JP2023011697A - 核酸産物およびその投与方法 - Google Patents
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Abstract
Description
本出願は、2016年8月17日に出願された米国特許仮出願第62/376,209号、および2017年5月22日に出願された米国特許仮出願第62/509,350号に対する優先権を主張する。前述の特許出願の全内容は、参照により本明細書に組み込まれる。
本発明は、一部分は、細胞、組織、器官、および患者において核酸を産生し、これらに送達するための方法、組成物、および産物、細胞、組織、器官、および患者において、タンパク質を発現させるための方法、ならびにこれらの方法、組成物、および産物を用いて生成される細胞、治療薬、および化粧品に関する。
本出願は、EFSウエブによりASCIIフォーマットで提出された配列表を含み、参照によりその全体が本明細書に組み込まれる。2017年8月17日に作成された該ASCIIコピーは、FAB-010PC_ST25と命名され、2.32MBのサイズである。
リボ核酸(RNA)は、原核細胞および真核細胞の両方で広く分布し、メッセンジャーRNAの形態で遺伝情報をコードし、トランスファーRNAの形態でアミノ酸を結合および輸送し、リボソームRNAの形態でアミノ酸をタンパク質に構築し、マイクロRNAおよび長鎖非コードRNAの形態での遺伝子発現制御を含む多数の他の機能を実施する。RNAは、直接的な化学合成およびインビトロ転写を含む方法により、合成的に生成することができ、治療的使用のために患者に投与できる。しかし、以前に記載されている合成RNA分子は、ヒト細胞において、不安定であり、強力な自然免疫応答を誘発する。加えて、患者、器官、組織、およびインビボの細胞に、核酸を効率的に非ウイルス的送達するための方法は、以前に記載されていない。既存の合成RNA技術および核酸の送達方法の多くの欠点により、それらの技術および方法が、治療的または美容的使用にとって望ましくないものになっている。
細胞は、それらを、特定の細胞外キュー(cue)に曝露することにより、および/または特定のタンパク質、マイクロRNAなどの異所性発現によりリプログラミングすることができる。いくつかのリプログラミング方法が以前に記載されているが、異所性発現に依存するほとんどのものは、変異の危険を伴う可能性がある外来DNAの導入を必要とする。リプログラミングタンパク質の直接送達に基づく、DNAフリーのリプログラミング方法が報告されている。しかし、これらの方法は商業的使用には、あまりにも非効率的で信頼できない。加えて、RNAベースのリプログラミング方法が記載されている(例えば、Angel.MIT Thesis.2008.1-56;Angel et al.PLoS ONE.2010.5,107;Warren et al.Cell Stem Cell.2010.7,618-630;Angel.MIT Thesis.2011.1-89;and Lee et al.Cell.2012.151,547-558、を参照されたい。これらの全ての内容は、参照により本明細書に組み込まれる)。しかし、既存のRNAベースのリプログラミング方法は、成熟細胞に実施される場合、時間がかかり、信頼できず、非効率的であり、(著しい費用およびエラーの可能性をもたらす)多くのトランスフェクションを必要とし、限られた数の細胞型のみをリプログラミングすることができ、細胞を限られた数の細胞型のみへとリプログラミングすることしかできず、免疫抑制剤の使用を必要とし、血液由来HSAおよびヒト線維芽細胞フィーダーを含む複数のヒト由来成分の使用を必要とする。以前に開示されたRNAベースのリプログラミング方法の多くの欠点により、これらの方法が、研究、治療的、または美容的使用にとって望ましくないものになっている。
