JP2022132353A - 疼痛関連障害を処置するための物質及び方法 - Google Patents
疼痛関連障害を処置するための物質及び方法 Download PDFInfo
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Abstract
Description
本出願は、2016年7月6日出願の米国特許仮出願第62/358,763号、及び2017年2月22日出願の米国特許仮出願第62/461,874号の利益を請求するものであり、これらは両方とも、参照によってその全体が本明細書に援用される。
本出願は、コンピューター読み取り可能な形式の配列表[ファイル名:170152PCT (SCN9A) sequence listing (Part 1):18,643,508バイト-ASCIIテキストファイル;2017年6月28日作成、;170152PCT (SCN9A) sequence listing (Part 2):16,350,005バイト-ASCIIテキストファイル;2017年6月28日作成;及び170152PCT (SCN9A) sequence listing (Part 3):14,922,048バイト]を含み、これらは、その全体が参照によって本明細書に援用され、かつ本開示の一部を形成する。
配列番号1~620は、Casエンドヌクレアーゼオルソログ配列である。
I.序論
ゲノム編集
本開示は、生体の遺伝情報(ゲノム)を標的特異的変化させるためのストラテジー及び技法を提供する。本明細書で使用する場合、「変化」または「遺伝情報の変化」という用語は、細胞のゲノムの任意の変化を指す。遺伝性障害を処置する文脈では、変化には、これに限定されないが、挿入、欠失及び修正が含まれ得る。本明細書で使用する場合、「挿入」という用語は、DNA配列での1個または複数のヌクレオチドの付加を指す。挿入は、いくつかのヌクレオチドの小さな挿入から、大きなセグメント、例えばcDNAまたは遺伝子の挿入までの範囲であり得る。「欠失」という用語は、DNA配列における1つもしくは複数のヌクレオチドの喪失もしくは除去または遺伝子の機能の喪失もしくは除去を指す。場合によっては、欠失には、例えば、いくつかのヌクレオチド、エキソン、イントロン、遺伝子セグメント、または遺伝子の全配列の喪失が含まれ得る。場合によっては、遺伝子の欠失は、遺伝子の機能もしくは発現またはその遺伝子産物の除去または低減を指す。これは、遺伝子内またはその近傍の配列の欠失からだけでなく、遺伝子の発現を破壊する他の事象(例えば挿入、ナンセンス変異)からも生じ得る。「修正」という用語は、本明細書で使用する場合、挿入、欠失または置換によるかに関わらず、細胞内のゲノムの1つまたは複数のヌクレオチドの変化を指す。そのような修正は、構造または機能においてに関わらず、修正されたゲノム部位に、より好ましい遺伝子型または表現型結果をもたらし得る。「修正」の非限定的例の1つは、構造または機能を遺伝子またはその遺伝子産物(複数可)に回復する、野生型配列に対する変異または欠損配列の修正を含む。変異の性質に応じて、修正は、本明細書で開示する様々なストラテジーによって達成され得る。非限定的一例では、ミスセンス変異は、変異を含む領域をその野生型カウンターパートに置き換えることによって修正し得る。別の例として、遺伝子における重複変異(例えば、リピート伸長)は、余分な配列を除去することによって修正し得る。
CRISPR(クラスター化して規則的な配置の短い回文配列リピート;Clustered Regularly Interspaced Short Palindromic Repeats)ゲノム遺伝子座は、多くの原核生物(例えば、細菌及び古細菌)のゲノムにおいて見出され得る。原核生物では、CRISPR遺伝子座は、外来侵入物、例えば、ウイルス及びファージに対して原核生物を防御するために役立つ免疫系の1タイプとして機能する産物をコードする。CRISPR遺伝子座機能には3つの段階がある:CRISPR遺伝子座への新たな配列の組込み、CRISPR RNA(crRNA)の発現、及び外来侵入物核酸のサイレンシング。5種のCRISPRシステム(例えば、I型、II型、III型、U型、及びV型)が同定されている。
天然におけるII型CRISPRシステムでのcrRNA生合成は、トランス活性化CRISPR RNA(tracrRNA)を必要とする。II型CRISPRシステムの非限定的例は、図1のA及びBに示されている。tracrRNAは、内在性RNアーゼIIIによって修飾され得、次いで、ハイブリダイズして、プレcrRNAアレイでcrRNAリピートになる。内在性RNアーゼIIIは、プレcrRNAを切断するために動員され得る。切断されたcrRNAは、エキソリボヌクレアーゼトリミングに供されて、成熟型crRNA(例えば、5’トリミング)を生じ得る。tracrRNAは、crRNAとハイブリダイズされたまま残存し得、tracrRNA及びcrRNAは、部位特異的ポリペプチド(例えば、Cas9)と会合する。crRNA-tracrRNA-Cas9複合体のcrRNAは、複合体を標的核酸にガイドし得る(標的核酸へcrRNAがハイブリダイズし得る)。標的核酸に対するcrRNAのハイブリダイゼーションは、標的核酸切断に関してCas9を活性化し得る。II型CRISPRシステムにおける標的核酸は、プロトスペーサー隣接モチーフ(protospacer adjacent motif;PAM)と呼ばれる。天然では、PAMは、標的核酸への部位特異的ポリペプチド(例えば、Cas9)の結合を容易にするために必須である。II型システム(NmeniまたはCASS4とも呼ばれる)はさらに、II-A(CASS4)型及びII-B(CASS4a)型に細分される。Jinek et al.,Science,337(6096):816-821(2012)は、CRISPR/Cas9システムが、RNAプログラム可能ゲノム編集に有用であることを示しており、国際特許出願公開番号WO2013/176772は、部位特異的遺伝子編集のためのCRISPR/Casエンドヌクレアーゼシステムの多数の例及び用途を提供している。
V型CRISPRシステムは、II型システムとはいくつかの重要な相違を有する。例えば、Cpf1は、II型システムとは対照的に、tracrRNAをもたない単一のRNAガイドされるエンドヌクレアーゼである。実際に、Cpf1関連CRISPRアレイは、追加のトランス活性化tracrRNAを必要とせずに、成熟crRNAへとプロセシングされ得る。V型CRISPRアレイは、42~44ヌクレオチド長の短い成熟crRNAにプロセシングされ得、各成熟crRNAは、19ヌクレオチドのダイレクトリピートから始まり、23~25ヌクレオチドのスペーサー配列が続く。対照的に、II型システムの成熟crRNAは、20~24ヌクレオチドのスペーサー配列から始まり、約22ヌクレオチドのダイレクトリピートが続き得る。また、Cpf1はTリッチプロトスペーサー隣接モチーフを利用し得て、Cpf1-crRNA複合体が、短いTリッチPAMが先行する標的DNAを効率的に切断するようになっているが、これは、II型システムでは標的DNAの後であるGリッチPAMとは対照的である。したがって、V型システムが、PAMから離れたポイントで切断する一方で、II型システムは、PAMに隣接するポイントで切断する。加えて、II型システムとは対照的に、Cpf1は、スタッガード(staggered)DNA二本鎖切断を介して、4または5ヌクレオチドの5’オーバーハングを伴ってDNAを切断する。II型システムは、ブラント二本鎖切断を介して切断する。II型システムと同様に、Cpf1は、予測されたRuvC様エンドヌクレアーゼドメインを含有するが、第2のHNHエンドヌクレアーゼドメインを欠いていて、これは、II型システムとは対照的である。
例示的なCRISPR/Casポリペプチドは、Fonfara et al.、Nucleic Acids Research、42:2577-2590(2014)で公開されているとおりのCas9ポリペプチドを含む。CRISPR/Cas遺伝子命名システムは、Cas遺伝子が発見されて以来広範に書き換えを受けてきた。Fonfara et al.も、様々な種からのCas9ポリペプチドでのPAM配列を提供している(上記表1も参照されたい)。
