JP2020050660A - 脊髄疾患の遺伝子療法 - Google Patents
脊髄疾患の遺伝子療法 Download PDFInfo
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Abstract
Description
本発明は、対象の運動機能、特に、脳および/または脊髄に対する疾患または損傷に侵された運動機能に影響を及ぼす障害を処置するための組成物および方法に関する。
遺伝子療法は、中枢神経系(CNS)に影響を及ぼす障害のための新たな治療法である。CNS遺伝子療法は、有糸分裂後ニューロンへの効率的な感染能を有するウイルスベクターの開発により促進された。中枢神経系は脊髄および脳から構成される。脊髄は末梢神経系から脳へ知覚情報を伝え、さらに、脳から様々なエフェクターへ運動情報を伝える。中枢神経系への遺伝子送達用ウイルスベクターの総説については、Davidsonら(2003)Nature Rev.4:353−364を参照のこと。
本発明は、トランスジーンを含む組換え神経向性ウイルスベクターを対象の脳の深部小脳核(DCN)領域の少なくとも1つの領域へ投与することによる、対象の脊髄および/または脳幹領域へトランスジーンを送達するための方法および組成物を提供する。ウイルス送達は、脊髄および/または脳幹領域でのトランスジーンの発現を助ける条件下でのものである。
本発明がより容易に理解され得るために、特定の用語をまず定義する。さらなる定義は発明の詳細な説明を通して示される。
AAVベクター力価を、ゲノムコピー数(1ミリリットルあたりのゲノム粒子)により測定した。ゲノム粒子濃度は、以前に報告されたように(Clarkら(1999)Hum.Gene Ther.,10:1031−1039;Veldwijkら(2002)Mol.Ther.,6:272−278)、ベクターDNAのTaqman(登録商標)PCRに基づいた。簡単に言うと、精製AAV−ASMを、カプシド消化バッファー(50mMのトリス−HCl,pH8.0,1.0mMのEDTA,0.5%SDS,1.0mg/mlプロテイナーゼK)で50℃、1時間処理し、ベクターDNAを放出させた。DNA試料を、プロモーター領域、トランスジーンまたはポリA配列のごときベクターDNA中の特異的配列にアニールするプライマーを用いるポリメラーゼ連鎖反応(PCR)に供した。次いで、PCR結果を、Perkin Elmer−Applied Biosystems(Foster City,CA)Prism 7700 Sequence Detector Systemにより提供されるようなReal−time Taqman(登録商標)ソフトウェアにより定量した。
ASMKOマウスは、ニーマン・ピック病AおよびB型の一般に認められたモデルである(Horinouchiら(1995)Nat.Genetics 10:288−293;Jinら(2002)J.Clin.Invest.109:1183−1191;およびOtterbach(1995)Cell 81:1053−1061)。ニーマン・ピック病(NPD)はリソソーム蓄積症として分類され、酸性スフィンゴミエリナーゼ(ASM;スフィンゴミエリンコリンホスホヒドロラーゼ,EC3.1.3.12)の遺伝的欠損により特徴付けられる遺伝性神経代謝障害である。機能性ASM蛋白質の欠如は、脳全体にわたるニューロンおよびグリアのリソソーム内にスフィンゴミエリン基質の蓄積をもたらす。これにより、周核体において多数の膨張したリソソームが形成され、これは、NPD A型の顕著な特徴であり、主要な細胞表現型である。膨張したリソソームの存在は、正常な細胞機能の喪失および罹患した個人に幼児期での死をもたらす進行性の神経変性過程に相関する(The Metabolic and Molecular bases of Inherited Diseases,eds.Scriverら,McGraw−Hill,New York,2001,pp.3589−3610)。第2の細胞表現型(例えば、さらなる代謝異常)も、リソソームコンパートメント内の高レベルのコレステロール蓄積が顕著である、この疾患に関連する。スフィンゴミエリンはコレステロールに対して強い親和性を有し、ASMKOマウスおよびヒト患者のリソソーム内に多量のコレステロールの隔離をもたらす(Leventhalら(2001)J.Biol.Chem.276:44976−44983;Slotte(1997)Subcell.Biochem.28:277−293;およびViana et la.(1990)J.Med.Genet.27:499−504)。
AAV血清型の関数としての陽性hASM染色された領域。*は、陽性hASMが検出限界より低いにも関わらず、コレステロール病変の補正が生じたことを示す。
ヒトASMをコードする種々のAAV血清型(n=3/血清型;2/1、2/2、2/5、2/7および2/8)をASMKOマウスの深部小脳核へ小脳内注入した後の選択した脳領域における、AAV−βgalで処置したASMKOマウスと比較した、フィリピン(すなわち、コレステロール)クリアランスにおける減少パーセント。
ヒトASMをコードする種々のAAV血清型(n=3/血清型;2/1、2/2、2/5、2/7および2/8)をASMKOマウスの深部小脳核へ小脳内注入した後の、WTおよびASMKOマウスの小脳葉I−Xにおけるプルキンエ細胞数。太字のイタリックで示す数字は、KOマウス(すなわち、AAV2/1−βgalで処置したマウス)と有意に異なる。p≦.01.