いくつかの天然のタンパク質は、特定のDNA配列を認識できるDNA結合ドメイン、例えば、ジンクフィンガー(ZF)および転写活性化因子様エフェクター(TALE)を含有する。これらのDNA結合ドメインおよびFokIエンドヌクレアーゼの切断ドメインの内の1つまたは複数を含有する融合タンパク質を、細胞内のDNAの所望の領域に、二本鎖切断を形成するために用いることができる(例えば、米国特許出願公開第US2012/0064620号、米国特許出願公開第US2011/0239315号、米国特許第8,470,973号、米国特許出願公開第US2013/0217119号、米国特許第8,420,782号、米国特許出願公開第US2011/0301073号、米国特許出願公開第US2011/0145940号、米国特許第8,450,471号、米国特許第8,440,431号、米国特許第8,440,432号、および米国特許出願公開第2013/0122581号(これら全ての内容は、参照により本明細書に組み込まれる)を参照されたい)。他の遺伝子編集タンパク質としては、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(CRISPR)関連タンパク質が挙げられる。しかしながら、細胞を遺伝子編集するための現在の方法は、非効率的で、無制御変異誘発の危険を伴うため、これらの方法が、研究、治療的、および美容的使用にとって望ましくないものとなっている。体細胞のDNAフリーの遺伝子編集のための方法は、以前に検討されておらず、体細胞の同時または順次の遺伝子編集およびリプログラミングのための方法もまた、検討されていない。加えて、患者において、(すなわち、インビボで)、細胞を直接遺伝子編集するための方法は、以前に検討されておらず、そのような方法の開発は、DNA結合ドメインの乏しい結合にある程度起因する、許容可能な標的の欠如、非効率的な送達、遺伝子編集タンパク質/タンパク質(複数)の非効率的な発現、発現された遺伝子編集タンパク質/タンパク質(複数)による非効率的な遺伝子編集と、FokI切断ドメインの無向二量体形成およびDNA結合ドメインの不十分な特異性にある程度起因する、過剰なオフターゲット効果と、ならびに他の要因により制限されている。すなわち、抗菌、抗ウイルス、および抗癌治療における遺伝子編集の使用は、以前に検討されていない。
「分子」は、分子実体(分子、イオン、複合体など)を意味する。
実施例1 RNA合成
緑色蛍光タンパク質(「GFP」)、NOVEPOETIN(「EPO」)、エラスチン(「ELN」)、チロシナーゼ(「TYR」)、メラノコルチン1受容体(「MC1R」)、HAS1、HAS2、HAS3、COL3A1、COL7A1、COL1A1、COL1A2、hTERT、ホリーGFP、フレズノRFP、Blitzen Blue、RIBOSLICE遺伝子編集タンパク質、TALEN、Cas9、Oct4、Sox2、Klf4、c-Myc-2(T58A)、Lin28、IL2、IL6、IL15、IL22、BMP2、BMP7、BDNF、LIF、BMP6、IL15RA、FGF21、LIF、PTH、KRT5、KRT5-GFP、KRT14、KRT14-GFP、GDF15およびESM1をコードし、標準および非標準ヌクレオチドの種々の組み合わせを含むRNAを、製造者の説明書ならびに本発明者らにより先に開示された発明(米国特許出願第13/465,490号(現在米国特許第8,497,124号)、国際出願第PCT/US12/67966号、米国特許出願第13/931,251号、国際出願第PCT/US13/68118号、および国際出願第PCT/US2015/013949号、これら全ての内容は全体として参照により本明細書に組み込まれる)に従って、T7高収率RNA合成キットおよびmRNAキャップ2′-O-メチルトランスフェラーゼを有するVacciniaCappingSystemキット(全てNewEnglandBiolabs,Inc.製)を用いて、DNAテンプレートから合成した(表4)。次に、RNAを、100ng/pL~2000ng/pLまでヌクレアーゼ非含有水で希釈した。ある特定の実験のために、RNase阻害剤(Superase・In、LifeTechnologiesCorporation)を、RNA100μg当たり1μLの濃度で添加した。RNA溶液を室温、4℃、-20℃、または-80℃で保存した。リプログラミング実験のために、Oct4、Sox2、Klf4、c-Myc-2(T58A)、およびLin28をコードするRNAを、3:1:1:1:1のモル比で混合した。