SCN9A遺伝子またはSCN9A遺伝子の制御エレメントをコードする他のDNA配列の欠失または変異によって、ゲノムに恒久的変化をもたらすためにゲノム操作ツールを使用するための細胞ex vivo及びin vivo方法を本明細書において提供する。そのような方法は、エンドヌクレアーゼ、例えば、CRISPR関連(Cas9、Cpf1など)ヌクレアーゼを使用して、SCN9A遺伝子またはSCN9A遺伝子の制御エレメントをコードする他のDNA配列のゲノム遺伝子座内またはその近傍で恒久的に編集する。この方法で、本開示で記載する例は、(患者の寿命にわたって有望な治療を送達するのではなく)わずか1回の処置でSCN9A遺伝子の発現を減少させる、または除去するために役立ち得る。
部位特異的ポリペプチドは、DNAを切断するためにゲノム編集で使用されるヌクレアーゼである。部位特異的ポリペプチドを、1種もしくは複数のポリペプチド、またはそのポリペプチドをコードする1種もしくは複数のmRNAのいずれかとして細胞または患者に投与することができる。配列番号1~620に列挙されている、または本明細書で開示する酵素またはオルソログのいずれかを、本明細書に記載の方法で利用し得る。一分子ガイドRNAは、部位特異的ポリペプチドと事前複合体化することができる。部位特異的ポリペプチドは、本明細書で開示するDNAエンドヌクレアーゼのいずれかであり得る。
本開示は、関連ポリペプチド(例えば、部位特異的ポリペプチド)の活性を標的核酸内の特異的標的配列へと指示し得るゲノムターゲティング核酸を提供する。ゲノムターゲティング核酸はRNAであり得る。ゲノムターゲティングRNAは、本明細書では「ガイドRNA」または「gRNA」と称される。ガイドRNAは、目的の標的核酸配列、及びCRISPRリピート配列とハイブリダイズする少なくとも1つのスペーサー配列を含み得る。II型システムでは、gRNAはまた、tracrRNA配列と呼ばれる第2のRNAを含む。II型ガイドRNA(gRNA)では、CRISPRリピート配列及びtracrRNA配列は、相互にハイブリダイズして二重鎖を形成する。V型ガイドRNA(gRNA)では、crRNAは二重鎖を形成する。両方のシステムで、ガイドRNA及び部位特異的ポリペプチドが複合体を形成するように、二重鎖は部位特異的ポリペプチドに結合し得る。ゲノムターゲティング核酸は、部位特異的ポリペプチドとのその会合により、標的特異性を複合体に与え得る。したがって、ゲノムターゲティング核酸は、部位特異的ポリペプチドの活性を指示し得る。
ゲノムターゲティング核酸の一部の例では、スペーサーエクステンション配列は、活性を修飾し得る、安定性をもたらし得る、及び/またはゲノムターゲティング核酸を修飾するための位置をもたらし得る。スペーサーエクステンション配列は、オンターゲットまたはオフターゲット活性または特異性を修飾し得る。一部の例では、スペーサーエクステンション配列を付与することができる。スペーサーエクステンション配列は、1、5、10、15、20、25、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、220、240、260、280、300、320、340、360、380、400、1000、2000、3000、4000、5000、6000、もしくは7000超またはそれ以上のヌクレオチドの長さを有し得る。スペーサーエクステンション配列は、1、5、10、15、20、25、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、220、240、260、280、300、320、340、360、380、400、1000、2000、3000、4000、5000、6000、7000未満またはそれ以上のヌクレオチドの長さを有し得る。スペーサーエクステンション配列は、10未満のヌクレオチド長さであり得る。スペーサーエクステンション配列は、10から30の間のヌクレオチド長さであり得る。スペーサーエクステンション配列は、30から70の間のヌクレオチド長さであり得る。
スペーサー配列は、目的の標的核酸内の配列とハイブリダイズする。ゲノムターゲティング核酸のスペーサーは、ハイブリダイゼーション(すなわち、塩基対合)を介して、配列特異的に標的核酸と相互作用し得る。スペーサーのヌクレオチド配列は、目的の標的核酸の配列に依存して変化し得る。
一部の態様では、ミニマムCRISPRリピート配列は、基準CRISPRリピート配列(例えばS.pyogenes由来のcrRNA)に対して少なくとも約30%、約40%、約50%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%、または100%配列同一性を有する配列である。
ミニマムtracrRNA配列は、基準tracrRNA配列(例えばS.pyogenes由来の野生型tracrRNA)に対して少なくとも約30%、約40%、約50%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%、または100%配列同一性を有する配列であり得る。
場合によっては、ミニマムCRISPR RNA及びミニマムtracrRNAとの間の二重鎖に、「バルジ」が存在し得る。バルジは、二重鎖内のヌクレオチドの非対合領域である。バルジは、部位特異的ポリペプチドへの二重鎖の結合に寄与し得る。バルジは、二重鎖の片側に、非対合5’-XXXY-3’(ここで、Xは、任意のプリンであり、Yは、逆ストランド上のヌクレオチドとゆらぎ対を形成し得るヌクレオチドを含む)、及び二重鎖の他の側に、非対合ヌクレオチド領域を含み得る。二重鎖の2つの側にある非対合ヌクレオチドの数は、異なり得る。
様々な例で、1つまたは複数のヘアピンが、3’tracrRNA配列内のミニマムtracrRNAの3’側に位置し得る。
3’tracrRNA配列は、基準tracrRNA配列(例えばS.pyogenes由来のtracrRNA)に対して少なくとも約30%、約40%、約50%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%、または100%配列同一性を有する配列を含み得る。
tracrRNAが一分子ガイドまたは二重分子ガイドの状況にあるかに関わらず、tracrRNAエクステンション配列を付与してよい。tracrRNAエクステンション配列は、約1ヌクレオチド~約400ヌクレオチドの長さを有し得る。tracrRNAエクステンション配列は、1、5、10、15、20、25、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、220、240、260、280、300、320、340、360、380、または400ヌクレオチド超の長さを有し得る。tracrRNAエクステンション配列は、約20~約5000またはそれ以上のヌクレオチドの長さを有し得る。tracrRNAエクステンション配列は、1000ヌクレオチド超の長さを有し得る。tracrRNAエクステンション配列は、1、5、10、15、20、25、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、220、240、260、280、300、320、340、360、380、400未満またはそれ以上のヌクレオチドの長さを有し得る。tracrRNAエクステンション配列は、1000ヌクレオチド未満の長さを有し得る。tracrRNAエクステンション配列は、10ヌクレオチド未満の長さを含み得る。tracrRNAエクステンション配列は、10~30ヌクレオチドの長さであり得る。tracrRNAエクステンション配列は、30~70ヌクレオチドの長さであり得る。
