JP2022184901A - モジュラーAAV送達システムによるCRISPR-Casゲノム編集 - Google Patents
モジュラーAAV送達システムによるCRISPR-Casゲノム編集 Download PDFInfo
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Abstract
【解決手段】CRISPRベースのゲノムまたはエピゲノム編集用の組み換え系であって、(a)(i)C-インテインをコードするポリヌクレオチド、(ii)C-Cas9をコードするポリヌクレオチド、および(iii)第一のベクターのためのプロモーター配列、を含む第一の発現ベクター;および(b)(i)N-Cas9をコードするポリヌクレオチド、(ii)N-インテインをコードするポリヌクレオチド、および(iii)第二のベクターのためのプロモーター配列、を含む第二の発現ベクターを含んで成り、前記第一と第二の発現ベクターの同時発現が完全なCas9タンパク質の発現をもたらす、前記組み換え系を提供する。
【選択図】図2
Description
本出願は、2016年8月18日に出願の米国出願第62/376,855号、2016年11月1日出願の米国出願第62/415,858号、および2017年4月4日出願の米国出願第62/481,589号に対する米国特許法35 U.S.C. 119(e)に基づく優先権を主張する。その全内容が参照として援用される。
表1は、実施例1に用いられるガイドRNAスペーサー配列の一覧である。
〔定義〕
汎用される辞書に定義されるもののような用語は、本願および関連技術分野の範囲内の意味と一致する意味を有すると解釈すべきであり、かつ本明細書中でそのように表現上定義されない限り、理想化されたまたは過度に形式ばった意味で解釈すべきではない。下記に明示的に定義されないが、そのような用語はそれらの一般的な意味に従って解釈すべきである。
「ハイブリダイゼーション」とは、1以上のポリヌクレオチドが反応してヌクレオチド残基の塩基間の水素結合によって安定化される複合体を形成する反応のことを指す。水素結合はワトソン・クリック塩基対合、ホーグステイン結合、または他の任意の配列特異的方式により起こりうる。複合体は二重鎖構造を形成する二本の鎖、多重鎖複合体を形成する三本以上の鎖、一本の自己ハイブリダイズ鎖、またはそれらの任意組み合わせを含むことができる。ハイブリダイゼーション反応は、より広範囲のプロセスの中の一工程、例えばPC反応の開始、またはリボザイムによるポリヌクレオチドの酵素的開裂といった工程を構成することができる。
〔発明を実施する方法〕
Split-Casシステム
(b) (i) N-Casをコードするポリヌクレオチド、(ii) N-インテインをコードするポリヌクレオチド、および(iii)プロモーター配列、を含む、または本質的にから成る、またはから成る第二の発現ベクターと
を含む、または本質的にから成る、またはから成り、
ここで前記第一および第二の発現ベクターの同時発現が、機能的Cas9タンパク質の発現をもたらす、前記組み換え発現システムに関する。
〔時間的調節のためのエフェクター要素〕
〔組織特異性のためのエフェクター要素〕
HeLa:
miR-21-5p:uagcuuaucagacugauguuga
挿入される標的:TCAACATCAGTCTGATAAGCTAAGATCTA
HUVEC:
miR-126-3p:ucguaccgugaguaauaaugcg
挿入される標的:CGCATTATTACTCACGGTACGAAGATCAC
心臓:
miR-1a-3p:uggaauguaaagaaguauguau
挿入される標的:ATACATACTTCTTTACATTCCAAGATCAC
肝臓:
miR-122a-5p:uggagugugacaaugguguuug
挿入される標的:CAAACACCATTGTCACACTCCAAGATCAC
またはそれらの各々の生物学的同等物。組織特異的なmiRNAを選択し、このmiRNAにより標的されるmiRNA回路を作製することにより、ベクターの発現を高度に組織特異的となるように較正することができる。
〔遺伝子編集のためのエフェクター要素〕
〔特定の用途のためのgRNA〕
(genscript.com/gRNA-database.html)のような多数のgRNAデータベースの1つの中に見つけることができる。更にgRNAおよび/または標的遺伝子は、これらの非限定の典型的方法のための、および/または、gRNAおよび/または標的遺伝子に関連する任意の他の疾患もしくは障害のための組み換え発現系によりターゲティングすることができることを理解すべきである。
ノックアウトのためのgRNA:
NAV 1.3:TCGTGGATTTCTATCACTTT
NAV 1.8:CTTGGTAACGTCTTCTCTTG
NAV 1.9:Crgatgrgttcrchhacrgtgrchhaata
TRPV1:TAAGCTGAATAACACCGTTG
抑制のためのgRNA:
NAV 1.3:Crcrgrcttcrctgttctgagatc
NAV 1.8:Gtchhacrgagttcrchhacrcrctgrcrc
NAV 1.9:CAGCCTGGATGGCTTACCTC