RNAの1マイクログラムごとに、1μgのRNA、および1μLのトランスフェクション試薬(リポフェクタミン3000、LifeTechnologiesCorporation)を、まず、複合体形成培地(Opti-MEM、LifeTechnologiesCorporation、またはDMEM/F12+10pg/mLのインスリン+5.5pg/mLのトランスフェリン+6.7ng/mLの亜セレン酸ナトリウム+2pg/mLのエタノールアミン)で別々に希釈して、それぞれ5μL~100μLの総量にした。次に、希釈したRNAおよびトランスフェクション試薬を、トランスフェクション試薬の製造者の説明書にしたがって、混合し、室温で10分間インキュベートした。
複合体を実施例2に従って調製した後、培養液中の細胞に直接添加した。6ウェルプレートでトランスフェクトするため、10μL~250μLの複合体を、1ウェル当たり2mLのトランスフェクション培地を既に含有している6ウェルプレートの各ウェルに添加した。プレートを穏やかに振盪して、複合体をウェル全体に分配させた。細胞を4時間から一晩、複合体とインキュベートした後、培地を新しいトランスフェクション培地(2mL/ウェル)と交換した。あるいは、培地を交換しなかった。量を、24ウェルおよび96ウェルプレートでのトランスフェクションのために調整した。
初代ヒト線維芽細胞を、実施例1に従って合成されたRNAで、実施例2にしたがってトランスフェクションした。細胞を、Oct4に対する抗体を用いて、トランスフェクションの20~24時間後に固定および染色した。RNAの相対的な毒性を、固定時の細胞密度を評価することにより決定した。
表5に示す複合体形成反応物を、実施例1に従って合成された、緑色蛍光タンパク質(GFP)またはVII型コラーゲンαI(COL7)をコードするRNAを用いて調製した。RNAストック溶液の濃度は、500μg/mLであった。
NOVEPOETINをコードするRNAを、ヌクレオチドの3つの組み合わせ:1)U、G、U、C、2)U、G、5moU、C、および3)U、G、psU、Cを用いて、実施例1に従って合成した。EpiLife培地中で培養された初代ヒトケラチノサイトの副集密層(sub-confluentlayer)を、1ウェル当たり1μgのRNAで、実施例3に従って6ウェルプレートのウェルにトランスフェクトした。トランスフェクションの12、24、36、および48時間後に、0.5mLの培地を除去し、0.5mLの新しいEpiLife培地をプレートに添加した。最後の培地サンプリングの後、細胞をトリプシン処理により収集し、全RNAを、RNeasyミニキット(Qiagen)を用いて単離した。ゲノムDNAを、DNaseIを用いて消化し、RNAを精製した。インターフェロン-βおよびGAPDHの発現を、RT-PCRで測定した(図5)。
ヒトテロメラーゼ逆転写酵素(hTERT)をコードするRNAを、以下のヌクレオチド:U、G、5moU、Cを用いて、実施例1に従って合成した。DMEM+10%FBS中で培養された初代ヒト皮膚線維芽細胞の副集密層を、1ウェル当たり0.25μgのRNAで、実施例3に従って24ウェルプレートのウェルにトランスフェクトした。トランスフェクションの12時間後に細胞を固定し、ウサギ抗hTERT抗体(Millipore、パーツ番号:MABE14)の1:50希釈液を用いて、染色した(図16)。
初代ヒト線維芽細胞を、トランスフェクション培地中の10,000細胞/ウェルの密度で、組換えヒトフィブロネクチンおよび組換えヒトビトロネクチン(それぞれ1μg/mL、1mL/ウェルの濃度までDMEM/F12で希釈し、1時間室温でインキュベートした)でコーティングされた6ウェルプレートに播種した。翌日、細胞を、実施例1に従って合成されたRNAで、実施例2のようにトランスフェクションした。翌日、1つのウェル中の細胞を、再度トランスフェクションした。2回目のトランスフェクションの2日後に、遺伝子編集の効率を、変異特異的ヌクレアーゼアッセイを用いて測定した。