一分子ガイド核酸のリンカー配列は、約3ヌクレオチド~約100ヌクレオチドの長さを有し得る。Jinek et al.(前出)では、例えば、単純な4ヌクレオチド「テトラループ」(-GAAA-)が使用された(Science、337(6096):816-821(2012))。リンカーの実例は、約3ヌクレオチド(nt)~約90nt、約3nt~約80nt、約3nt~約70nt、約3nt~約60nt、約3nt~約50nt、約3nt~約40nt、約3nt~約30nt、約3nt~約20nt、約3nt~約10ntの長さを有する。例えば、リンカーは、約3nt~約5nt、約5nt~約10nt、約10nt~約15nt、約15nt~約20nt、約20nt~約25nt、約25nt~約30nt、約30nt~約35nt、約35nt~約40nt、約40nt~約50nt、約50nt~約60nt、約60nt~約70nt、約70nt~約80nt、約80nt~約90nt、または約90nt~約100ntの長さを有し得る。一分子ガイド核酸のリンカーは、4から40の間のヌクレオチドであり得る。リンカーは、少なくとも約100、500、1000、1500、2000、2500、3000、3500、4000、4500、5000、5500、6000、6500、もしくは7000またはそれ以上のヌクレオチドであり得る。リンカーは、多くとも約100、500、1000、1500、2000、2500、3000、3500、4000、4500、5000、5500、6000、6500、もしくは7000またはそれ以上のヌクレオチドであり得る。
一部の態様では、本明細書においてさらに記載するとおり、かつ当技術分野で公知のとおり、細胞に導入されるポリヌクレオチドは、例えば、活性、安定性または特異性を増強するために、送達を変化させるために、宿主細胞における自然免疫応答を低下させるために、または他の増強のために個別に、または組み合わせて使用することができる1つまたは複数の修飾を含み得る。
目的の標的DNAを含有する細胞内での発現のために当技術分野で標準的な方法に従って、部位特異的ポリペプチドをコードするポリヌクレオチドをコドン最適化することができる。例えば、意図されている標的核酸がヒト細胞内にあれば、Cas9をコードするヒトコドン最適化ポリヌクレオチドが、Cas9ポリペプチドを生成するために使用されるように企図される。
ゲノムターゲティング核酸は、部位特異的ポリペプチド(例えば、核酸ガイドされるヌクレアーゼ、例えばCas9)と相互作用し、それによって、複合体を形成する。ゲノムターゲティング核酸は、部位特異的ポリペプチドを標的核酸に配向させる。
部位特異的ポリペプチド及びゲノムターゲティング核酸をそれぞれ、細胞または患者に別々に投与することができる。他方で、部位特異的ポリペプチドを、tracrRNAと一緒に1つもしくは複数のガイドRNA、または1つもしくは複数のcrRNAと事前複合体化することができる。次いで、事前複合体化物質を細胞または患者に投与することができる。そのような事前複合体化物質は、リボ核タンパク質粒子(RNP)として公知である。RNP中の部位特異的ポリペプチドは、例えば、Cas9エンドヌクレアーゼまたはCpf1エンドヌクレアーゼであり得る。部位特異的ポリペプチドは、N末端、C末端、またはN末端及びC末端の両方で1つまたは複数の核移行シグナル(NLS)と隣接し得る。例えば、Cas9エンドヌクレアーゼは、2つのNLSと隣接し得て、1つのNLSはN末端に位置し、第2のNLSはC末端に位置する。NLSは、当技術分野で公知の任意のNLS、例えば、SV40 NLSであり得る。RNPにおけるゲノムターゲティング核酸と部位特異的ポリペプチドとの重量比は、1:1であり得る。例えば、RNPにおけるsgRNAとCas9エンドヌクレアーゼとの重量比は、1:1であり得る。
本開示は、本開示のゲノムターゲティング核酸をコードするヌクレオチド配列、本開示の部位特異的ポリペプチド、及び/または本開示の方法の態様を実施するために必要な任意の核酸またはタンパク質分子を含む核酸を提供する。
本明細書で提供されるのは、疼痛を有する患者を治療するための方法である。そのような方法の1つの態様は、ex vivoでの細胞ベースの治療である。例えば、患者の末梢神経の生検が行われる。神経組織は、患者の皮膚または脚から分離され得る。次いで、末梢神経系の細胞(例えば、神経内のシュワン細胞または神経節内のサテライトグリア細胞などのニューロンまたはグリア細胞)は、生検材料から単離される。次いで、末梢神経系の細胞(例えば、神経内のシュワン細胞または神経節内のサテライトグリア細胞などのニューロンまたはグリア細胞)の染色体DNAは、本明細書に記載の材料及び方法を用いて編集され得る。最後に、末梢神経系の編集細胞(例えば、神経内のシュワン細胞または神経節内のサテライトグリア細胞などのニューロンまたはグリア細胞)は、患者に移植される。任意の起源または細胞の種類は、前駆細胞として使用され得る。
いくつかの態様において、本開示の方法は、一方または両方の対立遺伝子を編集することを含み得る。対立遺伝子(複数可)を改変するための遺伝子編集は、標的遺伝子または遺伝子産物を恒久的に改変するという利点を有する。
特定の参照遺伝子座に対する5’境界及び/または3’境界の位置のシフトは、本明細書でさらに説明及び図示されるように、編集のために選択されたエンドヌクレアーゼシステムに部分的に依存する、遺伝子編集の特定の適用を容易にするかまたは高めるために使用され得る。
本明細書に記載及び例示されるように、SCN9Aに関連する疼痛または任意の障害を改善するために、遺伝子編集の主な標的はヒト細胞である。例えば、ex vivoでの方法において、ヒト細胞は、体細胞であり得、それは記載の技術を用いて改変された後、分化した細胞、例えば、末梢神経系のニューロンまたは前駆細胞を生じ得る。例えば、in vivoでの方法において、ヒト細胞は、末梢神経系のニューロン、または他の罹患器官由来の細胞であり得る。
本明細書に記載の遺伝子操作されたヒト細胞は、人工多能性幹細胞(iPSC)であり得る。iPSCを用いることの利点は、前記細胞が、前駆細胞が投与されるのと同じ対象に由来し得ることである。すなわち、体細胞は、対象から得られ、人工多能性幹細胞に再プログラム化され、次いで、前記対象に投与されるべき前駆細胞(例えば、自己細胞)に再分化され得る。前駆体は、本質的に自家供給源に由来するので、生着拒絶またはアレルギー反応の危険性は、他の対象または対象群由来の細胞の使用と比較して、減少させ得る。さらに、iPSCの使用は、胚供給源から得られた細胞の必要性を否定する。したがって、1つの態様において、開示された方法で使用される幹細胞は、胚性幹細胞ではない。
いくつかの態様において、本明細書に記載の遺伝子操作されたヒト細胞は、脳及び脊髄の外側のニューロン及び神経である。情報を処理するニューロン、及び神経系への機械的及び代謝的支持を提供するグリア細胞は、末梢神経系の細胞の2つの主要なクラスである。ニューロンの非限定的な例には、感覚ニューロン(皮膚、筋肉、及び臓器などの領域内の感覚受容体からインパルスを収集し、それらのインパルスを神経を通してCNSに伝達する。)及び運動ニューロン(前記CNSから発信メッセージを収集し、どのような行動をとる必要があるのかを指示しながら、適切な身体器官にそれらを送達する。)が含まれる。グリア細胞の非限定的な例には、神経内のシュワン細胞または神経節内のサテライト細胞が含まれる。
本開示のex vivoでの方法の1つの工程は、患者特異的iPS細胞、患者特異的iPS細胞(複数可)、または患者特異的iPS細胞株を作製することを含み得る。Takahashi and Yamanaka 2006;Takahashi,Tanabe et al.2007に記載されているように、患者特異的iPS細胞を作製するための当該分野において確立された多くの方法がある。例えば、前記作製工程は、a)皮膚細胞または線維芽細胞などの体細胞を患者から単離すること、及びb)多能性幹細胞になるように細胞を誘導するために、1組の多能性関連遺伝子を体細胞に導入すること、を含み得る。多能性関連遺伝子のセットは、OCT4、SOX1、SOX2、SOX3、SOX15、SOX18、NANOG、KLF1、KLF2、KLF4、KLF5、c-MYC、n-MYC、REM2、TERT、及びLIN28からなる群から選択される1つ以上の遺伝子であり得る。
生検または吸引は、身体から採取された組織または体液のサンプルである。生検や吸引には様々な種類がある。それらのほとんどすべては、少量の組織を除去するために、鋭利な道具を用いることを含む。生検が皮膚または他の敏感な部分にある場合は、麻痺薬を最初に適用し得る。生検または吸引は、当該分野で公知の方法のいずれかに従って行われ得る。例えば、骨髄吸引液において、大きな針は、骨盤骨に入れて、骨髄を集めるために用いられる。例えば、末梢神経系のニューロンを単離するための皮膚または脚からの神経生検の場合には、神経部分は切除され、最小限の機械的損傷を与えている。神経を圧迫したり伸ばしたりすることは避けられ、脂肪や結合組織の過剰な除去は試みられない。
