JP2018527013A - アレル選択的な遺伝子編集およびその使用 - Google Patents
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Abstract
Description
本願は、ARC5237WO_SL.txtという名前のASCIIファイルとして、電子的に提出された配列表を含む。
いくつかの実施態様において、リンカー基のモノマーは、アンロックドヌクレオモノマー(UNAモノマー)であってもよく、これは、以下に示される、プロパン−1,2,3−トリ−イル−トリスオキシ構造に基づく、有機小分子である。
本発明のU−ガイド分子は、式Iの構造を有し得る。
配列番号2
5’CTGGTGCACAGCAGTGCATCT3’
および
配列番号3
5’CCTCTCTCTGAGCCCTCTAGCTGGTA3’
を用いて増幅した。
配列番号4
5’CTGGTGCACAGCAGTGCATCT3’
および
配列番号5
5’CCTCTCTCTGAGCCCTCTAGCTGGTA3’
を用いて増幅した。
順方向(イントロン1):5’−tgtcttctctacacccagggcac−3’
逆方向(エクソン2):5’−gcaaaccacagctagaggagagga−3’。
配列番号559
5’ACAACTGGTAAGAAGGAGTGAC3’および
配列番号560
5’CCTTGGGTTTTGGGTGATCC3’
を用いて増幅した。
配列番号561
5’TCGACACTTACGTTCCTGAT3’または
配列番号562
5’CATACTTGACCTCTGCCTAC3’
のいずれかのプライマーを用いて、サンガーシークエンスした。
配列番号605
5’−GUUUUAGAGCUAUGCU−3’である。
配列番号606
5’-mA*mG*mC*mAmUmAmGmCmAAGUUAAAAUAAGGCUAGUCCGUUAUCAAmCmUmUmGmAmAmAmAmAmGmUmGmGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU-3’である。
Claims (45)
- ゲノムDNAを標的とするガイド化合物であって、crRNAと結合している14〜24個の連続するモノマーの標的ガイド鎖を含み、ゲノムDNAのCRISPR遺伝子編集を導く、ガイド化合物。
- ガイド化合物が、ヒト遺伝子TTRに二本鎖切断を導き、標的ガイド鎖が、5’−UGCAUGGCCACAUUGAUGGC−3’(配列番号13)の16〜20個の連続するモノマーおよびその置換体または修飾体を含み、crRNAが、標的ガイド鎖の3’末端において結合している、請求項1に記載のガイド化合物。
- 配列番号32を含む、請求項2に記載のガイド化合物。
- ガイド化合物が、ヒト遺伝子TTRに二本鎖切断を導き、標的ガイド鎖が、5’−CACAUGCAUGGCCACAUUGA−3’(配列番号40)の16〜20個の連続するモノマーおよびその置換体または修飾体を含み、crRNAが、標的ガイド鎖の3’末端において結合している、請求項1に記載のガイド化合物。
- 配列番号61を含む、請求項4に記載のガイド化合物。
- crRNAが、5’−GUUUUAGAGCUAUGCU−3’(配列番号605)であり、その置換型または修飾型である、請求項1に記載のガイド化合物。
- モノマーがUNAモノマーおよび核酸モノマーを含み、ガイド化合物が、ゲノムDNAのCRISPR遺伝子編集を導くことを標的とする塩基配列を含む、請求項1に記載のガイド化合物。
- 1以上のUNAモノマーを含む、請求項2に記載のガイド化合物。
- 1以上のUNAモノマーを含む、請求項4に記載のガイド化合物。
- 標的ガイド鎖の塩基配列が、ゲノムDNAから最大で3つのミスマッチを有する、請求項7に記載のガイド化合物。
- 1〜5個のUNAモノマーを含む、請求項7に記載のガイド化合物。
- 核酸モノマーが、天然ヌクレオチド、非天然ヌクレオチド、修飾ヌクレオチド、化学修飾ヌクレオチドおよびそれらの組合せから選択される、請求項7に記載のガイド化合物。
- 1以上の核酸モノマーが、2’−O−メチルリボヌクレオチド、2’−O−メチルプリンヌクレオチド、2’−デオキシ−2’−フルオロリボヌクレオチド、2’−デオキシ−2’−フルオロピリミジンヌクレオチド、2’−デオキシリボヌクレオチド、2’−デオキシプリンヌクレオチド、ユニバーサル塩基ヌクレオチド、5−C−メチルヌクレオチド、逆位デオキシ脱塩基モノマー残基、3’末端が安定化されたヌクレオチド、3’−グリセリルヌクレオチド、3’−逆位脱塩基ヌクレオチド、3’−逆位チミジン、ロックド核酸ヌクレオチド(LNA)、2’−O,4’−C−メチレン−(D−リボフラノシル)ヌクレオチド、2’−メトキシエトキシ(MOE)ヌクレオチド、2’−メチル−チオ−エチル、2’−デオキシ−2’−フルオロヌクレオチド、2’−O−メチルヌクレオチド、2’,4’−拘束2’−O−メトキシエチル(cMOE)、2’−O−エチル(cEt)、2’−アミノヌクレオチド、2’−O−アミノヌクレオチド、2’−C−アリルヌクレオチド、2’−O−アリルヌクレオチド、N6−メチルアデノシンヌクレオチド、修飾された塩基5−(3−アミノ)プロピルウリジンを有するヌクレオチド、修飾された塩基5−(2−メルカプト)エチルウリジンを有するヌクレオチド、修飾された塩基5−ブロモウリジンを有するヌクレオチド、修飾された塩基8−ブロモグアノシンを有するヌクレオチド、修飾された塩基7−デアザアデノシンを有するヌクレオチド、2’−O−アミノプロピル置換されたヌクレオチド、または2’−OH基を、2’−R、2’−OR、2’−ハロゲン、2’−SRもしくは2’−アミノに置換したヌクレオチド(ここでRは、H、アルキル、アルケニル、またはアルキニルであり得る)である、請求項7に記載のガイド化合物。
