JP7457302B2 - Hla遺伝子のrnaガイドゲノム編集を使用して関節リウマチを処置する方法 - Google Patents
Hla遺伝子のrnaガイドゲノム編集を使用して関節リウマチを処置する方法 Download PDFInfo
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- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 1
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- 208000007089 vaccinia Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000010451 viral insertion Methods 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
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- 210000005253 yeast cell Anatomy 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
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Description
本出願は、2017年4月28日に出願された米国仮特許出願第62/491,487号の利益を主張するものであり、その開示内容の全体は、参照により本明細書に組み込まれる。
「核酸」、「ポリヌクレオチド」、および「オリゴヌクレオチド」という用語は、交換可能に使用され、直鎖状または環状の高次構造であり、かつ一本鎖形態または二本鎖形態のいずれかにおける、デオキシリボヌクレオチドまたはリボヌクレオチドポリマーを指す。本開示の目的において、これらの用語は、ポリマーの長さに関して限定的であるものと解釈されないものとする。これらの用語は、天然ヌクレオチドの公知の類似体、ならびに塩基、糖、および/またはリン酸部分(例えばホスホロチオエート骨格)において修飾されているヌクレオチドを包含し得る。概して、特定のヌクレオチドの類似体は、同じ塩基対形成特異性を有する。すなわち、Aの類似体はTと塩基対を形成する。
DRB1分子は高度に多型性であり、DRB1*04:01は、関節リウマチに対する感受性に関連する遺伝子である。対照的に、DRB1*04:02は、関節リウマチに対する抵抗性がある。本発明者らは、これら2つの対立遺伝子間のRA感受性における差の主要因である71位における単一アミノ酸残基を特定した。この単一点突然変異は、71位におけるリジンをグルタミン酸に変化させる(DRB1*04:01K71E)。よって、一態様において、本発明は、本明細書に記載される方法を使用した、RAを患う対象におけるDRB1*04:01対立遺伝子の標的化および改変に関する。いくつかのDR4対立遺伝子、特にDRB1*04:01、*04:04、および*04:05は、RAに強く関連しているが、DRB1*04:02にこれは当てはまらない。加えて、DRB1*01:01、*01:02、*10:01、および*14:02が、場合により、特に非ヨーロッパ人において、RAと関連付けられている。これらの異種の対立遺伝子は、ペプチド結合溝の70~74位における共通のアミノ酸セットである「共通エピトープ」の存在を介して、RAに寄与すると仮定されている。
本開示のDRB1*04:01対立遺伝子を標的化および改変する方法において、DRB1*04:01対立遺伝子は、ヌクレアーゼによって直接的に改変の標的とされ得る。本開示の方法および組成物において、DRB1*04:01対立遺伝子を、例えばコドン71において、改変の標的とするヌクレアーゼをコードする1つまたは複数の核酸は、CRISPR(クラスター化した規則的な配置の短い回文配列リピート)関連(Cas)ヌクレアーゼ、または転写活性化因子様エフェクターヌクレアーゼ(TALEN)、またはジンクフィンガーヌクレアーゼ(ZFN)であり得る。好ましくは、コードされるヌクレアーゼは、Cas9ヌクレアーゼである。