末梢神経系のニューロンは、当該技術分野における任意の既知の方法に従って単離され得る。例えば、神経セグメントは、無菌条件下で、最小の機械的損傷を与えて切除される。神経を圧迫したり伸ばしたりすることは、厳密に避けられ、脂肪や結合組織の過剰な除去は、試みられない。神経線維は、機械的損傷に対して非常に敏感であるため、近位神経切断が最初に行われる。単離後、最も外側の結合組織層である上尿膜が除去され、酵素消化のために集められる。すべての束が個々の繊維に分離されるまで、前記繊維は、細い鉗子の助けを用いて裂かれる。次いで、上尿膜及び裂かれた繊維は、ディスパーゼII及びI型コラゲナーゼを用いて、一晩酵素消化に供される。消化された生成物は、濾過され、遠心分離により集められる。得られた細胞懸濁液は、接着剤PLL/ラミニン基質上にプレーティングされる。接着細胞は、解析のために培養される(Andersen et al.,Scientific Reports-Nature,2016,6:31781)。
間葉系幹細胞は、患者の骨髄または末梢血からなど、当該技術分野において公知の任意の方法に従って単離され得る。例えば、骨髄吸引液は、ヘパリンと共に注射器に集められ得る。細胞は、洗浄され、Percollで遠心され得る。前記細胞は、10%ウシ胎児血清(FBS)を含有するダルベッコ改変イーグル培地(DMEM)(低グルコース)中で培養され得る(Pittinger MF,Mackay AM,Beck SC et al.,Science 1999;284:143-147)。
用語「遺伝子改変細胞」は、ゲノム編集によって(例えば、CRISPR/Cas9またはCRISPR/Cpf1システムを用いて)導入された、少なくとも1つの遺伝子改変を含む細胞のことをいう。本明細書中のいくつかのex vivoの例において、遺伝子改変細胞は、遺伝子改変前駆細胞であり得る。本明細書中のいくつかのin vivoでの例において、遺伝子改変細胞は、末梢神経系の遺伝子改変ニューロンであり得る。外因性ゲノムターゲティング核酸及び/またはゲノムターゲティング核酸をコードする外因性核酸を含む遺伝子改変細胞は、本明細書で企図される。
本開示のex vivoでの方法の別の工程は、ゲノム編集されたiPSCを末梢神経系の細胞(例えば、神経内のシュワン細胞または神経節内のサテライトグリア細胞などのニューロンまたはグリア細胞)に分化させることを含み得る。分化する工程は、当該技術分野において公知の任意の方法に従って実施され得る。例えば、iPSCの神経分化は、脳由来の神経栄養因子(BDNF)、グリア細胞由来神経栄養因子(GDNF)、神経成長因子(NGF)、及びジブチリルサイクリックAMP(dbcAMP)の組み合わせを用いて誘導される。次いで、iPSC由来の神経細胞は、毛様体神経栄養因子(CNTF)、ニューレグリン1β、及びdbcAMPを用いて、シュワン細胞にさらに分化させる(Wang et al.,Biomaterials.2011;32(22):5023-5032)。
本開示のex vivoでの方法の別の工程は、ゲノム編集された間葉系幹細胞を末梢神経系の細胞(例えば、神経節のシュワン細胞または神経節のサテライトグリア細胞などのニューロンまたはグリア細胞)に分化させることを含み得る。分化する工程は、当該技術分野において公知の任意の方法に従って実施され得る。例えば、MSCは、塩基性線維芽細胞増殖因子、ヒト組換え血小板由来増殖因子、フォルスコリン、及びグリア増殖因子-2を含む様々な因子及びホルモンで治療される(Ladak et al.,Experimental Neurology 228(2011)242-252)。
本開示のex vivoでの方法の別の工程は、末梢神経系のゲノム編集されたニューロンを患者に移植することを含み得る。この移植工程は、当該技術分野において公知の任意の移植方法を用いて達成され得る。例えば、遺伝子改変細胞は、前記患者の血液に直接注入されるか、他の方法で前記患者に投与され得る。
薬学的に許容される担体
本明細書で企図される対象に前駆細胞を投与するex vivo方法は、前駆細胞を含む治療用組成物の使用を伴う。
本開示のガイドRNAを、特定の投与様式及び剤形に応じて、薬学的に許容される添加剤、例えば担体、溶媒、安定剤、アジュバント、希釈剤などで製剤化することができる。ガイドRNA組成物は、生理学的に適合性なpH、ならびに製剤及び投与経路に応じて約3のpHから約11までのpH、約pH3~約pH7の範囲を達成するように製剤化することができる。場合によっては、pHを約pH5.0~約pH8の範囲に調節することができる。場合によっては、組成物は、少なくとも1種の本明細書に記載の化合物の治療有効量を1種または複数の薬学的に許容される添加剤と共に含み得る。任意選択で、組成物は、本明細書に記載の化合物の組み合わせを含むことができるか、または細菌成長の処置もしくは予防に有用な第2の活性成分(例えば、限定ではないが抗細菌薬または抗菌薬)を含むことができるか、または本開示の試薬の組み合わせを含むことができる。
ガイドRNAポリヌクレオチド(RNAまたはDNA)及び/またはエンドヌクレアーゼポリヌクレオチド(複数可)(RNAまたはDNA)を当技術分野で公知のウイルスまたは非ウイルス送達ビヒクルによって送達することができる。別法では、エンドヌクレアーゼポリペプチド(複数可)を、当技術分野で公知のウイルスまたは非ウイルス送達ビヒクル、例えば電気穿孔法または脂質ナノ粒子によって送達することができる。さらなる代替の態様では、DNAエンドヌクレアーゼを、1種または複数のポリペプチドとして、単独で、あるいはtracrRNAと一緒に1つもしくは複数のガイドRNA、または1つもしくは複数のcrRNAと事前複合体化して送達することができる。
組換えアデノ随伴ウイルス(AAV)ベクターを送達のために使用することができる。送達されるポリヌクレオチド、rep及びcap遺伝子、ならびにヘルパーウイルス機能を含むパッケージングされたAAVゲノムを細胞に供給するrAAV粒子を生成するための技法は、当技術分野で標準的である。rAAVの生成は典型的には、次の成分が単細胞(本明細書ではパッケージング細胞と示される)内に存在することを必要とする:rAAVゲノム、rAAVゲノムとは別の(すなわち、その中にはない)AAVrep及びcap遺伝子、及びヘルパーウイルス機能。AAVrep及びcap遺伝子は、組換えウイルスを誘導し得る任意のAAV血清型からのものであってよく、かつこれに限定されないが、本明細書に記載のAAV血清型を含む、rAAVゲノムITRとは異なるAAV血清型からのものであってよい。偽型rAAVの生成が例えば、国際特許出願公開WO01/83692に開示されている。
本開示の組成物、例えば、エンドヌクレアーゼ、ドナー配列、またはRNAガイド分子をコードするポリヌクレオチドをパッケージングする本開示のAAV粒子は、任意の天然または組換えAAV血清型を含むか、またはそれから誘導されていてよい。