筋萎縮側索硬化症(ALS)は、皮質、脳幹および脊髄にある運動ニューロンの選択的損失により特徴付けられる致命的な神経変性疾患である。疾患の進行は、四肢筋、体軸筋および呼吸筋の萎縮に至り得る。運動ニューロン細胞死は、反応性神経膠症、ニューロフィラメント異常、ならびに皮質脊髄路および前根における大きな有髄繊維の有意な欠損に付随する1−6。ALSの病因は不明なところが多いが、蓄積の証拠は、特発性(SALS)および家族性(FALS)ALSが多くの類似する病理学的特徴を共有することを示し、故に、いずれかの形態の研究が共通の処置をもたらし得ることが期待される7。FALSは、診断症状の約10%を占め、その20%はCu/Znスーパーオキシドジスムターゼ(SOD1)における優性遺伝性突然変異に関連する8。突然変異ヒトSOD1蛋白質を発現するトランスジェニックマウス(例えば、SOD1G93Aマウス)は、ALSの多くの病理学的特徴を再現し、ALSを研究するために利用可能な動物モデルである9。SALSでは、興奮性毒、毒物暴露、プロテアソーム機能障害、ミトコンドリア損傷、ニューロフィラメント崩壊および神経栄養支持の欠損を含む無数の病理学的機序が根底にある原因に関係があるとされる10、11。
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8.Rosen,D.R.et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature 362,59-62(1993).
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10.Rowl and,L.P.& Shneider,N.A.amyotrophic lateral sclerosis.N Engl J Med 344,1688-700(2001).
11.Bruijn,L.I.,Miller,T.M.& Cleveland,D.W.Unraveling the mechanisms involved in motor neuron degeneration in ALS.Annu Rev Neurosci 27,723-49(2004).
12.Cleveland,D.W.& Rothstein,J.D.From Charcot to Lou Gehrig:deciphering selective motor neuron death in ALS.Nat Rev Neurosci 2,806-19(2001).
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15.Clement,A.M.et al.Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice.Science 302,113-7(2003).
16.Matsushita,M.Projections from the lowest lumber and sacral-caudal segments to the cerebellar nuclei in the rat,studied by anterograde axonal tracing.J Comp Neurol 404,21-32(1999).
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Claims (17)
- 脊髄および/または脳幹へのトランスジーン産物の送達を助ける条件下で、トランスジーンを含む組換え神経向性ウイルスベクターを脳の深部小脳核領域の少なくとも1つの領域へ投与することを含む方法。
- 脊髄へのトランスジーン産物の送達を助ける条件下で、トランスジーンを含む組換え神経向性ウイルスベクターを脳の運動皮質領域へ投与することを含む方法。
- 対象の運動ニューロンへトランスジーンを送達させる方法であって、該トランスジーンを含む組換え神経向性ウイルスベクターを脳の深部小脳核領域の少なくとも1つの領域へ投与することを含み、該トランスジーンが該投与部位に対して遠位の運動ニューロンで発現されるか、または該運動ニューロンへ送達されるものである、方法。
- 対象の運動ニューロンへトランスジーンを送達させる方法であって、該トランスジーンを含む神経向性ウイルスベクターを脳の運動皮質領域へ投与することを含み、該トランスジーンが該投与部位に対して遠位の運動ニューロンで発現されるか、または該運動ニューロンへ送達されるものである、方法。
- 対象における運動ニューロン障害の処置方法であって、治療用トランスジーンを含む組換え神経向性ウイルスベクターを脳の深部小脳核領域の少なくとも1つの領域へ投与することを含み、トランスジーン産物が脊髄の少なくとも1つの小区分および/または脳幹の少なくとも1つの区分へ治療上有効量で送達されるものである、方法。
- 対象における運動ニューロン障害の徴候の改善方法であって、治療用トランスジーンを含む組換え神経向性ウイルスベクターを脳の運動皮質領域へ投与することを含み、ここで、トランスジーン産物が脊髄の少なくとも1つの小区分へ治療上有効量で送達されるものである、方法。
- 神経向性ウイルスベクターがアデノ随伴ウイルスベクター(AAV)である、請求項1〜6いずれか1項に記載の方法。
- 神経向性ウイルスベクターが、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7およびAAV8からなる群より選択されるアデノ随伴ウイルスベクターである、請求項1〜6いずれか1項に記載の方法。
- 脳の深部小脳核領域の領域が、内側領域、中間領域および外側領域からなる群より選択される、請求項1、3または5いずれか1項に記載の方法。