6ウェルプレートでのトランスフェクションのために、1μgのヒトAPP遺伝子のエキソン16を標的とする遺伝子編集タンパク質をコードするRNA、1μgの標的細胞に存在しなかったPstI制限酵素部位を含有する一本鎖修復テンプレートDNA、および6μLのトランスフェクション試薬(リポフェクタミンRNAiMAX、LifeTechnologiesCorporation)を、まず、複合体形成培地(Opti-MEM、LifeTechnologiesCorporation)で別々に希釈して、120μLの総量にした。次に、希釈されたRNA、修復テンプレート、およびトランスフェクション試薬を、トランスフェクション試薬の製造者の指示にしたがって、混合し、室温で15分間インキュベートした。複合体を、培養液中の細胞に添加した。約120μLの複合体を、1ウェル当たり2mLのトランスフェクション培地を既に含有している6ウェルプレートの各ウェルに添加した。プレートを穏やかに振盪して、複合体をウェル全体に分配させた。細胞を4時間から一晩、複合体とインキュベートした後、培地を新しいトランスフェクション培地(2mL/ウェル)と交換した。翌日、培地をDMEM+10%のFBSに交換した。トランスフェクションの2日後、ゲノムDNAを分離および精製した。APP遺伝子内の領域をPCRにより増幅し、増幅産物を、PstIで消化し、ゲル電気泳動により分析した。
40匹の雌のNCrnu/nuマウスに、50%のマトリゲル(BDBiosciences)中の5x106のMDA-MB-231腫瘍細胞を皮下注入した。細胞注入量は、0.2mL/マウスであった。試験開始時のマウスの週齢は、8~12週であった。腫瘍が100~150mm3の平均サイズに達した時に、ペアマッチを行い、動物をそれぞれ10匹ずつの4つのグループに分け、治療を開始した。体重を、初めの5日間は毎日、その後試験の終了までは隔週で測定した。治療は、ビークル(リポフェクタミン2000、LifeTechnologiesCorporation)と複合体形成したRIBOSLICEBIRC5-1.2で構成された。各群に対する投与溶液を調製するために、308μLの複合体形成緩衝液(Opti-MEM、LifeTechnologiesCorporation)を、2つの滅菌したRNaseフリーの1.5mLのチューブのそれぞれにピペッティングした。22μLのRIBOSLICEBIRC5-1.2(500ng/pL)を、2つのチューブの内の1つに添加し、チューブの内容物をピペッティングにより混合した。22μLのビークルを、第2のチューブに添加した。第2のチューブの内容物を混合し、次に第1のチューブに移し、ピペッティングにより第1のチューブの内容物と混合し、複合体を形成した。複合体を、10分間室温でインキュベートした。インキュベーションの間、シリンジに装填した。動物に、動物1匹当たり1μgのRNAの総投与量として、動物1匹当たり60μLの総量を、静脈内または腫瘍内注入した。1日おきに注入して合計5回の治療を実施した。用量の体重による調整は行わなかった。動物を、17日間追跡調査した。平均体重に大きな減少は観察されず、RIBOSLICE遺伝子編集RNAのインビボ安全性が実証された。
ポリエチレンイミン(PEI)、種々の商用の脂質系トランスフェクション試薬、ペプチド系トランスフェクション試薬(N-TER、Sigma-AldrichCo.LLC.)、ならびにいくつかの脂質系およびステロール系送達試薬を含む送達試薬を、インビトロでのトランスフェクション効率および毒性に関してスクリーニングした。送達試薬を、RIBOSLICEBIRC5-1.2と複合体形成し、複合体を培養液中のHeLa細胞に送達した。毒性を、トランスフェクションの24時間後に細胞密度を分析することにより評価した。トランスフェクション効率を、形態学的変化を分析することにより評価した。試験した試薬は、広範囲の毒性およびトランスフェクション効率を示した。より高い割合のエステル結合を含有する試薬は、より低い割合のエステル結合を含有する試薬またはエステル結合を含有しない試薬よりも低い毒性を示した。
500ng/μLのRNAの1μgを3μLの複合体形成培地(Opti-MEM、LifeTechnologiesCorporation)と混合し、RNAの1μg当たり2.5μLのトランスフェクション試薬(リポフェクタミン2000、LifeTechnologiesCorporation)を2.5μLの複合体形成培地と混合することにより、高濃度リポソームRIBOSLICEを調製した。次に、希釈したRNAおよびトランスフェクション試薬を、混合し、室温で10分間インキュベートして、高濃度リポソームRIBOSLICEを形成した。あるいは、DOSPAまたはDOSPERを含有するトランスフェクション試薬を用いる。
