JP7037490B2 - 副腎脊髄ニューロパチーの治療のためのabcd1をコードする核酸配列の髄腔内送達 - Google Patents
副腎脊髄ニューロパチーの治療のためのabcd1をコードする核酸配列の髄腔内送達 Download PDFInfo
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Description
本研究は、National Institutes of Healthにより授与された助成金番号R21NS081374-01およびR01NS072446-01により支援を受けた。政府は本発明における一定の権利を有する。
特に定義のない限り、本明細書において使用される全ての技術および科学用語は、本発明が属する分野の当業者により一般に理解される意味と同一の意味を有する。矛盾する場合、本出願が定義を含め優先される。
本発明の組成物および方法は、X連鎖性副腎白質ジストロフィー(X-ALD)のための治療を提供する。X連鎖性副腎白質ジストロフィーは、主として男性において生じ、主に神経系および副腎を冒すABCD1遺伝子中の突然変異により引き起こされる遺伝障害である。脳および脊髄のミエリンが劣化し(脱髄)、それが神経の機能的能力を低減させる。さらに、副腎の外層(副腎皮質)への損傷は、あるホルモンの不足を引き起こす(副腎皮質不全)。いくつかの区別されるタイプのX連鎖性副腎白質ジストロフィー、例として、小児大脳型、副腎脊髄ニューロパチー(AMN)タイプ、およびアジソン病と呼ばれる型が存在する。本明細書において使用されるX-ALDは、ツェルウェーガースペクトル障害のペルオキシソーム生合成障害に属し、ABCD1中の突然変異に無関連の「新生児副腎白質ジストロフィー」を含まない。X-ALDまたはAMNを有する対象を診断または同定する方法は当分野において公知であり、それとしては血漿超長鎖脂肪酸(VLCFA)レベルの計測および/または遺伝子試験を挙げることができ;例えば、Engelen et al,Orphanet J Rare Dis.2012;7:51;Aubourg and Chaussain,Horm Res.2003;59 Suppl 1:104-5;Steinberg et al.,Curr Protoc Hum Genet.2008 Chapter 17:Unit 17.6;Steinberg SJ,Moser AB,Raymond GV.X-Linked Adrenoleukodystrophy.1999 Mar 26[Updated 2015 Apr 9].In:Pagon RA,Adam MP,Ardinger HH,et al.,editors.GeneReviews(登録商標)[Internet].Seattle(WA):University of Washington,Seattle;1993-2016参照。ncbi.nlm.nih.gov/books/NBK1315/)から利用可能である。
AAV9-ABCD1の産生の間の多量の細胞死/細胞変性効果は既に観察されており、それらはおそらく産生細胞中のABCD1タンパク質の過剰発現に起因する。この毒性は、AAVベクター収量を低減させた。毒性を緩和し、ベクター収量を改善するため、siRNAのプールを使用してABCDImRNAを標的化した。
1.5μMのプール(25%の4つのsiRNAのそれぞれ)siRNA溶液を、1×siRNA緩衝液(GE Healthcare)または原液からの別の適切なRNアーゼフリー溶液中で調製する。
2.別個のチューブ中で、siRNA(チューブ1中100ul)および適切なDharmaFECT形質移入試薬(チューブ2中30ul)を、血清フリーDMEM培地により2ml容量にそれぞれ希釈する。
3.それぞれのチューブの含有物を、上下に慎重にピペッティングすることにより穏やかに混合する。室温において5分間インキュベートする。
4.チューブ1の含有物をチューブ2に添加し、総容量4mlとする。上下に慎重にピペッティングすることにより混合し、室温において20分間インキュベートする。12mlの完全DMEM(10%のFBS)をこの4mlに添加する。
5.3.75e6個の細胞/mlの濃度における完全培地中の4mlの再懸濁293T細胞(合計1.5E7個の細胞)を、ステップ4からの16mlの形質移入混合物に添加する(25nMの最終siRNA濃度)。
6.15cmディッシュ中にプレーティングし、24時間インキュベートする。
