JP2023011868A - Mps-i関連失明の治療のためのaav-iduaベクター - Google Patents
Mps-i関連失明の治療のためのaav-iduaベクター Download PDFInfo
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Abstract
Description
本発明の別の態様は、IDUAを発現するAAV粒子を含む剤であって、対象の角膜にIDUAを送達することにおいて使用する為の該剤に関する。
本発明の別の態様は、IDUAを発現するアデノ随伴ウイルス(AAV)粒子を含む剤であって、対象におけるムコ多糖症I型(MPS-I)関連角膜混濁を治療又はその発症を遅延することにおいて使用する為の該剤に関する。
本明細書及び添付の特許請求の範囲では、以下の用語を用いる。
本発明は、IDUAをコードするヌクレオチド配列を含んでいて、対象の角膜においてIDUAを発現させることができるパルボウイルスベクター(例えばAAVベクター)を提供する。
1 CACCGGTCGC CACCATGCGA CCACTGAGACCACGGGCCGC TCTGCTGGCT
51 CTGCTGGCTT CACTGCTGGC CGCTCCCCCT GTCGCTCCTGCTGAGGCTCC
101 CCACCTGGTG CATGTGGACG CAGCTCGCGC CCTGTGGCCACTGAGGAGAT
151 TCTGGAGGAG CACAGGCTTT TGCCCACCTC TGCCTCACAGCCAGGCTGAC
201 CAGTACGTGC TGTCCTGGGA TCAGCAGCTG AACCTGGCATATGTGGGAGC
251 CGTCCCCCAC AGGGGGATCA AACAGGTGAG AACTCATTGGCTGCTGGAGC
301 TGGTCACCAC ACGAGGATCT ACTGGAAGGG GGCTGAGTTACAACTTCACC
351 CACCTGGACG GCTATCTGGA TCTGCTGAGA GAGAATCAGCTGCTGCCTGG
401 ATTTGAACTG ATGGGCTCAG CCAGCGGACA TTTCACCGACTTTGAGGATA
451 AGCAGCAGGT GTTCGAATGG AAAGACCTGG TCAGCTCCCTGGCTCGGCGC
501 TACATTGGGC GGTATGGCCT GGCACACGTG AGTAAGTGGAACTTTGAGAC
551 TTGGAATGAA CCAGACCACC ATGACTTCGA TAACGTGTCAATGACCATGC
601 AGGGGTTTCT GAATTACTAT GATGCCTGCT CCGAGGGCCTGCGGGCAGCC
651 TCTCCAGCTC TGCGACTGGG AGGACCAGGC GATTCCTTCCACACACCACC
701 CAGAAGTCCC CTGTCATGGG GCCTGCTGCG GCACTGTCATGACGGAACCA
751 ACTTCTTTAC AGGAGAAGCA GGGGTGAGAC TGGATTACATCTCCCTGCAT
801 CGAAAGGGGG CCAGGTCTAG TATCTCTATT CTGGAGCAGGAAAAGGTGGT
851 CGCTCAGCAG ATCCGGCAGC TGTTCCCCAA ATTTGCCGACACACCTATCT
901 ACAATGACGA GGCTGATCCT CTGGTGGGAT GGTCTCTGCCTCAGCCATGG
951 CGAGCCGATG TGACTTATGC TGCAATGGTG GTCAAAGTCATTGCTCAGCA
1001 CCAGAACCTG CTGCTGGCAA ATACTACCAG TGCTTTCCCATACGCACTGC
1051 TGAGTAACGA CAATGCCTTC CTGTCATATC ACCCCCATCCTTTTGCCCAG
1101 AGAACACTGA CTGCTCGGTT TCAGGTGAAC AATACCCGACCTCCACATGT
1151 GCAGCTGCTG AGGAAGCCTG TCCTGACAGC CATGGGCCTGCTGGCTCTGC
1201 TGGACGAGGA ACAGCTGTGG GCAGAGGTGT CTCAGGCCGGGACTGTCCTG