40匹の雌のNCrnu/nuマウスに、1x107のU-251腫瘍細胞を皮下注入した。細胞注入量は、0.2mL/マウスであった。試験開始時のマウスの週齢は、8~12週であった。腫瘍が35~50mm3の平均サイズに達した時に、ペアマッチを行い、動物をそれぞれ10匹ずつの4つのグループに分け、治療を開始した。体重を、初めの5日間は毎日、その後試験の終了までは隔週で測定した。キャリパー測定を隔週で行い、腫瘍サイズを算出した。治療は、ビークル(リポフェクタミン2000、LifeTechnologiesCorporation)と複合体形成したRIBOSLICEBIRC5-2.1で構成された。投与溶液を調製するために、294μLの複合体形成緩衝液(Opti-MEM、LifeTechnologiesCorporation)を、196μLのRIBOSLICEBIRC5-1.2(500ng/μL)を含有するチューブにピペッティングし、チューブの内容物をピペッティングにより混合した。245μLの複合体形成緩衝液を、245μLのビークルを含有するチューブにピペッティングした。第2のチューブの内容物を混合し、次に第1のチューブに移し、ピペッティングにより第1のチューブの内容物と混合し、複合体を形成した。複合体を、10分間室温でインキュベートした。インキュベーションの間、シリンジに装填した。動物に、動物1匹当たり2μgまたは5μgのRNAの総投与量のいずれかに相当する、動物1匹当たり20μLまたは50μLの総量のいずれかを、腫瘍内注入した。1日おきに注入して合計5回の治療を実施した。用量の体重による調整は行わなかった。動物を、25日間追跡調査した。
リポソームを、次の配合物:3.2mg/mLのN-(カルボニルエトキシポリエチレングリコール2000)-1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(MPEG2000-DSPE)、9.6mg/mLの完全水素化ホスファチジルコリン、3.2mg/mLのコレステロール、2mg/mLのアンモニウムスルフェート、および緩衝液としてのヒスチジンを用いて調製する。pHを、水酸化ナトリウムを用いて調節し、等張性を、ショ糖を用いて維持する。リポソームを形成するため、脂質を、有機溶媒中で混合し、乾燥させ、撹拌しながら水和させ、800nmの平均孔径を有するポリカーボネートフィルターを通して押出すことにより一定の大きさにする。核酸を、核酸1μg当たり10μgのリポソーム配合物を組み合わせ、5分間室温でインキュベートすることによりカプセル化する。
リポソームを、以下の製剤:3.2mg/mLのN-(カルボニル-エトキシポリエチレングリコール2000)-1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン(MPEG2000-DSPE)、9.6mg/mLの完全水素化ホスファチジルコリン、3.2mg/mLのコレステロール、2mg/mLのアンモニウムスルフェート、および緩衝液としてのヒスチジンを用いて調製し、0.27mg/mLの1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン-N-[葉酸(ポリエチレングリコール)-5000](FA-MPEG5000-DSPE)を脂質混合物に添加した。pHを、水酸化ナトリウムを用いて調節し、等張性を、ショ糖を用いて維持する。リポソームを形成するため、脂質を、有機溶媒中で混合し、乾燥させ、撹拌しながら水和させ、800nmの平均孔径を有するポリカーボネートフィルターを通して押出すことにより一定の大きさにする。核酸を、核酸1μg当たり10μgのリポソーム配合物を組み合わせ、5分間室温でインキュベートすることによりカプセル化する。
実施例1に従って合成された治療用タンパク質をコードする合成RNAをカプセル化するリポソームを、実施例14または実施例15に従って調製する。リポソームを、注入または静脈内点滴により投与する。