7.AAVプラスミドのリン酸カルシウム形質移入の1時間前に培地を10%のFBSの完全DMEMに交換する。
8.標準的AAV産生および精製プロトコルを進行させる。
1.ベクターを、ヌクレアーゼフリー水中で1:100~1:1000に希釈し、ボルテックスに供する。qPCRにおいて使用する。
2.プラスミド675.5(5999bp)をゲノムコピー数(GC)標準として使用する。107~102gc/mLから標準を作出する。
3.標準および試料をトリプリケートで計測するために十分多い量でマスターミックスを調製する。マスターミックスは、2ulのH2O、1.2ulのプライマーミックス(FおよびR=5ulのそれぞれの100umの原液、90ulの水中)、1ulのプライマーミックス(FおよびR=6ulのそれぞれの100umの原液、88ulの水中)、0.8ulのTM FAMプローブ2.5uM、1ulのTM FAMプローブ2uM(4ulの100uMの原液+196ulの水)、および5ulのTaqMan FastユニバーサルPCRマスターミックス2×を含む。
4.混合し、プレートのウェル中9ulでアリコート化する。
5.水中で希釈した1ulのテンプレートを添加する。
6.ステージ1がサイクル数1、95℃:20秒を有し、ステージ2がサイクル数40、95℃:03秒;60℃:30秒を有する熱サイクリングパラメータを有するように7500装置をプログラムする。
7.データを分析する。標準についての傾きは、約-3.3であるべきである。
自己相補的AAV9GFP(scAAV9GFP)およびABCD1をコードするrAAV9(rAAV9-ABCD1)を、Abcd1-/-マウスに、2分間の持続時間にわたるボーラスにより、または24時間の持続時間にわたる浸透圧ポンプにより髄腔内(IT)送達し、偽対照としてPBS注射を用いた。注射の2週間後、マウスを安楽死させ、マウスに4%のPFAを灌流させた。次いで、組織を回収し、切片化し、免疫蛍光分析のために染色した。
C26:0は、副腎脊髄ニューロパチーの生化学的特徴である。AAV9遺伝子送達後の遊離超長鎖脂肪酸(VLCFA)の存在を評価するため、脂質分解分析を脊髄試料に対して実施した。C26:0およびC24:0の絶対値ならびにC26:0/C22:0の比を報告する。髄腔内浸透圧ポンプ(1×1011gc)を介するrAAV9媒介ABCD1遺伝子導入は、脊髄中のC26:0レベルの20%低減をもたらすことが決定された(図13)。髄腔内浸透圧ポンプ送達後のレベルは、髄腔内ボーラス送達後のものと同等であるが、全身漏出を回避する。
本発明をその詳細な説明とともに記載した一方、上記説明は、添付の特許請求の範囲の範囲により定義される本発明を説明するものであり、その範囲を限定するものではないことを理解すべきである。他の態様、利点、および改変は、以下の特許請求の範囲の範囲内である。
本発明は、以下の態様を包含し得る。
[1]
培養下で増殖する形質移入産生細胞中のアデノ随伴ウイルス9(AAV9)ベクタータイターを増加させる方法であって、
i)ATP結合カセットサブファミリーDメンバー1(ABCD1)をコードするmRNAに相補的な核酸配列を前記細胞とインキュベートするステップ、および
ii)ABCD1をコードするヌクレオチド配列を含むAAV9ベクター(AAV9-ABCD1ベクター)を前記細胞中に形質移入するステップ
を含み、前記AAV9ベクターから発現されるABCD1mRNAの量を減少させ、それにより細胞溶解物および/または培地中のAAV9-ABCD1ベクター収量を参照標準と比較して約1倍~約50倍だけ増加させる方法。
[2]
ABCD1をコードするmRNAに相補的な前記核酸配列が、干渉RNAである、上記[1]に記載の方法。
[3]
前記干渉RNAが、shRNAまたはsiRNAである、上記[2]に記載の方法。
[4]
前記siRNAが、配列番号4、配列番号5、配列番号6、配列番号7、またはそれらの組合せを含む、上記[3]に記載の方法。
[5]
前記参照標準が、ABCD1をコードするmRNAに相補的な核酸配列とインキュベートしなかった産生細胞からの細胞溶解物および/または培地中のAAV9-ABCD1ベクター収量を含む、上記[1]に記載の方法。
[6]
X連鎖性副腎白質ジストロフィー(X-ALD)の治療が必要とされる対象におけるX連鎖性副腎白質ジストロフィーを治療する方法であって、上記[1]に記載の産生細胞から得られた精製AAV9-ABCD1ベクターを含む組成物を前記対象に投与することを含む方法。
[7]