1251 GATAGTAACC ACACCGTGGG CGTCCTGGCT TCTGCACATCGACCTCAGGG
1301 ACCAGCAGAC GCTTGGCGAG CAGCTGTGCT GATCTACGCATCAGACGATA
1351 CACGAGCACA CCCTAACCGA AGCGTGGCAG TCACTCTGCGACTGCGAGGA
1401 GTGCCACCTG GACCAGGACT GGTGTACGTC ACCCGCTATCTGGACAATGG
1451 CCTGTGCTCT CCCGATGGAG AGTGGCGAAG GCTGGGGAGGCCCGTGTTCC
1501 CTACAGCAGA GCAGTTTAGA CGGATGAGAG CAGCCGAAGATCCAGTGGCT
1551 GCAGCACCAC GACCACTGCC TGCAGGAGGC AGACTGACCCTGCGGCCAGC
1601 CCTGCGCCTG CCAAGCCTGC TGCTGGTGCA CGTCTGCGCAAGGCCTGAAA
1651 AGCCACCCGG ACAGGTGACA AGGCTGAGAG CTCTGCCACTGACTCAGGGA
1701 CAGCTGGTGC TGGTCTGGTC AGACGAGCAT GTGGGGAGCAAATGTCTGTG
1751 GACTTACGAA ATTCAGTTCA GCCAGGATGG GAAGGCCTATACCCCTGTGA
1801 GCCGGAAACC CAGCACCTTC AACCTGTTCG TCTTTTCCCCAGACACCGGG
1851 GCCGTGTCCG GCTCTTACCG GGTCCGCGCT CTGGACTATTGGGCAAGGCC
1901 AGGCCCCTTC AGCGATCCTG TGCCATACCT GGAAGTGCCTGTGCCTCGCG
1951 GCCCACCATC TCCTGGAAAC CCTTGAGGGG ATCCGTCGAC TAG
本発明はさらに、ウイルスベクターの生産方法を提供する。ある特定の実施形態では、本発明は、組換えパルボウイルス粒子の生産方法であって、パルボウイルス複製を許容する細胞に、(a)(i)IDUAをコードする核酸と(ii)パルボウイルスITRとを含む組換えパルボウイルス鋳型、(b)Rep及びCapコード配列を含むポリヌクレオチドを、組換えパルボウイルス鋳型の複製及びパッケージングに十分な条件下で、与え、もって細胞内で組換えパルボウイルス粒子を産生させることを含む方法を提供する。組換えパルボウイルス鋳型の複製及びパッケージングに十分な条件は、例えば、パルボウイルス鋳型の複製及びパルボウイルスカプシド内への被包に十分なAAV配列(例えば、パルボウイルスrep配列及びパルボウイルスcap配列)の存在並びにアデノウイルス及び/又はヘルペスウイルス由来のヘルパー配列の存在である。特定の実施形態では、パルボウイルス鋳型は2つのパルボウイルスITR配列を含んでいて、それらは異種核酸配列の5’側及び3’側に位置するが、異種核酸配列と直接接している必要はない。
本発明のウイルスベクターは、インビトロ、エクスビボ及びインビボでの細胞への核酸の送達に有用である。特に、本ウイルスベクターは、哺乳動物細胞を始めとする動物に核酸を送達又は導入するのに好適に使用できる。特に、本発明のウイルスベクターは、IDUAをコードする核酸を対象の角膜に送達するのに有用である。
本発明に係るウイルスベクター及びカプシドは、獣医学用途及び医学用途の両方に用途が見出される。適切な対象には、鳥類及び哺乳動物が包含される。本明細書で用いる「鳥類」という用語には、ニワトリ、アヒル、ガチョウ、ウズラ、シチメンチョウ、キジ、オウム、インコ等が包含されるが、これらに限定されない。本明細書で用いる「哺乳動物」という用語には、ヒト、ヒト以外の霊長類、ウシ、ヒツジ、ヤギ、ウマ、ネコ、イヌ、ウサギ等が包含されるが、これらに限定されない。ヒト患者には、新生児、乳児、少年及び成人が包含される。
別の実施形態では、対象は、角膜の少なくとも部分的な混濁を有し、例えば、対象の視力は、MPS-Iを有していない対象に比して、約10%未満、例えば、約10%未満、20%未満、30%未満、40%未満、50%未満、60%未満、70%未満、80%未満又は90%未満低下する。
材料及び方法