「鋳型核酸」とは、標的とされる核酸(例えば、DRB1ゲノムDNA)の構造を変化させるために、ヌクレアーゼ(例えば、Cas9分子)およびガイドRNA分子と併せて使用され得る核酸配列を指す。標的とされる核酸は、典型的に、切断部位またはその付近において、鋳型核酸の配列の一部または全てを有するように改変される。鋳型核酸は、一本鎖であっても二本鎖であってもよい。鋳型核酸は、DNA(例えば、二本鎖DNA)、または一本鎖DNA、またはRNA(例えば、二本鎖RNAまたは一本鎖RNA)であってもよい。鋳型核酸は、ヌクレアーゼおよび/またはガイドRNAと同じベクター骨格(例えば、AAVゲノム、プラスミドDNA)上でコードされてよく、鋳型核酸は、ベクター骨格からインビボで切除されてよい(例えば、これにガイドRNA認識配列が隣接する)。鋳型DNAは、ILDVにおいてコードされてもよい。鋳型核酸は、外因性核酸配列であってもよい。鋳型核酸配列は、内因性核酸配列(例えば、内因性相同領域)であってもよい。鋳型核酸は、核酸配列のプラス鎖またはマイナス鎖に対応する一本鎖オリゴヌクレオチドであってもよい。
上述の異なるヌクレアーゼを使用した遺伝子の標的化および改変の技術は、多くの異なる標的細胞を使用して行なうことができる。例えば、形質導入細胞は、内皮細胞、肝細胞、または幹細胞を含み得る。一実施形態において、細胞は、インビボで標的とされ得る。一実施形態において、細胞は、エクスビボのアプローチを使用して標的とされ、対象に再導入され得る。
核酸デリバリーの方法は、当技術分野において周知である(例えば、PCT公開第WO2012/051343号を参照されたい)。本開示の方法において、記載されるヌクレアーゼをコードする核酸は、DNAまたはRNA、一本鎖または二本鎖として細胞に導入されてよく、直鎖状または環状の形態で細胞に導入されてよい。一実施形態において、ヌクレアーゼをコードする核酸は、mRNAとして細胞に導入される。鋳型配列は、一本鎖または二本鎖のDNAとして細胞に導入されてよく、直鎖状または環状の形態で細胞に導入されてよい。直鎖状形態で導入される場合、核酸の末端は、当業者に公知の方法によって保護されていてもよい(例えばエキソヌクレアーゼによる分解から)。例えば、1つまたは複数のジデオキシヌクレオチド残基が直鎖状分子の3’末端に付加され、かつ/または自己相補的オリゴヌクレオチドが一方または両方の末端にライゲートされる[例えば、Chang et al. (1987) Proc. Natl. Acad. Sci. USA 84:4959-4963、Nehls et al. (1996) Science 272:886-889を参照されたい]。外因性ポリヌクレオチドを分解から保護するための更なる方法は、ホスホロチオエート、ホスホロアミデート、およびO-メチルリボースまたはデオキシリボース残基などの、末端アミノ基の付加、および修飾されたヌクレオチド間結合の使用を含むが、これらに限定されない。
エクスビボ遺伝子改変
ウイルスベクターを使用せずに行なわれ得るエクスビボ遺伝子改変戦略の例を提供する。電気穿孔およびCas9ヌクレアーゼを使用して、ヒトRA患者から誘導されたHSCにおいて、71位にグルタミン酸残基を有するタンパク質(DRB1*04:01K71E)を発現するようにDRB1*04:01対立遺伝子を改変するために、遺伝子材料を送達する。
ヒトにおける第VIII因子遺伝子改変のためのプロトコール
血液試料の取得:血液増生内皮細胞(BOEC)におけるDRB1*04:01対立遺伝子の改変のためのプロトコールを、以下の実施例に記載する。まず、静脈切開術のための標準的な医学的ガイドラインに従い、静脈穿刺を行ない、抗凝固試薬を含む市販の医療用収集デバイスに収集することにより、50~100mLの患者血液試料を得ることで、血液試料を得る。使用される抗凝固試薬は、ヘパリン、クエン酸ナトリウム、および/またはエチレンジアミン四酢酸(EDTA)を含む。血液収集後、無菌技術に関する標準的な臨床的慣行を用いて、すべての工程を進める。