全RNAを、製造業者の説明書にしたがって、RNeasyミニキット(QIAGEN GmbH)を用いて、ヒト新生児皮膚線維芽細胞から抽出した。ヒトエラスチンをコードするcDNAを、MonsterScript(商標)逆転写酵素(EpicentreBiotechnologies)およびプライマー:AAAAAAACCGGTTCATTTTCTCTTCCGGCCAC(配列番号483)を用いて調製した。インビトロ転写(ivT)テンプレートを、プライマーF:AAAAAAGCTAGCATGGCGGGTCTGACG(配列番号484)、およびR:AAAAAAACCGGTTCATTTTCTCTTCCGGCCAC(配列番号485)を用いて、エラスチンコード配列(CDS)のPCR増幅によりcDNAから調製した。次に、PCR産物を、アガロースゲル電気泳動およびQIAquickゲル抽出キット(QIAGENGmbH)を用いることにより精製し、ヒトβグロビン(HBB)5’および3’非翻訳領域ならびに強力なコザック配列を含有するベクターに挿入した。ベクターを、RNA合成に先立って増幅、精製、および直線化した。
全RNAを、製造業者の説明書にしたがって、RNeasyミニキット(QIAGENGmbH)を用いて、ヒト表皮メラノサイトから抽出した。ヒトチロシナーゼをコードするcDNAを、MonsterScript(商標)逆転写酵素(EpicentreBiotechnologies)を用いて調製した。インビトロ転写(ivT)テンプレートを、チロシナーゼコード配列(CDS)のPCR増幅によりcDNAから調製した。次に、PCR産物を、アガロースゲル電気泳動およびQIAquickゲル抽出キット(QIAGENGmbH)を用いることにより精製し、ヒトβグロビン(HBB)5’および3’非翻訳領域ならびに強力なコザック配列を含有するベクターに挿入した。ベクターを、RNA合成に先立って増幅、精製、および直線化した。
ヒトチロシナーゼをコードするRNAを、製造者の説明書にしたがって、実施例18のDNAテンプレートおよびT7高収率RNA合成キット(NewEnglandBiolabs,Inc.)を用いて実施例1に従って合成した(表4)。RNAの試料を、アガロースゲル電気泳動により分析して、RNAの品質を評価した。次に、RNAを1μg/μLまで希釈した。RNA溶液を、4℃で保存した。
実施例19のRNAを、シリンジに装填し、約30秒間にわたって健康な33歳の男性患者の腹側前腕に皮内注入により投与した。
実施例20で治療された皮膚の領域を、コンデンサーに電気的に接続された2電極アレイを用いて、10V~155Vおよび約10ミリ秒~約1秒の電気パルスに曝露した。患者は、全ての電圧と侵入深度で打診痛知覚を報告した。治療範囲が、24~48時間後に黒くなった。実験を数回繰り返し、同様の結果を得た。
実施例19のRNAまたは実施例16のリポソームを、角質層の破壊を伴ってまたは伴わずに皮膚に直接適用する、または平方センチメートル当たり1マイクログラム以下の用量を用いて皮内注入する、または注入により表皮に投与する。場合により、電場を、RNAの送達を増強するために、実施例21と同様に、または表面接触パッチを用いて適用する。
エラスチンをコードするRNAを、実施例1にしたがって調製した。RNAを、実施例20、21、または22と同様に送達する。
コラーゲンをコードするRNAを、実施例1にしたがって調製する。RNAを、実施例20、21、または22と同様に送達する。
NOVEPOETINをコードするRNAを、実施例1に従って調整した。RNAを、実施例20、21、または22と同様に送達する。
アクチンをコードするRNAを、実施例1にしたがって調製する。RNAを、実施例20、21、または22と同様に電場を用いて、または用いずに筋肉内注入で患者に送達する。
塩基性線維芽細胞増殖因子またはIL22をコードするRNAを、実施例1にしたがって調製する。RNAを、実施例20、21、または22と同様に送達する。
コラゲナーゼをコードするRNAを、実施例1にしたがって調製する。RNAを、実施例20、21、または22と同様に送達する。
ボツリヌス毒素をコードするRNAを、実施例1にしたがって調製する。RNAを、実施例20、21、または22と同様に送達する。
ヒトCOL1A1遺伝子のコード配列を含むRNAを、実施例1に従って合成した。初代ヒト皮膚線維芽細胞を、24ウェルプレートに播種し、実施例2にしたがってトランスフェクションした。トランスフェクションの24~72時間後に、細胞を固定し、コラーゲンIを標的とする抗体を用いて染色した。多くのコラーゲン細胞外沈着物が、トランスフェクトされたウェル中で認められた。
ヒトCOL7遺伝子のコード配列を含むRNAを、実施例1に従って合成した。初代ヒト皮膚線維芽細胞を、24ウェルプレートに播種し、実施例2にしたがってトランスフェクションした。トランスフェクションの24~72時間後に、細胞を固定し、VII型コラーゲンを標的とする抗体を用いて染色した。トランスフェクトされた細胞は、トランスフェクトされていない対照と比較して、高レベルのVII型コラーゲンを示した。