精製AAV9-ABCD1ベクターを含む前記組成物を、髄腔内投与により前記対象を投与する、上記[6]に記載の方法。
[8]
X連鎖性副腎白質ジストロフィー(X-ALD)の治療が必要とされる対象におけるX連鎖性副腎白質ジストロフィーを治療する方法であって、ATP結合カセットサブファミリーDメンバー1(ABCD1)をコードするアデノ随伴ウイルス(AAV)ベクターを前記対象に投与することを含み、前記ベクターを髄腔内投与により前記対象に投与する方法。
[9]
前記髄腔内投与が、浸透圧ポンプにより媒介される、上記[8]に記載の方法。
[10]
ベクターの用量が、約1×10 13 GC~約10×10 13 GCである、上記[8]に記載の方法。
[11]
前記AAVが、AAV9である、上記[8]に記載の方法。
[12]
X連鎖性副腎白質ジストロフィー(X-ALD)を有する対象にATP結合カセットサブファミリーDメンバー1(ABCD1)を提供する方法であって、ABCD1をコードするベクターを前記対象に投与することを含み、前記ベクターを髄腔内投与により前記対象に投与し、中枢神経系中の前記ベクターからのABCD1発現は、末梢器官中の前記ベクターからのABCD1発現よりも少ない方法。
[13]
前記中枢神経系中の前記ベクターからのABCD1発現が、X-ALDを有さない未治療対象の中枢神経系中のABCD1の発現よりも約3倍多い、上記[12]に記載の方法。
[14]
末梢器官中の前記ベクターからの前記ABCD1発現が、X-ALDを有さない未治療対象の末梢器官中のABCD1の発現よりも約90%少ない、上記[13]に記載の方法。
Claims (12)
- X連鎖性副腎白質ジストロフィー(X-ALD)の治療が必要とされる対象におけるX連鎖性副腎白質ジストロフィーを治療するための組成物であって、ATP結合カセットサブファミリーDメンバー1(ABCD1)をコードするアデノ随伴ウイルス血清型9(AAV9)ベクターを含み、前記ベクターは、髄腔内投与により前記対象に投与され、かつ、前記ベクターは、配列番号10を含む機能的ABCD1タンパク質をコードする核酸配列を含む、組成物。
- 前記髄腔内投与が、ポンプにより媒介される、請求項1に記載の組成物。
- ベクターの用量が、約1×1013 ゲノムコピー(GC)~約10×1013GCである、請求項1または2に記載の組成物。
- 前記核酸配列が、配列番号9の相補体を含む、請求項1から3のいずれか一項に記載の組成物。
- X連鎖性副腎白質ジストロフィー(X-ALD)を有する対象にABCD1を提供するための組成物であって、ABCD1をコードするベクターを含み、前記組成物は、ABCD1をコードするベクターを髄腔内投与により前記対象に投与することを含む方法において使用され、中枢神経系中の前記ベクターからのABCD1発現は、末梢器官中の前記ベクターからのABCD1発現よりも多く、前記ベクターは、配列番号10を含む機能的ABCD1タンパク質をコードする核酸配列を含むAAV9ベクターである、組成物。
- 前記中枢神経系中の前記ベクターからのABCD1発現が、X-ALDを有さない未治療対象の中枢神経系中のABCD1の発現よりも約3倍多い、請求項5に記載の組成物。
- 末梢器官中の前記ベクターからの前記ABCD1発現が、X-ALDを有さない未治療対象の末梢器官中のABCD1の発現よりも約90%少ない、請求項6に記載の組成物。
- 前記髄腔内投与が、ポンプにより媒介される、請求項4から7のいずれか一項に記載の組成物。
- 核酸発現カセットを含むAAV9ベクターであって、前記核酸発現カセットが、順番に、
逆方向末端反復配列(ITR)、サイトメガロウイルス前初期(CMV IE)エンハンサー、ニワトリベータ-アクチンプロモーター、ベータ-アクチンエキソン、キメライントロン、配列番号10を含む機能的ABCD1タンパク質をコードする核酸配列、ウッドチャック肝炎ウイルス転写後調節エレメント(WPRE)、SV40ポリA配列、ウシ成長ホルモン(BGH)ポリA配列およびITRを含む、AAV9ベクター。 - 前記機能的ABCD1タンパク質をコードする核酸配列が、配列番号9を含むmRNA配列をコードする、請求項9に記載のAAV9ベクター。
- X-ALDの治療のための医薬を調製するための、請求項9または10に記載のAAV9ベクターの使用。
- X-ALDを治療するための、請求項9または10に記載のAAV9ベクターを含む組成物。
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