CRISPR/Cas9系のためのガイド配列の設計および試験
本発明者らは、CRISPR/Cas9系のためのガイド配列を設計し、評価し、クローニングするために、CRISPOR(crispor.tefor.net)を使用した。ホモ・サピエンス(Homo sapiens)ゲノム、およびSpCas 9に対して特異的なプロトスペーサー隣接モチーフ(PAM)を使用して(ガイドの20塩基対配列には、NGGが続く必要がある)、HLA-DRB1*04:01の配列を分析した。50超の特異性スコアを有するガイド配列は複数特定されたが、DRB1*04:01の標的領域にわたったガイドは3つのみであった。1つのガイドは高いGC含量を有したため除外したが、他の2つのガイド配列(185/revおよび208/fwd)を更なる評価のために選択した:
ガイド185/rev:5’cggcccgcttctgctccagg 3’(配列番号2)
ガイド208/fwd:5’cctggagcagaagcgggccg 3’(配列番号3)
CRISPR/Cas9編集後のHLA-DR発現
ヌクレオフェクション(Lonza)を使用して、208/fwdガイドまたは185/revガイドRNAおよびCas 9タンパク質を細胞株に導入した。208/fwdおよび185/revのための合成ガイドRNAは、Synthegoから購入した。各ガイドとSynthego Cas9-2NLSタンパク質を混合して、1:5.25の比におけるCas9:sgRNA RNP複合体を形成した。RNP複合体をT2-DRB1*04:01細胞株にヌクレオフェクトして、編集効率を評価した。非トランスフェクト細胞(図3A)およびスクランブルsgRNA(図3B)を陰性対照として試験した。
トランスジェニックマウス
本発明者らはまた、HLA-DRB1*04:01トランスジェニックマウスにおける関節炎誘発性ペプチドに対する抗原特異的T細胞応答を、HLA-DRB1*04:01K71Eトランスジェニックマウスに対して比較するために、ヒトHLA-DRB1*04:01K71Eのみを発現するトランスジェニックマウスを開発した。これらのマウスは、DRβ1*04:01を発現する個体におけるRAに対する増加した感受性が、天然のペプチドの結合に干渉することによりシトルリン化されたペプチドおよびコラーゲンの結合を促進するK71の存在に起因することを示すために使用される。よって、DRβ1*04:01K71Eを発現するトランスジェニックマウスは、シトルリン化されたペプチドおよびコラーゲンに対する強力なT細胞応答を生じない。このマウスは、HLA-DRB1*04:01マウスに移植されたDRB1*04:01K71Eマウス由来の幹細胞が移植片対宿主病を引き起こさないことも示す。
Claims (17)
- 改変された造血細胞を作製する方法であって、
a)コドン71を含むHLA-DRB1*04:01対立遺伝子の少なくとも一部分を含む鋳型核酸を造血幹細胞/前駆細胞に導入すること、ここで、前記鋳型核酸のコドン71の核酸配列がグルタミン酸をコードし、造血幹細胞/前駆細胞がコドン71でリジンをコードするゲノムHLA-DRB1*04:01対立遺伝子を含む、導入すること;
b)Cas9分子ならびにCGGCCCGCTTCTGCTCCAGG(配列番号2)、およびCCTGGAGCAGAAGCGGGCCG(配列番号3)から選択されるヌクレオチドを含むガイドRNA分子を前記細胞に導入すること;ここで、Cas9分子が、Cas9タンパク質またはCas9タンパク質をコードするポリヌクレオチドである;および
c)少なくともゲノムHLA-DRB1*04:01対立遺伝子においてリジンをコードするコドン71を、グルタミン酸をコードする鋳型核酸のコドン71と置換すること
を含む、方法。 - 改変された造血細胞が、ヒト細胞、初代血液細胞および血液細胞の集団、の1以上から選択される、請求項1に記載の方法。