AAVベクターの作製:細胞培養実験に関して、実施例で使用したベクターの生産には、文献に記載されたトリプルトランスフェクション法を使用した(Grieger et al., Nat. Protoc. 1(3):1412(2006))。この方法ではpXR2又はpXR8G9プラスミドを使用したが、これらはいずれもAAVのrep2を含んでおり、それぞれ表記のセロタイプのカプシド遺伝子を含む。pTR-CMV-eGFPのegfp遺伝子をAgeI及びSalI部位でコドン最適化IDUA cDNA(GenScript社から提供)で置換することによって、所期のAAVゲノムを含むプラスミドを最初に構築した。AAV産生及び塩化セシウム勾配分離(Grieger et al., Nat. Protoc. 1(3):1412(2006))後に、ピーク画分をPBSで透析し、定量的PCR(CMV_F CAA GTA CGC CCC CTA TTG AC(配列番号2)、CMV_R AAG TCC CGT TGA TTT TGG TG(配列番号3))で力価を測定し、これをサザンドットブロット(Grieger et al., Nat. Protoc. 1(3):1412(2006))で確認した。ヒト外植片での実験のため、GMPグレードのベクター標品はUNC Vector Coreから提供された。
ウェスタンブロット用に、タンパク質溶解物を4×Nupageサンプル緩衝液中の5%β-メルカプトエタノール溶液に添加した。得られた溶液を10分間煮沸し、氷上で10分間冷却し、次いで10%ビス-トリスプレキャストゲルに流した。ゲルを1×MOPSランニング緩衝液中で泳動し、ニトロセルロースメンブレンに移した。メンブレンをddH2O中の5%ミルクでブロッキングし、PBS-Tween溶液(1×PBS中0.5%Tween20)で1:500希釈したマウス宿主IDUA抗体(R&D Systems MAB-4119)で2時間又はPBS-Tweenで1:5000希釈したマウス宿主β-アクチン抗体(Sigma社)と反応させた。次いで、PBS-Tweenで1:10000希釈したマウス西洋ワサビペルオキシダーゼ二次抗体を反応させた。Western-Bright Sirius化学発光試薬を製品プロトコールに従って使用し、ブロットをオートラジオグラフィーフィルムを用いて露光した。
MPS-I線維芽細胞におけるAAV IDUA発現カセット
AAV IDUA発現カセットを開発するために、ヒトidua cDNA(NM_000203)をヒト発現のためにコドン最適化し(opt-IDUA)、AAV末端逆位反復配列セロタイプ2プラスミドコンテクストにおけるCMVプロモーターとSV40ポリアデニル化配列との間に配置させた(図1A)。AAV2-opt-IDUAベクターを文献に記載の通り調製し(Grieger et al.,Adv. Biochem. Eng. Biotechnol. 99:119(2005))、MPS-I患者由来線維芽細胞の特性解析に使用した。不死化正常ヒト線維芽細胞(NHF)を対照細胞株として用いた(Simpson et al.,J. Carcinog. 4:18(2005))。用量漸増実験において、MPS-I線維芽細胞のAAV2-opt-IDUA形質導入によって、細胞溶解物及び培養上清の両方でIDUA回復レベルが増加した(図1B)。実際、NHFにおけるIDUAの静止レベルは比較的低いので、5000ウイルスゲノム/細胞の用量で、細胞溶解物及び培養上清のいずれにおいても既に超生理的レベルとなった(図1B)。IDUA機能は、形質導入したMPS-I患者の線維芽細胞において一貫して回復及び上昇し、検討した最も高い用量では細胞溶解物及び上清においてそれぞれ10倍及び30倍増大した(図1C及び図1D)。AAVベクター形質導入後のIDUA過剰産生にもかかわらず、色素排除アッセイではいずれの用量でも患者線維芽細胞に毒性は観察されなかった(図2)。重要な点として、これらの結果は、MPS-I患者におけるAAV2-opt-IDUAの機能性及び安全性を実証している。
角膜におけるAAV IDUA発現カセット