TRPV1:GGGACTTACCAGCTAGGTGC
またはそれらの各々の生物学的同等物。さらに別の例示的gRNAを下記に提供する:
CD81:CGAAATTGAAGACGAAGAGC
MUC13:GGAGACTGAGAGAGAGAAGC
Sr-b1:TGATGAGGGAGGGCACCATG
各またはそれの生物学的等価物。
CCR5 gRNA:GGTCCTGCCGCTGCTTGTCA
またはその生物学的同等物。
PDCD-1標的配列:
1. AGCCGGCCAGTTCCAAACCC
2. AGGGCCCGGCGCAATGACAG
またはそれの各々の生物学的同等物。
〔エフェクター要素の順序〕
〔カプシドの遺伝子操作〕
KTag-サブスタンスP:ATHIKFSKRD GSGSGS RPKPQQFFGLM
サブスタンスP-KTag:RPKPQQFFGLM GSGSGS ATHIKFSKRD
RVG-KTag:YTIWMPENPRPGTPCDIFTNSRGKRASNG GGK GGGSGSGS ATHIKFSKRD
KTag-RVG:ATHIKFSKRD GSGSGS GGK GG YTIWMPENPRPGTPCDIFTNSRGKRASNG
またはそれの生物学的同等物。
米国特許第7,867,484; 7,892,809; 9,012,224; 8,632,764; 9,409,953; 9,402,921; 9,186,419; 8,889,641; 7,790,154; 7,465,583; 7,923,436; 7,301,898; 7,172,893; 7,071,172; 8,784,799; 7,235,235; 6,541,010; 6,531,135; 6,531,235; 5,792,462; 6,982,082; 6,008,035; 5,792,462; 9,617,561; 9,593,346; 9,587,250; 9,567,607; 9,493,788; 9,382,551; 9,359,618; 9,315,825; 9,217,159; 9,206,238; 9,198,984; 9,163,260; 9,133,483; 8,999,678; 8,962,332; 8,962,233; 8,940,290; 8,906,675; 8,846,031; 8,834,863; 8,685,387; 米国特許公開公報第2016/120960; 2017/0096646; 2017/0081392; 2017/0051259; 2017/0043035; 2017/0028082; 2017/0021037; 2017/0000904; 2016/0271192; 2016/0244783; 2916/0102295; 2016/0097040; 2016/0083748; 2016/0083749; 2016/0051603; 2016/0040137; 2016/0000887; 2015/0352203; 2015/0315612; 2015/0230430; 2015/0159173; 2014/0271550, および、それらの特許および特許刊行物に関連したファミリーメンバー、またはそれらの譲渡人もしくは発明者に関連するもの。
〔組合せおよび方法〕
組織特異的促進物質であるmiRNA回路の使用、およびウイルスカプシド中の標的の癌に特異的なホーミングペプチドの組み込みは、処置が確実に所望の標的中の遺伝子だけに作用するようにすることができる。
実施例1―典型的なモジュラーAAVシステムの作製
ベクターの設計と構築
哺乳類細胞培養
AAVウイルスの生産
動物実験
ゲノムDNA抽出およびNGSプレップ
遺伝子発現解析およびqRT-PCR
AAVシュードタイピング
考察
実施例2-AAV2カプシド上への非天然アミノ酸の付加
実施例3:AAV2-SpyTag
実施例4:AAV-DJ
実施例5:組織特異性のためのmiRNA
実施例6:疼痛管理
実施例7:CD81抑制
実施8:疼痛管理
別に定義されない限り、本明細書中で使用される全ての技術用語および科学用語は、当該技術が属する技術分野の当業者により一般に理解されるものと同じ意味を有する。
[1]CRISPRベースのゲノムまたはエピゲノム編集用の組み換え系であって、
(a) (i)C-インテインをコードするポリヌクレオチド、(ii) C-Cas9をコードするポリヌクレオチド、および(iii) 第一のベクターのためのプロモーター配列、を含む第一の発現ベクター;および
(b) (i)N-Cas9をコードするポリヌクレオチド、(ii) N-インテインをコードするポリヌクレオチド、および(iii)第二のベクターのためのプロモーター配列、を含む第二の発現ベクター
を含んで成り、
ここで任意に、前記第一と第二の発現ベクターがアデノ随伴ウイルス(AAV)またはレンチウイルスベクターであり、そして
前記第一と第二の発現ベクターの同時発現が完全なCas9タンパク質の発現をもたらす、前記組み換え系。
[2]前記第一の発現ベクターのプロモーター配列が、CMVプロモーターを含んで成る、[1]に記載の組み換え系。
[3]前記第二のベクターのプロモーター配列が、gRNA配列に作用可能に連結された第一のプロモーター、任意にsgRNA、および第二のプロモーターを含んで成る、[1]または[2]に記載の組み換え系。