本開示によれば、AAV粒子は、これに限定されないが、AAV1、AAV10、AAV106.1/hu.37、AAV11、AAV114.3/hu.40、AAV12、AAV127.2/hu.41、AAV127.5/hu.42、AAV128.1/hu.43、AAV128.3/hu.44、AAV130.4/hu.48、AAV145.1/hu.53、AAV145.5/hu.54、AAV145.6/hu.55、AAV16.12/hu.11、AAV16.3、AAV16.8/hu.10、AAV161.10/hu.60、AAV161.6/hu.61、AAV1-7/rh.48、AAV1-8/rh.49、AAV2、AAV2.5T、AAV2-15/rh.62、AAV223.1、AAV223.2、AAV223.4、AAV223.5、AAV223.6、AAV223.7、AAV2-3/rh.61、AAV24.1、AAV2-4/rh.50、AAV2-5/rh.51、AAV27.3、AAV29.3/bb.1、AAV29.5/bb.2、AAV2G9、AAV-2-pre-miRNA-101、AAV3、AAV3.1/hu.6、AAV3.1/hu.9、AAV3-11/rh.53、AAV3-3、AAV33.12/hu.17、AAV33.4/hu.15、AAV33.8/hu.16、AAV3-9/rh.52、AAV3a、AAV3b、AAV4、AAV4-19/rh.55、AAV42.12、AAV42-10、AAV42-11、AAV42-12、AAV42-13、AAV42-15、AAV42-1b、AAV42-2、AAV42-3a、AAV42-3b、AAV42-4、AAV42-5a、AAV42-5b、AAV42-6b、AAV42-8、AAV42-aa、AAV43-1、AAV43-12、AAV43-20、AAV43-21、AAV43-23、AAV43-25、AAV43-5、AAV4-4、AAV44.1、AAV44.2、AAV44.5、AAV46.2/hu.28、AAV46.6/hu.29、AAV4-8/r11.64、AAV4-8/rh.64、AAV4-9/rh.54、AAV5、AAV52.1/hu.20、AAV52/hu.19、AAV5-22/rh.58、AAV5-3/rh.57、AAV54.1/hu.21、AAV54.2/hu.22、AAV54.4R/hu.27、AAV54.5/hu.23、AAV54.7/hu.24、AAV58.2/hu.25、AAV6、AAV6.1、AAV6.1.2、AAV6.2、AAV7、AAV7.2、AAV7.3/hu.7、AAV8、AAV-8b、AAV-8h、AAV9、AAV9.11、AAV9.13、AAV9.16、AAV9.24、AAV9.45、AAV9.47、AAV9.61、AAV9.68、AAV9.84、AAV9.9、AAVA3.3、AAVA3.4、AAVA3.5、AAVA3.7、AAV-b、AAVC1、AAVC2、AAVC5、AAVCh.5、AAVCh.5R1、AAVcy.2、AAVcy.3、AAVcy.4、AAVcy.5、AAVCy.5R1、AAVCy.5R2、AAVCy.5R3、AAVCy.5R4、AAVcy.6、AAV-DJ、AAV-DJ8、AAVF3、AAVF5、AAV-h、AAVH-1/hu.1、AAVH2、AAVH-5/hu.3、AAVH6、AAVhE1.1、AAVhER1.14、AAVhEr1.16、AAVhEr1.18、AAVhER1.23、AAVhEr1.35、AAVhEr1.36、AAVhEr1.5、AAVhEr1.7、AAVhEr1.8、AAVhEr2.16、AAVhEr2.29、AAVhEr2.30、AAVhEr2.31、AAVhEr2.36、AAVhEr2.4、AAVhEr3.1、AAVhu.1、AAVhu.10、AAVhu.11、AAVhu.11、AAVhu.12、AAVhu.13、AAVhu.14/9、AAVhu.15、AAVhu.16、AAVhu.17、AAVhu.18、AAVhu.19、AAVhu.2、AAVhu.20、AAVhu.21、AAVhu.22、AAVhu.23.2、AAVhu.24、AAVhu.25、AAVhu.27、AAVhu.28、AAVhu.29、AAVhu.29R、AAVhu.3、AAVhu.31、AAVhu.32、AAVhu.34、AAVhu.35、AAVhu.37、AAVhu.39、AAVhu.4、AAVhu.40、AAVhu.41、AAVhu.42、AAVhu.43、AAVhu.44、AAVhu.44R1、AAVhu.44R2、AAVhu.44R3、AAVhu.45、AAVhu.46、AAVhu.47、AAVhu.48、AAVhu.48R1、AAVhu.48R2、AAVhu.48R3、AAVhu.49、AAVhu.5、AAVhu.51、AAVhu.52、AAVhu.53、AAVhu.54、AAVhu.55、AAVhu.56、AAVhu.57、AAVhu.58、AAVhu.6、AAVhu.60、AAVhu.61、AAVhu.63、AAVhu.64、AAVhu.66、AAVhu.67、AAVhu.7、AAVhu.8、AAVhu.9、AAVhu.t19、AAVLG-10/rh.40、AAVLG-4/rh.38、AAVLG-9/hu.39、AAVLG-9/hu.39、AAV-LK01、AAV-LK02、AAVLK03、AAV-LK03、AAV-LK04、AAV-LK05、AAV-LK06、AAV-LK07、AAV-LK08、AAV-LK09、AAV-LK10、AAV-LK11、AAV-LK12、AAV-LK13、AAV-LK14、AAV-LK15、AAV-LK17、AAV-LK18、AAV-LK19、AAVN721-8/rh.43、AAV-PAEC、AAV-PAEC11、AAV-PAEC12、AAV-PAEC2、AAV-PAEC4、AAV-PAEC6、AAV-PAEC7、AAV-PAEC8、AAVpi.1、AAVpi.2、AAVpi.3、AAVrh.10、AAVrh.12、AAVrh.13、AAVrh.13R、AAVrh.14、AAVrh.17、AAVrh.18、AAVrh.19、AAVrh.2、AAVrh.20、AAVrh.21、AAVrh.22、AAVrh.23、AAVrh.24、AAVrh.25、AAVrh.2R、AAVrh.31、AAVrh.32、AAVrh.33、AAVrh.34、AAVrh.35、AAVrh.36、AAVrh.37、AAVrh.37R2、AAVrh.38、AAVrh.39、AAVrh.40、AAVrh.43、AAVrh.44、AAVrh.45、AAVrh.46、AAVrh.47、AAVrh.48、AAVrh.48、AAVrh.48.1、AAVrh.48.1.2、AAVrh.48.2、AAVrh.49、AAVrh.50、AAVrh.51、AAVrh.52、AAVrh.53、AAVrh.54、AAVrh.55、AAVrh.56、AAVrh.57、AAVrh.58、AAVrh.59、AAVrh.60、AAVrh.61、AAVrh.62、AAVrh.64、AAVrh.64R1、AAVrh.64R2、AAVrh.65、AAVrh.67、AAVrh.68、AAVrh.69、AAVrh.70、AAVrh.72、AAVrh.73、AAVrh.74、AAVrh.8、AAVrh.8R、AAVrh8R、AAVrh8R A586R変異体、AAVrh8R R533A変異体、BAAV、BNP61AAV、BNP62AAV、BNP63AAV、ウシAAV、ヤギAAV、Japanese AAV10、真型(true type)AAV(ttAAV)、UPENN AAV10、AAV-LK16、AAAV、AAV Shuffle100-1、AAV Shuffle100-2、AAV Shuffle100-3、AAV Shuffle100-7、AAV Shuffle10-2、AAV Shuffle10-6、AAV Shuffle10-8、AAV SM100-10、AAV SM100-3、AAV SM10-1、AAV SM10-2、及び/またはAAV SM10-8を含む血清型、及びそのバリアントのいずれかから選択される血清型を利用し得るか、またはそれに基づき得る。
「投与すること」、「導入すること」及び「移植すること」という用語は、所望の作用(複数可)が生じるように所望の部位、例えば、損傷または修復の部位で、導入された細胞の少なくとも部分的な局在化をもたらす方法または経路によって、細胞、例えば、前駆細胞を対象に配置する文脈で互換的に使用される。細胞、例えば前駆細胞、またはそれらの分化後代を、対象内の所望の位置への送達をもたらす任意の適切な経路によって、移植細胞または細胞の成分の少なくとも一部を生かしたままで投与することができる。対象への投与後の細胞の生存期間は、短くて数時間、例えば24時間、数日まで、長くて数年まで、またはさらには患者の寿命、すなわち、長期生着であり得る。例えば、本明細書に記載の一部の態様では、前駆細胞の有効量を全身投与経路、例えば腹腔内または静脈内経路を介して投与する。