- ガイド化合物の各末端における、最後の3つのモノマーのうちの1つ以上が、ホスホロチオエート結合、キラルなホスホロチオエート結合またはホスホロジチオエート結合で連結されている、請求項7に記載のガイド化合物。
- TTR、BIRC5、CDK16、STAT3、CFTR、F9、KRASおよびCARから選択される遺伝子において、二本鎖切断を導く、請求項1に記載のガイド化合物。
- ゲノムDNAが標的疾患に関連する一塩基多型を含む、請求項1に記載のガイド化合物。
- 疾患関連アレルにおいて二本鎖切断を導く、請求項1に記載のガイド化合物。
- V30M TTR、G284R ColA1、L132Pケラチン12、R135Tケラチン12、G85R SOD1、G272V Tau、P301L Tau、V337M Tau、R406W Tau、Q39STOPベータ−グロビン、T8993G/C mtDNA、G719S EGFR、およびG12C Krasから選択される疾患関連アレルにおいて、二本鎖切断を導く、請求項1に記載のガイド化合物。
- 30〜300個の連続するモノマーを含む、請求項1に記載のガイド化合物。
- CRISPR遺伝子編集がCas9を用いる、請求項1に記載のガイド化合物。
- オフターゲット活性の減少を伴って、遺伝子編集を導く、請求項7に記載のガイド化合物。
- 疾患関連アレルにおいて、野生型としての同一のアレルよりも多くの二本鎖切断を導く、請求項7に記載のガイド化合物。
- tracrRNAとアニールした、請求項1〜22のいずれかに記載のガイド化合物。
- tracrRNAが、肺炎レンサ球菌、化膿レンサ球菌、髄膜炎菌またはサーモフィラス菌由来である、請求項23に記載のガイド化合物。
- tracrRNAが配列番号606である、請求項23に記載のガイド化合物。
- tracrRNAとアニールし、CRISPR関連遺伝子編集タンパク質と複合体を形成している、請求項1〜22のいずれかに記載のガイド化合物。
- CRISPR関連遺伝子編集タンパク質がCas9である、請求項26に記載のガイド化合物。
- ゲノムDNAを標的とするガイド化合物であって、ガイド化合物がモノマー鎖であり、ゲノムDNAのCRISPR遺伝子編集を導き、ガイド化合物が標的ガイド鎖、CRISPR crDNA、およびCRISPR tracrRNAを一本鎖として含み、ここで標的ガイド鎖が14〜24個の長さの連続するモノマーであり、モノマーがUNAモノマーおよび核酸モノマーを含み、ガイド化合物が、ゲノムDNAのCRISPR遺伝子編集を導くことを標的とする塩基配列を含む、ガイド化合物。
- CRISPR/Cas9複合体において、遺伝子編集を導く、請求項28に記載のガイド化合物。
- 請求項23に記載の1以上のガイド化合物および薬学的に許容し得る担体を含む、医薬組成物。
- 薬学的に許容し得る担体が、ウイルスベクターまたは非ウイルスベクターを含む、請求項30に記載の組成物。
- 薬学的に許容し得る担体がリポソームを含む、請求項30に記載の組成物。
- 細胞内のゲノムDNAを編集する方法であって、細胞が、誘導性または構成的CRISPR遺伝子編集酵素を含み、該方法が、細胞を請求項30に記載の組成物と接触させることを含む、方法。
- 編集が、DNAを破壊し、またはDNAの転写を抑制する、請求項33に記載の方法。
- 編集が、オフターゲット活性の減少を伴って達成される、請求項33に記載の方法。
- CRISPR遺伝子編集酵素が、組成物と同時に導入される、請求項33に記載の方法。
- インビボにおいて、対象のゲノムDNAを編集する方法であって、対象が、誘導性または構成的CRISPR遺伝子編集酵素を含み、該方法が、対象に請求項30に記載の組成物を投与することを含む、方法。
- 編集が、DNAを破壊し、またはDNAの転写を抑制する、請求項37に記載の方法。
- 編集が、オフターゲット活性の減少を伴って達成される、請求項37に記載の方法。
- CRISPR遺伝子編集酵素が、組成物と同時に導入される、請求項37に記載の方法。
- それを必要とする対象において、標的ゲノムDNAに関連する疾患を予防、処置または改善する方法であって、対象が、誘導性または構成的CRISPR遺伝子編集酵素を含み、該方法が、対象に請求項30に記載の組成物を投与することを含む、方法。
- それを必要とする対象における、疾患または症状の予防、改善または処置のための、請求項30に記載の組成物の使用。
- 医学療法に使用する、請求項30に記載の組成物。
- ヒトまたは動物の身体の処置に使用する、請求項30に記載の組成物。
- それを必要とする対象において、疾患または症状を予防、改善または処置する薬物の調製または製造のための、請求項30に記載の組成物の使用。
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