- 送達が両側性である、請求項1〜6いずれか1項に記載の方法。
- 脊髄小区分が頸部小区分、胸部小区分、腰部小区分および尾部小区分からなる群より選択される、請求項5または6記載の方法。
- トランスジーンが脊髄の全小区分へ送達される、請求項5または6記載の方法。
- 複数回投与の少なくとも1回が両側性である、請求項12記載の方法。
- トランスジーンが、インスリン成長因子−1(IGF−1)、カルビンジンD28、パルブアルブミン、HIF1−アルファ、SIRT−2、VEGF、SMN−1、SMN−2およびCNTF(繊毛様神経栄養因子)からなる群より選択される、請求項1〜6いずれか1項に記載の方法。
- トランスジーンの発現が、筋萎縮性側索硬化症(ALS)、原発性側索硬化症(PLS)、球脊髄性筋萎縮症、脊髄小脳失調症、脊髄性筋萎縮症および外傷性脊髄損傷からなる群より選択される運動ニューロン障害の徴候を改善する、請求項6記載の方法。
- 対象がヒト患者である、請求項1〜6いずれか1項に記載の方法。
- トランスジーンが、インスリン成長因子−1(IGF−1)、EPO(エリスロポエチン)、CBP(cAMP応答要素結合蛋白質[CREB]結合蛋白質)、カルビンジンD28、パルブアルブミン、HIF1−アルファ、SIRT−2、VEGF、SMN−1、SMN−2およびCNTF(繊毛様神経栄養因子)からなる群より選択される蛋白質を治療用量で発現する、請求項1〜6いずれか1項に記載の方法。
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MX360595B (es) | 2006-02-08 | 2018-11-09 | Genzyme Corp | Terapia génica para la enfermedad de niemann-pick de tipo a. |
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- 2006-05-02 EP EP06752135A patent/EP1879623B1/en active Active
- 2006-05-02 BR BRPI0611540-3A patent/BRPI0611540A2/pt not_active Application Discontinuation
- 2006-05-02 WO PCT/US2006/016943 patent/WO2006119341A2/en active Application Filing
- 2006-05-02 CN CN201610153759.2A patent/CN105770909A/zh active Pending
- 2006-05-02 ES ES06752135T patent/ES2394482T3/es active Active
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- 2007-11-02 US US11/934,148 patent/US10744210B2/en active Active
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- 2012-12-26 JP JP2012282826A patent/JP2013082731A/ja active Pending
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Also Published As
Publication number | Publication date |
---|---|
EP1879623A2 (en) | 2008-01-23 |
CA2606490C (en) | 2018-02-06 |
US10744210B2 (en) | 2020-08-18 |
IL237658A0 (en) | 2015-04-30 |
PT1879623E (pt) | 2012-12-20 |
IL187023A (en) | 2015-10-29 |
PL1879623T3 (pl) | 2013-03-29 |
WO2006119341A2 (en) | 2006-11-09 |
IL187023A0 (en) | 2008-02-09 |
US20090069261A1 (en) | 2009-03-12 |
JP2017132774A (ja) | 2017-08-03 |
EP1879623B1 (en) | 2012-10-03 |
CN105770909A (zh) | 2016-07-20 |
ES2394482T3 (es) | 2013-02-01 |
MX2007013734A (es) | 2008-03-14 |
WO2006119341A3 (en) | 2007-06-28 |
JP2015163613A (ja) | 2015-09-10 |
AU2006242129A1 (en) | 2006-11-09 |
JP2013082731A (ja) | 2013-05-09 |
EP1879623A4 (en) | 2009-03-25 |
BRPI0611540A2 (pt) | 2010-09-21 |
US20210008227A1 (en) | 2021-01-14 |
JP5766389B2 (ja) | 2015-08-19 |
CA2606490A1 (en) | 2006-11-09 |
DK1879623T3 (da) | 2012-12-17 |
JP6887008B2 (ja) | 2021-06-16 |
JP2008540435A (ja) | 2008-11-20 |
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