SCN9Aは、疾患及び障害、例えば、これに限定されないが、先天性無痛覚、無嗅覚症、かのようなパーソナリティ、境界型人格障害、乳房悪性新生物、非小細胞肺癌、寒冷不耐性、熱性痙攣、糖尿病、真性糖尿病、解離性障害、てんかん、肢端紅痛症、原発性肢端紅痛症、顔面痛、ヘルペスウイルス感染、遺伝性感覚性ニューロパチー5型、過形成、神経痛、遺伝性感覚性自律神経性ニューロパチー、変性性多発性関節炎、疼痛、四肢痛、手術後疼痛、パーキンソン病、ヘルペス後神経痛、前立腺新生物、そう痒症、発作、身体表現性障害、喫煙障害、三叉神経痛、滑液嚢胞、慢性疼痛、急性発症疼痛、先天性パラミオトニア(障害)、不快感、感覚不快感、灼熱痛、疼痛不感症、炎症性疼痛、機械的疼痛、頭皮疼痛、遺伝性運動感覚性ニューロパチーII型、普通型片頭痛、痛みの感覚の欠如、前立腺悪性新生物、疼痛障害、変形性膝関節症、ニューロパチー、複合性局所疼痛症候群、強直間代性発作、遺伝性ニューロパチー、前立腺癌、乳癌、乳児重症ミオクローヌスてんかん、粘液様嚢胞、チャネロパチー、発作性激痛障害、有痛性神経障害、圧迫性ニューロパチー、常染色体劣性先天性疼痛不感症、全身性てんかん熱性けいれんプラス2型、全身性てんかん熱性けいれんプラス7、熱性けいれん家族性3B、及び小径線維ニューロパチー(成人発症型が小径線維ニューロパチーと称される)と関連している。本明細書に記載の方法のいずれかを使用するSCN9A遺伝子の編集を用いて、本明細書に記載の疾患及び障害の症状を処置、予防、及び/または軽減し得る。
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265990、rs796349008、rs796352290、rs796380704、rs796730002、rs796797940、rs796870168、rs796981058、rs767788312、rs767804500、rs7679
05631、rs768152740、rs768239772、rs768260693、rs768385834、rs768416620、rs768531332、rs768574136、rs768585281、rs768804885、and rs768853312である。
遺伝子編集は、特定の配列をターゲティングするように操作されたヌクレアーゼを用いて行うことができる。これまでのところ、4種の主要なヌクレアーゼ、すなわち、メガヌクレアーゼ及びそれらの誘導体、ジンクフィンガーヌクレアーゼ(ZFN)、転写活性化因子様エフェクターヌクレアーゼ(TALEN)、ならびにCRISPR-Cas9ヌクレアーゼ系がある。これらのヌクレアーゼプラットフォームは、設計の難しさ、標的密度、及び作用機序の点で異なり、特に、ZFN及びTALENの特異性は、タンパク質-DNA相互作用によるものであり、RNA-DNA相互作用は主にCas9を導く。
ジンクフィンガーヌクレアーゼ(ZFN)は、II型エンドヌクレアーゼFokIの触媒ドメインに連結された操作されたジンクフィンガーDNA結合ドメインからなるモジュラータンパク質である。FokIは二量体としてのみ機能するため、一対のZFNを操作して、両側のDNA鎖上の同族の標的の「ハーフ部位」配列に結合し、それらの間に正確な間隔を置いて触媒活性FokI二量体を形成することができるようにする必要がある。それ自体は配列特異性を有さないFokIドメインが二量体化されると、ゲノム編集の開始段階としてZFNのハーフ部位間にDNA二本鎖切断が生じる。
TALENは、ZFNと同様に、遺伝子操作されたDNA結合ドメインがFokIヌクレアーゼドメインに連結され、一対のTALENが標的DNAの切断を達成するように直列に作用する、モジュラーヌクレアーゼの別の形式を表す。ZFNとの主な違いは、DNA結合ドメインの性質及びそれに関連する標的DNA配列の認識特性である。TALENのDNA結合ドメインはTALEタンパク質に由来し、これはもともと植物の細菌性病原体Xanthomonas sp.に記されていた。TALEは、33~35アミノ酸リピートの縦列配列からなり、各リピートは、通常20bpまでの長さの標的DNA配列中の単一の塩基対を認識し、40bpまでの総標的配列長を与える。各リピートのヌクレオチド特異性は、位置12及び13のたった2つのアミノ酸を含むリピート可変二残基(RVD)によって決定される。グアニン、アデニン、シトシン、及びチミン塩基は主に、それぞれ4つのRVD、すなわち、Asn-Asn、Asn-Ile、His-Asp、及びAsn-Glyによって認識される。これは、ジンクフィンガーよりもはるかに単純な認識コードを構成し、ひいては、ヌクレアーゼ設計に関して後者よりも優れた利点を表す。それにもかかわらず、ZFNと同様に、TALENのタンパク質-DNA相互作用は、それらの特異性において絶対的なものではなく、TALENにもまた、オフターゲット活性を減少させるため、FokIドメインの偏性ヘテロダイマー変異体の使用が役立っている。
ホーミングエンドヌクレアーゼ(HE)は、配列特異的なエンドヌクレアーゼであり、長い認識配列(14~44塩基対)を有し、高い特異性で、すなわち、多くの場合当該ゲノムの特異部位でDNAを切断する。GIY-YIG、His-Cisボックス、H-N-H、PD-(D/E)xK、及びVsr様を含めた構造によって分類される少なくとも6つの既知のHEのファミリーがあり、これらは、真核生物、原生生物、細菌、古細菌、シアノバクテリア、及びファージを含めた広範な宿主に由来する。ZFN及びTALENと同様に、HEを使用して、ゲノム編集の最初の段階として、標的遺伝子座にDSBを作り出すことができる。さらに、いくつかの天然のHE及び操作されたHEは、DNAの一本鎖のみを切断し、部位特異的ニッカーゼとして機能する。HEの大きな標的配列及びそれらが提供する特異性は、それらを部位特異的DSBを作り出すための魅力的な候補にしている。
ハイブリッドヌクレアーゼのさらなる例として、MegaTALプラットフォーム及びTev-mTALENプラットフォームは、TALEの調節可能なDNA結合及び特異性の両方、ならびにHEの切断配列特異性を生かして、TALEのDNA結合ドメインと触媒活性HEとの融合を使用する。例えば、Boissel et al.,NAR 42:2591-2601(2014)、Kleinstiver et al.,G3 4:1155-65(2014)、及びBoissel and Scharenberg,Methods Mol. Biol.1239:171-96(2015)を参照されたい。
上記のヌクレアーゼプラットフォームの構造的及び機能的特性を組み合わせることで、固有の欠失の一部を潜在的に克服することができるゲノム編集へのさらなるアプローチが提供される。例として、CRISPRゲノム編集系は通常、単一のCas9エンドヌクレアーゼを使用してDSBを作り出す。標的化の特異性は、標的DNAとのワトソン・クリック塩基対合を経るガイドRNA中の20または24ヌクレオチド配列(それに加えて、S.pyogenes由来のCas9の例では、隣接するNAGまたはNGGのPAM配列のさらなる2塩基)によって促進される。かかる配列は、ヒトゲノムにおいて独特であるのに十分な長さであるが、RNA/DNA相互作用の特異性は絶対的なものではなく、特に標的配列の5’ハーフにおいてかなりの乱雑が許容されることがあり、特異性を促進する塩基の数を事実上低減させる。これに対する1つの解決策は、Cas9またはCpf1の触媒機能を完全に不活性化させること、すなわち、RNA誘導DNA結合機能のみを保持すること、及びその代わりに不活性化されたCas9にFokIドメインを融合させることであった。例えば、Tsai et al.,Nature Biotech 32:569-76(2014)、及びGuilinger et al.,Nature Biotech.32:577-82(2014)を参照されたい。FokIが触媒的に活性になるためには二量体になる必要があるため、2個のFokI融合物をごく接近してつないで二量体を形成し、DNAを切断するために、2個のガイドRNAが必要とされる。これは、本質的に、結合標的部位の塩基数を2倍にし、それによってCRISPRベースの系による標的化のストリンジェンシーを高める。
本開示は、本明細書に記載の方法を行うためのキットを提供する。あるキットは、ゲノムターゲティング核酸、ゲノムターゲティング核酸をコードするポリヌクレオチド、部位特異的ポリペプチド、部位特異的ポリペプチドをコードするポリヌクレオチド、及び/または本明細書に記載の方法の態様を行うために必要な任意の核酸もしくはタンパク質性分子、またはそれらの任意の組合せのうちの1つ以上を含み得る。