[4]前記第一のプロモーター配列がU6プロモーターである、[3]に記載の組み換え系。
[5]前記第二のプロモーター配列がCMVプロモーターである、[3]または[4]に記載の組み換え系。
[6]前記第一の発現ベクターと第二の発現ベクターの双方がポリAテールを更に含んで成る、[1]に記載の組み換え系。
[7]前記第一の発現ベクターがテトラサイクリン応答要素を更に含み、そして/または前記第二の発現ベクターがテトラサイクリン調節性活性化因子を更に含み、あるいは前記第一の発現ベクターがテトラサイクリン調節性活性化因子を更に含み、そして/または第二の発現ベクターがテトラサイクリン応答要素を更に含む、[1]に記載の組み換え発現系。
[8]前記テトラサイクリン応答要素がtetOの1以上の反復配列を含む、[7]に記載の組み換え発現系。
[9]前記テトラサイクリン応答要素がtetOの7つの反復配列を含む、[7]に記載の組み換え発現系。
[10]前記テトラサイクリン調節性活性化因子がrtTaおよび任意に2Aを含む、[7]に記載の組み換え発現系。
[11]前記C-Cas9がdC-Cas9でありそしてN-Cas9がdN-Cas9である、[1]に記載の組み換え発現系。
[12]前記第一の発現ベクターおよび/または第二の発現ベクターがKRAB、DNMT3AまたはDNMT3Lの1つ以上を更に含む、[11]に記載の組み換え発現ベクター。
[13]前記第一の発現ベクターおよび/または第二の発現ベクターがVP64、RtAまたはP65の1つ以上を更に含む、[11]に記載の組み換え発現系。
[14]抑制、サイレンシングまたは下方制御のために標的とされる遺伝子のgRNAを更に含んで成る、[12]に記載の組み換え発現系。
[15]発現、活性化または上方制御のために標的とされる遺伝子のgRNAを更に含んで成る、[13]に記載の組み換え発現系。
[16]発現、活性化または上方制御のために標的とされる遺伝子、および場合によりプロモーター、をコードする第三の発現ベクターを更に含む、[15]に記載の組み換え発現系。
[17]前記第一の発現ベクターおよび/または第二の発現ベクターがmiRNA回路を更に含む、[1]~[16]のいずれかに記載の組み換え発現系。
[18][1]に記載の組み換え発現系を含む組成物であって、前記第一の発現ベクターが第一のウイルスカプシド中に封入されており、そして第二の発現ベクターが第二のウイルスカプシド中に封入されており、ここで場合により、第一のウイルスカプシドおよび/または第二のウイルスカプシドがAAVまたはレンチウイルスカプシドである組成物。
[19]前記AAVがAAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11またはAAV-DJの1つである、[18]に記載の組成物。
[20]前記第一のウイルスカプシドおよび/または第二のウイルスカプシドが、非天然アミノ酸、SpyTagまたはKTagから成る群の1つ以上を含むように改変される、[18]に記載の組成物。
[21]前記非天然アミノ酸がN-ε-((2-アジドエトキシ)カルボニル)-L-リジンである、[20]に記載の組成物。
[22]前記第一のウイルスカプシドおよび/または第二のウイルスカプシドがペプチド、アプタマー、オリゴヌクレオチド、アフィボディ、DARPin、Kunitzドメイン、フィノマー、二環式ペプチド、アンチカリンまたはアドネクチンのうちの1つでシュードタイプ化される、[20]に記載の組成物。
[23]前記第一のウイルスカプシドおよび/または第二のウイルスカプシドがAAV2カプシドである、[18]に記載の組成物。
[24]前記非天然アミノ酸、SpyTagまたはKTagが、VP1のアミノ酸残基R447、S578、N587またはS662のところで組み込まれる、[23]に記載の組成物。
[25]前記第一のウイルスカプシドおよび/または第二のウイルスカプシドがAAV-DJカプシドである、[18]に記載の組成物。
[26]前記非天然アミノ酸、SpyTagまたはKTagが、VP1のアミノ酸残基N589のところで組み込まれる、[25]に記載の組成物。
[27]前記第一のウイルスカプシドと第二のウイルスカプシドが連結される、[18]に記載の組成物。
[28]疼痛管理を必要とする被験体における疼痛管理の方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物が、SCN9A、SCN10A、SCN11A、SCN3A、TrpV1、SHANK3、NR2B,IL-10、PENK、POMCまたはMVIIA-PCのうちの1以上を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[29]処置を必要とする被験体においてマラリアを治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がCD81、MUC13またはSR-B1のうちの1つ以上を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[30]処置を必要とする被験体においてC型肝炎を治