾患である、請求項14または15に記載の組成物。
- 前記神経変性疾患が脊髄性筋萎縮症である、請求項22に記載の組成物。
- 前記非イオン性の低浸透性造影剤がイオヘキソールである、請求項15に記載の組成物。
- 前記rAAVベクターと、前記非イオン性の低浸透性造影剤とが、別々の組成物で提供され、前記髄腔内投与前に混合される、請求項15に記載の組成物。
- 請求項2~4のいずれか一項に記載のrAAVベクターを含む第1の組成物と、非イオン性の低浸透性造影剤を含む第2の組成物とを含む、キット。
- 前記組成物を混合して、混合された組成物を形成し、その後、必要とする患者に前記混合された組成物を髄腔内投与するための指示書をさらに含む、請求項26に記載のキット。
- 請求項5に記載のDNAプラスミドを含む、細胞。
- rAAVベクターの製造方法であって、請求項5に記載のDNAプラスミドを細胞に導入する工程を含み、前記rAAVベクターが生成される、製造方法。
- 前記細胞が、HeLa細胞、293細胞、PerC.6細胞、MRC-5細胞、WI-38細胞、Vero細胞またはFRhL-2細胞である、請求項29に記載の製造方法。
- 請求項29または30に記載の製造方法によって生成される、rAAVベクター。
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