- 改変された造血細胞が、循環血液細胞、動員血液細胞、骨髄細胞、骨髄系前駆細胞、複能性前駆細胞、および系列限定前駆細胞からなる群から選択される、請求項1に記載の方法。
- 鋳型核酸が、コドン71においてAからGの点突然変異を含むHLA-DRB1*04:01対立遺伝子のヌクレオチドを含む、請求項1-3のいずれか一項に記載の方法。
- ガイドRNA分子およびCas9分子が、造血幹細胞/前駆細胞に、予め形成されたリボヌクレオチド複合体として導入される、請求項1に記載の方法。
- Cas9分子が、造血幹細胞/前駆細胞に、Cas9タンパク質をコードする核酸として導入される、請求項1に記載の方法。
- ガイドRNAが、造血幹細胞/前駆細胞に、ガイドRNAをコードする核酸として導入され、Cas9分子が、細胞に、Cas9タンパク質をコードする核酸として導入され、細胞が、ガイドRNAおよびCas9タンパク質を発現する、請求項1に記載の方法。
- ガイドRNA、Cas9タンパク質、および鋳型核酸が、アデノ随伴ウイルス(AAV)または組込み欠損レンチウイルス(ILDV)中で造血幹細胞/前駆細胞に導入される、請求項7に記載の方法。
- 導入する工程の後に改変された造血細胞をエクスビボで増殖させて、細胞のゲノムにおいてコドン71でグルタミン酸をコードするHLA-DRB1対立遺伝子を含む単離された細胞集団を形成することを更に含む、請求項1-8のいずれか一項に記載の方法。
- 対象の関節リウマチを処置または防止する組成物であって、該組成物は以下;
HLA-DRB1対立遺伝子内の標的核酸配列に対して相補的なガイドRNA、
Cas9タンパク質またはCas9タンパク質をコードするポリヌクレオチド、および
コドン71を含むHLA-DRB1*04:01対立遺伝子の少なくとも一部分を含む鋳型核酸、
を含み、
コドン71の鋳型核酸配列がグルタミン酸をコードし;
標的核酸配列が、リジンをコードするコドン71を含むHLA-DRB1*04:01対立遺伝子の未改変のゲノム配列を含み;かつ
前記ガイドRNAが、CGGCCCGCTTCTGCTCCAGG(配列番号2)およびCCTGGAGCAGAAGCGGGCCG(配列番号3)から選択されるヌクレオチドを含む、
組成物。 - ガイドRNA、Cas9タンパク質もしくはCas9タンパク質をコードするポリヌクレオチド、ならびに鋳型核酸がアデノ随伴ウイルス(AAV)または組込み欠損レンチウイルス(ILDV)中に含まれる、請求項10に記載の組成物。
- 細胞をさらに含み、ここでガイドRNA、Cas9タンパク質もしくはCas9タンパク質をコードするポリヌクレオチド、ならびに鋳型核酸が前記細胞にウイルス形質導入を介して導入され、前記細胞が、リジンをコードするHLA-DRB1*04:01コドン71を含む、請求項10または11に記載の組成物。
- ガイドRNA、Cas9タンパク質もしくはCas9タンパク質をコードするポリヌクレオチド、ならびに鋳型核酸がエクスビボで細胞に導入され、かつ前記細胞が対象から単離されている、請求項12に記載の組成物。
- ガイドRNA、Cas9タンパク質もしくはCas9タンパク質をコードするポリヌクレオチド、ならびに鋳型核酸が、予め形成されたリボヌクレオチド複合体として細胞に導入される、請求項12または13に記載の組成物。
- 前記細胞が初代血液細胞、造血幹細胞、造血前駆細胞、血液細胞の集団、およびそれらの組合せから選択される、請求項12-14のいずれか一項に記載の組成物。
- 前記細胞が、循環血液細胞、動員血液細胞、骨髄細胞、骨髄系前駆細胞、複能性前駆細胞、および系列限定前駆細胞(lineage restricted progenitor cell)からなる群から選択される、請求項12-14のいずれか一項に記載の組成物。
- 前記細胞が、自家骨髄移植片として対象に投与され、対象の骨髄を再増殖する、請求項12-16のいずれか一項に記載の組成物。
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