MPS1患者の角膜の分析から、角膜実質異常が、失明をもたらす角膜混濁の原因とされている(Huang et al.,Exp. Eye Res. 62(4):377(1996))。したがって、AAV-opt-IDUAの直接投与は、MPS-I患者の角膜実質区画におけるIDUA活性を回復し、MPS-I表現型を予防又は逆転させると期待される。以前の報告では、角膜に存在する最も一般的な細胞型の1つであるヒト角膜実質細胞の形質導入に対するAAV8(Hippert et al.,PLoS One、7(4):e35318(2012))及びAAV9(Sharma et al.,Exp. Eye Res. 91(3):440(2010))の有用性が実証されている。そこで、死後数週間生存可能である正常ヒト角膜外植片において、自己相補性(sc)AAV-CMV-GFPゲノムを有するこれらのカプシドを評価した。予備実験で、角膜実質への体積50μlの注射が、最小限の組織膨張及び成人角膜の約50%分布を伴って容認されることが墨汁を含有するベクタービヒクルを用いて実証された(図3)。したがって、GFPレポーター遺伝子を含むAAVセロタイプ8又は9を注射(50μl中1e10vg)によってヒト角膜実質に投与し、7日後にウェスタンブロッティングによって分析した。角膜形質導入に関するセロタイプ8及び9の両者についての報告があるので、AAV8カプシドにAAV9のガラクトース受容体を合体させたAAV8/9キメラカプシド(8G9)についても、同様の方法で検討した(Sharma et al.,Exp. Eye Res. 91(3):440(2010); Hippert et al.,PLoS One,7(4):e35318(2012))。ウェスタンブロッティングは、AAV8G9-GFPがいずれかの親セロタイプよりも大きな形質導入をもたすことを示している(図4A)。
インビボでの角膜におけるAAV IDUA発現カセット
インビボでのAAV IDUA発現の効果をMPS1イヌで試験した。イヌI-712の左眼に、図8A~図8Dに示すようにAAV8G9-CMV-optIDUA(1e9vg/μl)溶液を注射した。インスリン注射器の針先を角膜実質に挿入し(A)、溶液を徐々に注入して(B)全量(65μl)を投与した(C)。注射直後に、液体保持領域が、角膜表面の30%の部分の、軸角膜の曇り又は浮腫として視認された(D)。眼科用超音波生体顕微鏡によって、表記時点での中心角膜厚を測定することができた(図8E)。注射2分後にみられた膨張は2日以内に解消した。
Claims (24)
- ヒトα-L-イズロニダーゼ(IDUA)をコードする配列を含む組換え核酸であって、ヌクレオチド配列がヒト細胞内での発現のためにコドン最適化されている、組換え核酸。
- 配列番号1と90%以上同一のヌクレオチド配列を含む、請求項1に記載の組換え核酸。
- 配列番号1のヌクレオチド配列を含む、請求項1に記載の組換え核酸。
- 請求項1に記載の核酸を含むアデノ随伴ウイルス(AAV)ベクターゲノム。
- 前記核酸が構成型プロモーターに作動可能に連結されている,請求項4に記載のAAVベクターゲノム。
- 請求項4又は請求項5に記載のAAVベクターゲノムを含むインビトロ細胞。
- 前記ベクターゲノムが細胞ゲノムに安定的に組み込まれている、請求項6に記載の細胞。
- 請求項4又は請求項5に記載のAAVベクターゲノムを含むAAV粒子。
- AAVカプシドを含む組換えAAV粒子の生産方法であって、
インビトロで細胞に、AAV Cap及びAAV Repをコードする配列、請求項4又は請求項5に記載のAAVベクターゲノム並びに増殖的AAV感染を発生させるためのヘルパー機能を与えること、及び
AAVカプシドを含み、かつAAVベクターゲノムをカプシド内に被包する組換えAAV粒子を組み立てさせること
を含む方法。 - 請求項9に記載の方法によって生産されたAAV粒子。
- 当該AAV粒子がAAV2、AAV8又はAAV9粒子である、請求項8又は請求項10に記載のAAV粒子。
- 当該AAV粒子がキメラAAV8/AAV9粒子である、請求項8又は請求項10に記載のAAV粒子。
- 請求項8又は請求項10乃至請求項12のいずれか1項に記載のAAV粒子と薬学的に許容される媒体とを含む医薬製剤。
- 対象の角膜にIDUAを送達する方法であって、対象の角膜に、IDUAを発現するAAV粒子の有効量を投与し、もって対象の角膜にIDUAを送達することを含む方法。
- 対象におけるムコ多糖症I型(MPS-I)関連角膜混濁を治療又はその発症を遅延させる方法であって、対象の角膜に、IDUAを発現するAAV粒子の治療有効量を投与し、もって対象におけるMSP-I関連角膜混濁を治療又はその発症を遅延させることを含む方法。