ヒトCOL1A1遺伝子またはヒトCOL7遺伝子のコード配列を含むRNAを、実施例1に従って合成した。RNAをシリンジに装填し、約30秒にわたって、または実施例20、21、または22と同様に患者の真皮に送達する。
実施例32で治療された皮膚の領域を、電源に電気的に接続された多電極アレイを用いて、10V~155Vおよび約50マイクロ秒~約1秒の電気パルスに曝露する。
GFPをコードするRNAを用いた複合体形成反応物を、実施例5に従って調製した。10分間のインキュベーション後、複合体形成反応物を3つの等分に分割し、1つは、FactorPlex(商標)複合体形成培地で1:10に希釈し、1つは、滅菌したヌクレアーゼ不含水中1:10に希釈し、1つは、未希釈のままにした。次いで、3部の各々をさらに4つの等分に分割し、1つは、実施例3に従って初代ヒト皮膚線維芽細胞に適用し、1つは、室温で6時間放置した後に、実施例3に従って初代ヒト皮膚線維芽細胞に適用し、1つは、4℃で6時間放置した後に、実施例3に従って初代ヒト皮膚線維芽細胞に適用し、1つは、液体窒素中で急速凍結し、-80℃で6時間放置した後に、実施例3に従って初代ヒト皮膚線維芽細胞に適用した。細胞は、第一のトランスフェクションの約24時間後に蛍光顕微鏡を用いて撮像した(図17)。全てのウェルは、GFP陽性細胞を含有し、合成RNA複合体が、試験した全ての保存条件で安定で、また、活性を維持したことが実証された。
NOVEPOETINをコードするRNAは、A、G、5moU、Cのヌクレオチド組み合わせで、実施例1に従って合成された。本実施例では、NOVECRITは、脂質送達ビークル、特に、リポフェクタミン3000で製剤化された。本実施例では、NOVECRITは、新規の高安定性赤血球生成刺激剤であるNOVEPOETINをコードした。
本RNAベースの遺伝子編集手法をCOL7A1遺伝子に適用した。この遺伝子は、とりわけ、ジストロフィー表皮水疱症に頻繁に関与するために興味深い。図21は、COL7A1遺伝子内に位置する配列TGAGCAGAAGTGGCTCAGTG(配列番号467)およびTGGCTGTACAGCTACACCCC(配列番号468)を標的とするRNATALENでトランスフェクトされた初代成人ヒト皮膚線維芽細胞のDNAを用いたSURVEYORアッセイを示す。+RNAレーンに存在するバンドは、ジストロフィー表皮水疱症に高頻度に関与する遺伝子の領域の編集を示す。図22は、今度はCOL7A1遺伝子内に位置する配列TTCCACTCCTGCAGGGCCCC(配列番号469)およびTCGCCCTTCAGCCCGCGTTC(配列番号470)を標的にするRNATALENでトランスフェクトされた初代成人ヒト皮膚線維芽細胞のDNAを用いた別のSURVEYORアッセイを示す。+RNAレーンに存在するバンドは、ジストロフィー表皮水疱症に高頻度に関与する遺伝子の領域の編集を示す。このデータは、とりわけ、ジストロフィー表皮水疱症などの特定の遺伝性障害の治療に対する遺伝子編集手法を示す。
実験は、非標準ヌクレオチドを含有し、遺伝子編集タンパク質をコードするインビトロ転写合成RNA分子を用いて実施した。(1)非標準ヌクレオチドとしてプソイドウリジン(psU)のみ、(2)非標準ヌクレオチドとして5-メチルシチジン(5mC)のみ、および(3)非標準ヌクレオチドとしてプソイドウリジンおよび5-メチルシチジンの両方を有するインビトロ転写合成RNA分子(ならびに対照)の免疫原性、および遺伝子編集効率を評価した。
COL7A1遺伝子中の以下の配列を標的にする遺伝子編集タンパク質をコードするRNAを、実施例1に従って合成した:TGAGCAGAAGTGGCTCAGTG(配列番号473)、およびTGGCTGTACAGCTACACCCC(配列番号468)(以下の表も参照されたい)。
野生型BMP7をコードするRNA、およびBMP7のバリアントをコードするRNAを、実施例1に従って合成した(以下の表も参照されたい)。
PTHをコードするRNAを、実施例1に従って合成した(下表も参照されたい)。