したがって、本開示は、特に、本開示に従う以下の非限定的な方法に関する。第一の方法、すなわち、方法1において、本開示は、細胞の電位依存性ナトリウムチャネルアルファサブユニット9(SCN9A)遺伝子を、以下を含むゲノム編集によって編集するための方法を提供する。すなわち、SCN9A遺伝子またはSCN9A調節要素の中もしくはその近傍で、該SCN9A遺伝子の中もしくはその近傍の少なくとも1つのヌクレオチドの永久的な挿入、欠失、または突然変異の1つ以上をもたらす1つ以上の一本鎖切断(SSB)または二本鎖切断(DSB)をきたすために当該細胞に1つ以上のデオキシリボ核酸(DNA)エンドヌクレアーゼを導入し、それにより、SCN9A遺伝子産物の発現もしくは機能を低減または除去する。
「含む(comprising)」または「含む(comprise)」という用語は、本開示にとって必須の組成物、方法、及びそれらのそれぞれの成分(複数可)に関して用いられるが、必須であるかどうかにかかわらず、特定されていない要素の包含も受け入れる。
本開示は、本発明の例示的な非限定的態様を与える以下の実施例を参照することにより、さらに十分に理解されるであろう。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、NRG配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号18989~56863に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、NNGRRT配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号8562~13614に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、NNAGAAW配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号6251~8561に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、NAAAAC配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号5305~6250に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、NNNNGHTT配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号13615~18988に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
SCN9A遺伝子の領域を、標的部位についてスキャンした。各領域を、YTN配列を有するプロトスペーサー隣接モチーフ(PAM)についてスキャンした。配列表の配列番号56864~125469に示す通り、該PAMに対応するgRNAの20bpスペーサー配列を次に特定した。
候補のガイドを次に、オンターゲット及びオフターゲットの両方の部位での理論的結合ならびに実験的に評価される活性の両方を含む単一過程または多段過程でスクリーニング及び選択する。実例として、隣接PAMとともに特定のオンターゲットの部位、例えば、SCN9A遺伝子内の部位とマッチする配列を有する候補のガイドを、以下により詳細に記載及び説明する通り、オフターゲットでの結合を評価するために利用可能な様々なバイオインフォマティクスツールの1つ以上を用いて、同様の配列を有するオフターゲットの部位で切断するそれらの可能性を評価し、目的のもの以外の染色体位置での影響の可能性を評価することができる。
同族DNA標的領域を編集することができる広範囲のgRNA対を特定するため、in vitro転写(IVT)gRNAのスクリーニングを行った。関連ゲノム配列を、gRNA設計ソフトウェアを用いる分析に供した。得られたgRNAのリストは、配列の一意性(ゲノムの他の部位で完全なマッチがないgRNAのみを選抜した)、及び最小のオフターゲット予測に基づいて上記のgRNAの選択リストに絞った。このgRNAのセットをin vitroで転写し、Lipofectamine MessengerMAXを用いてCas9を構成的に発現するHEK293T細胞にトランスフェクトした。細胞を、トランスフェクションの48時間後に採取し、ゲノムDNAを単離し、TIDE分析を用いて切断効率を評価した(図2A~G、図3A~C)。
上記実施例におけるIVTスクリーニングからの最良のオンターゲット活性を有するgRNAを、オフターゲット活性に関して、ハイブリッドキャプチャ分析、GUIDE Seq.、及び全ゲノム配列決定を他の方法に加えて用いて検討した。
CRISPR-Cas9/ガイドの組み合わせを再評価した後、先頭の処方を動物モデルにてin vivoで試験する。
当業者であれば、日常的な実験のみを用いて、本明細書に記載の本発明に従う特定の実施例に対する多くの均等物を認識し、または確認することができるであろう。本開示の範囲は、上記の説明に限定されることを意図するものではなく、添付の特許請求の範囲に記載の通りである。
本開示は、本開示の様々な態様及び/またはその潜在的な用途を例示する目的で様々な特定の態様の説明を提供すると同時に、当業者には、変形及び修正が想到されるであろうことが理解される。従って、本明細書に記載の本発明(複数可)は、本明細書に提供する特定の例示的な態様によってより狭く定義されるものではなく、少なくともそれらが請求される通りの広さであるように理解されるべきである。
Claims (39)
- ゲノム編集によって細胞内で電位依存性ナトリウムチャネルアルファサブユニット9(SCN9A)遺伝子を編集するための方法であって、前記細胞に1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼを導入して、前記SCN9A遺伝子またはSCN9A制御エレメント内またはその近傍で1つまたは複数の一本鎖切断(SSB)または二本鎖切断(DSB)を行い、前記SCN9A遺伝子内またはその近傍に少なくとも1つのヌクレオチドの1つまたは複数の恒久的挿入、欠失または変異をもたらし、それによって、SCN9A遺伝子産物の発現または機能を低減または除去することを含む前記方法。
- SCN9A関連状態または障害を有する患者を処置するためのex vivo方法であって、
(a)患者特異的誘導多能性幹細胞(iPSC)を電位依存性ナトリウムチャネルアルファサブユニット9(SCN9A)遺伝子または前記SCN9A遺伝子の制御エレメントをコードする他のDNA配列内またはその近傍で編集すること;
(b)前記編集されたiPSCを末梢神経系のニューロンに分化させること;及び
(c)前記末梢神経系のニューロンを前記患者に投与すること
を含む前記方法。 - 前記編集ステップが、前記iPSCに1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼを導入して、前記SCN9A遺伝子またはSCN9A制御エレメント内またはその近傍で1つまたは複数の一本鎖切断(SSB)または二本鎖切断(DSB)を行い、前記SCN9A遺伝子内またはその近傍に少なくとも1つのヌクレオチドの1つまたは複数の恒久的挿入、欠失または変異をもたらし、それによって、SCN9A遺伝子産物の発現または機能を低減または除去することを含む、請求項2に記載の方法。
- SCN9A関連状態または障害を有する患者を処置するためのex vivo方法であって、
(a)間葉系幹細胞を電位依存性ナトリウムチャネルアルファサブユニット9(SCN9A)遺伝子または前記SCN9A遺伝子の制御エレメントをコードする他のDNA配列内またはその近傍で編集すること;
(b)前記編集された間葉系幹細胞を末梢神経系のニューロンに分化させること;及び
(c)前記末梢神経系のニューロンを前記患者に投与すること
を含む前記方法。 - 前記編集ステップが、前記間葉系幹細胞に1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼを導入して、前記SCN9A遺伝子またはSCN9A制御エレメント内またはその近傍で1つまたは複数の一本鎖切断(SSB)または二本鎖切断(DSB)を行い、前記SCN9A遺伝子内またはその近傍に少なくとも1つのヌクレオチドの1つまたは複数の恒久的挿入、欠失または変異をもたらし、それによって、SCN9A遺伝子産物の発現または機能を低減または除去することを含む、請求項4に記載の方法。