- インビトロ又はエクスビボで角膜にIDUAを送達する方法であって、角膜を、IDUAを発現するAAV粒子の有効量と接触させ、もって角膜にIDUAを送達することを含む方法。
- 前記角膜を、それを必要とする対象に移植することをさらに含む、請求項16に記載の方法。
- 前記AAV粒子が、請求項8又は請求項10乃至請求項12のいずれか1項に記載のAAV粒子或いは請求項13に記載の医薬製剤である、請求項14乃至請求項17のいずれか1項に記載の方法。
- 前記AAV粒子が、実質内注射によって角膜に投与される、請求項14乃至請求項18のいずれか1項に記載の方法。
- 前記AAV粒子が角膜に局所的に投与される、請求項14乃至請求項18のいずれか1項に記載の方法。
- 前記対象がヒト患者である、請求項14乃至請求項20のいずれか1項に記載の方法。
- 前記対象がMPS-Iと診断されている、請求項14乃至請求項21のいずれか1項に記載の方法。
- 前記対象が角膜の混濁を未だに発症していない、請求項14乃至請求項22のいずれか1項に記載の方法。
- 前記対象が角膜の混濁を発症している、請求項14乃至請求項22のいずれか1項に記載の方法。
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2017
- 2017-02-22 RU RU2018132517A patent/RU2018132517A/ru unknown
- 2017-02-22 US US16/076,654 patent/US11116850B2/en active Active
- 2017-02-22 MX MX2018009426A patent/MX2018009426A/es unknown
- 2017-02-22 CN CN201780012623.2A patent/CN108697774A/zh active Pending
- 2017-02-22 CA CA3011943A patent/CA3011943A1/en active Pending
- 2017-02-22 EP EP17757103.1A patent/EP3419639A4/en active Pending
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2018
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2021
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2022
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BR112018017125A2 (pt) | 2018-12-26 |
JP7231922B2 (ja) | 2023-03-02 |
US11116850B2 (en) | 2021-09-14 |
CN108697774A (zh) | 2018-10-23 |
MX2018009426A (es) | 2018-12-19 |
US20190048363A1 (en) | 2019-02-14 |
IL260643A (ja) | 2018-09-20 |
EP3419639A1 (en) | 2019-01-02 |
US20220047721A1 (en) | 2022-02-17 |
IL260643B1 (en) | 2023-03-01 |
RU2018132517A (ru) | 2020-03-24 |
JP2019511927A (ja) | 2019-05-09 |
KR20180109945A (ko) | 2018-10-08 |
IL260643B2 (en) | 2023-07-01 |
CA3011943A1 (en) | 2017-08-31 |
AU2017223465A1 (en) | 2018-08-09 |
HK1255692A1 (zh) | 2019-08-23 |
RU2018132517A3 (ja) | 2020-06-10 |
WO2017147123A1 (en) | 2017-08-31 |
EP3419639A4 (en) | 2019-08-07 |
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