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がCD81、MUC13、SR-B1、GYPA、GYPC、PKLRまたはACKR1の1つ以上を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[31]処置を必要とする被験体において造血幹細胞療法の免疫拒絶を治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がCCR5を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[32]処置を必要とする被験体においてHIVを治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がCCR5を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[33]処置を必要とする被験体において筋ジストロフィーを治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がジストロフィンを標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[34]処置を必要とする被験体において癌を治療または改善する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がPDCD-1、NODALまたはJAK-2の1つ以上を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[35]処置を必要とする被験体においてシトクロムp450疾患を治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がCYP2D6を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[36]処置を必要とする被験体においてアルツハイマー病を治療または予防する方法であって、[27]に記載の組成物の有効量を該被験体に投与することを含み、ここで該組成物がLilrB2を標的とするgRNAをコードするベクターを含むことを特徴とする方法。
[37]前記被験体が哺乳類である、[29]~[36]のいずれかに記載の方法。
[38]前記被験体がネズミ、イヌ、ネコ、ウマ、ウシ、サル、またはヒト患者である、[37]に記載の方法。
[39]VP1のアミノ酸残基R447、S578、N587またはS662の所に非天然アミノ酸、SpyTagまたはKTagを含む改変型AAV2カプシド。
[40]前記非天然アミノ酸がN-ε-((2-アジドエトキシ)カルボニル)-L-リジンである、[39]に記載の改変型AAV2カプシド。
[41]前記改変型AAV2カプシドがペプチド、アプタマー、オリゴヌクレオチド、アフィボディ、DARPin、Kunitzドメイン、フィノマー、二環式ペプチド、アンチカリンまたはアドネクチンの1つによりシュードタイプ化される、[39]に記載の改変型AAV2カプシド。
[42]リポフェクタミンで被覆された[39]に記載の改変型AAV2カプシド。
[43]VP1のアミノ酸残基N589の所に非天然アミノ酸、SpyTagまたはKTagを含む改変型AAV-DJカプシド。
[44]前記非天然アミノ酸がN-ε-((2-アジドエトキシ)カルボニル)-L-リジンである、[43]に記載の改変型AAV-DJカプシド。
[45]前記改変型AAV-DJカプシドがペプチド、アプタマー、オリゴヌクレオチド、アフィボディ、DARPin、Kunitzドメイン、フィノマー、二環式ペプチド、アンチカリンまたはアドネクチンの1つによりシュードタイプ化される、[43]に記載の改変型AAV-DJカプシド。
[46]リポフェクタミンで被覆された[43]に記載の改変型AAV-DJカプシド。
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Claims (1)
- CRISPRベースのゲノムまたはエピゲノム編集用の組み換え系であって、
(a) (i)C-インテインをコードするポリヌクレオチド、(ii) C-Cas9をコードするポリヌクレオチド、および(iii) 第一のベクターのためのプロモーター配列、を含む第一の発現ベクター;および
(b) (i)N-Cas9をコードするポリヌクレオチド、(ii) N-インテインをコードするポリヌクレオチド、および(iii)第二のベクターのためのプロモーター配列、を含む第二の発現ベクター
を含んで成り、
ここで任意に、前記第一と第二の発現ベクターがアデノ随伴ウイルス(AAV)またはレンチウイルスベクターであり、そして
前記第一と第二の発現ベクターの同時発現が完全なCas9タンパク質の発現をもたらす、前記組み換え系。
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JP2019524162A (ja) | 2019-09-05 |
JP2024056895A (ja) | 2024-04-23 |
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