- SCN9A関連障害を有する患者を処置するためのin vivo方法であって、前記患者の細胞内で前記電位依存性ナトリウムチャネルアルファサブユニット9(SCN9A)遺伝子を編集することを含む前記方法。
- 前記編集ステップが、前記細胞に1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼを導入して、前記SCN9A遺伝子またはSCN9A制御エレメント内またはその近傍で1つまたは複数の一本鎖切断(SSB)または二本鎖切断(DSB)を行い、前記SCN9A遺伝子内またはその近傍に少なくとも1つのヌクレオチドの1つまたは複数の恒久的挿入、欠失または変異をもたらし、それによって、SCN9A遺伝子産物の発現または機能を低減または除去することを含む、請求項6に記載の方法。
- 前記細胞が末梢神経系のニューロンである、請求項6~7のいずれか1項に記載の方法。
- 前記1種または複数のデオキシリボ核酸(DNA)エンドヌクレアーゼを、直接的な神経節内もしくは髄腔内注射、または髄腔内送達を介して前記末梢神経系のニューロンに送達する、請求項8に記載の方法。
- 細胞内でSCN9A遺伝子の連続ゲノム配列を変化させる方法であって、前記細胞を、1種または複数のデオキシリボ核酸(DNA)エンドヌクレアーゼと接触させて、1種または複数の一本鎖切断(SSB)または二本鎖切断(DSB)を行うことを含む前記方法。
- 前記連続ゲノム配列の変化が前記SCN9A遺伝子の1つまたは複数のエキソンで生じる、請求項10に記載の方法。
- 前記1種または複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが、配列番号1~620の配列のいずれか、及び配列番号1~620において開示されている配列のいずれかに対して少なくとも90%相同性を有するバリアントから選択される、請求項1~11のいずれか1項に記載の方法。
- 前記1種または複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが1つまたは複数のタンパク質またはポリペプチドである、請求項12に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが、前記1つまたは複数のDNAエンドヌクレアーゼをコードする1種または複数のポリヌクレオチドである、請求項12に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが、前記1つまたは複数のDNAエンドヌクレアーゼをコードする1つまたは複数のリボ核酸(RNA)である、請求項14に記載の方法。
- 前記1つまたは複数のリボ核酸(RNA)が、1つまたは複数の化学修飾RNAである、請求項15に記載の方法。
- 前記1つまたは複数のリボ核酸(RNA)が、前記コード領域で化学修飾されている、請求項16に記載の方法。
- 前記1つもしくは複数のポリヌクレオチドまたは1つもしくは複数のリボ核酸(RNA)がコドン最適化されている、請求項14~17のいずれか1項に記載の方法。
- 前記細胞に、1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAを導入することをさらに含む、請求項1~18のいずれか1項に記載の方法。
- 前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAが、前記SCN9A遺伝子内またはその近傍のDNA配列に対して相補的であるスペーサー配列を含む、請求項19に記載の方法。
- 前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAが化学修飾されている、請求項19~20のいずれか1項に記載の方法。
- 前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAが、前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼと事前複合体化されている、請求項19~21のいずれか1項に記載の方法。
- 前記事前複合体化が、前記1つもしくは複数のgRNAまたは1種もしくは複数のsgRNAと前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼとの共有結合を伴う、請求項22に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼがリポソームまたは脂質ナノ粒子に製剤化されている、請求項12~23のいずれか1項に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが、前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAも含むリポソームまたは脂質ナノ粒子に製剤化されている、請求項19~23のいずれか1項に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼがAAVベクター粒子内でコードされる、請求項10、または19~20のいずれか1項に記載の方法。
- 前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAがAAVベクター粒子内でコードされる、請求項19~20のいずれか1項に記載の方法。
- 前記1つまたは複数のデオキシリボ核酸(DNA)エンドヌクレアーゼが、前記1つもしくは複数のgRNAまたは1つもしくは複数のsgRNAもコードするAAVベクター粒子内でコードされる、請求項19~20のいずれか1項に記載の方法。
- 前記AAVベクター粒子が、配列番号4734~5302及び表2に開示されているもののうちのいずれかからなる群から選択される、請求項26~28のいずれか1項に記載の方法。
- 配列番号5305~125469のいずれかに対応するRNA配列である少なくとも1つのスペーサー配列を含む、一分子ガイドRNA。
- 前記一分子ガイドRNAがスペーサーエクステンション領域をさらに含む、請求項30に記載の一分子ガイドRNA。
- 前記一分子ガイドRNAがtracrRNAエクステンション領域をさらに含む、請求項30に記載の一分子ガイドRNA。
- 前記一分子ガイドRNAが化学修飾されている、請求項30~32に記載の一分子ガイドRNA。
- DNAエンドヌクレアーゼと事前複合体化している、請求項30~33のいずれか1項に記載の一分子ガイドRNA。
- 前記DNAエンドヌクレアーゼがCas9またはCpf1エンドヌクレアーゼである、請求項34に記載の一分子ガイドRNA。
- 前記Cas9またはCpf1エンドヌクレアーゼが、S.pyogenes Cas9、S.aureus Cas9、N.meningitides Cas9、S.thermophilus CRISPR1 Cas9、S.thermophilus CRISPR 3 Cas9、T.denticola Cas9、L.bacterium ND2006 Cpf1及びAcidaminococcus sp.BV3L6 Cpf1、ならびに前記エンドヌクレアーゼに対して少なくとも90%相同性を有するバリアントからなる群から選択される、請求項35に記載の一分子ガイドRNA。
- 前記Cas9またはCpf1エンドヌクレアーゼが1つまたは複数の核移行シグナル(NLS)を含む、請求項36に記載の一分子ガイドRNA。
- 少なくとも1つのNLSが、前記Cas9またはCpf1エンドヌクレアーゼのアミノ末端に、またはその50アミノ酸以内にあり、及び/または少なくとも1つのNLSが、前記Cas9またはCpf1エンドヌクレアーゼのカルボキシ末端に、またはその50アミノ酸以内にある、請求項37に記載の一分子ガイドRNA。
- 請求項30~33のいずれか1項に記載の一分子ガイドRNAをコードするDNA。
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