100,000個のヒト表皮ケラチノサイト(HEKn、Gibco)を、EpiLife+サプリメントS7に播種した。細胞を、実施例3に従って、PTHをコードする1μgのRNAでトランスフェクトした。トランスフェクション24時間後に、培地をサンプリングし、分泌されたPTHレベルを、製造業者の説明書に従って、ヒトPTHELISAキット(EIA-PTH-1、RayBiotech)を用いて測定した。分泌されたPTHレベルを、マイクロプレートリーダー(EMaxPlus、MolecularDevices)を用いて、450nmの吸光度を測定することにより決定した。分泌されたPTHレベルを図31に示す。
貧血を治療するためのNovecritの繰り返し投与毒性試験を実施した。具体的には、8~10週齢の雄のSpragueDawleyラットに、1日目、8日目、および15日目に1日1回、皮内、皮下、直腸、または鼻腔内経路を介してNovecritを投与した。動物をグループに割り当て、下表に示すように治療した:
ZDSDラットモデルを利用して、糖尿病性腎症を予防および治療のための、BMP7バリアントをコードするRNAの効果を試験した。具体的には、ZDSDラットを、皮内投与された、BMP7バリアントをコードするRNAで治療した。試験設計の概要を図33に提供する。動物をグループに割り当て、下表に示すように治療した:
100,000個のヒト表皮ケラチノサイト(HEK、Gibco)を、EpiLife+サプリメントS7に播種した。細胞を、実施例3に従って、BDNF、BMP-2、BMP-6、IL-2、IL-6、IL-15、IL-22、LIF、またはFGF-21をコードする2μgのRNAでトランスフェクトした。トランスフェクション24時間後に、培地をサンプリングし、分泌されたタンパク質レベルを、製造業者の説明書に従って、ヒトELISAキット(以下の表を参照)を用いて測定した。分泌されたタンパク質レベルを、マイクロプレートリーダー(EMaxPlus、MolecularDevices)を用いて、450nmの吸光度を測定することにより決定した。分泌されたタンパク質レベルを図34、パネルA~Iに示す。
100,000個のヒト表皮ケラチノサイト(HEK、Gibco)を、EpiLife+サプリメントS7に播種した。細胞を、実施例3に従って、IL-15をコードする2μgのRNA、またはIL-15をコードする1μgのRNA、およびIL-15RAをコードする1μgのRNAでトランスフェクトした。トランスフェクション24時間後に、培地をサンプリングし、分泌されたIL-15レベルを、製造業者の説明書に従って、ヒトIL-15ELISAキット(D1500、R&DSystems)を用いて測定した。分泌されたIL-15レベルを、マイクロプレートリーダー(EMaxPlus、MolecularDevices)を用いて、450nmの吸光度を測定することによって、決定した。分泌されたIL-15レベルを図35に示す。図35に示すように、IL-15とIL-15RAの共トランスフェクションは、IL-15のみによるトランスフェクションと比較して、分泌されたIL-15レベルを著しく増加させた。
試験は、種々のRNAの皮内投与に対するSpragueDawleyラットの応答を評価するために実施した。具体的には、8~10週齢の雌の約200g~約350gの重量のSpragueDawleyラットをこの試験に使用した。全部で33匹のラットを試験し、動物を試験群に割り当て、以下の表に示すように治療した:
初代ヒト表皮ケラチノサイト(HEKn-APF)を、200,000細胞/ウェルの密度で、組換えヒト1型コラーゲンでコーティングされた6ウェルプレートのケラチノサイト培地(EpiLife+サプリメントS7)に播種した。24時間後、細胞を、実施例1に従って合成したIL22をコードするRNAの2μg/ウェルでトランスフェクトし、このウェルに50mMのD-グルコースを加えた。翌日、10μLのピペットチップ用いて各ウェルにひっかき傷により線を書き込んだ。ひっかき傷作成の0時間および24時間後に撮像した。引っ掻き傷の大きさを両方の時間に測定し、治癒を、24時間のひっかき傷の、0時間のひっかき傷に対する比率を計算することにより決定した(図40)。
A1AT遺伝子中の以下の配列を標的にする遺伝子編集タンパク質をコードするRNAを、実施例1に従って合成した:L1:TAAGGCTGTGCTGACCATCG(配列番号611)、R1:TAAAAACATGGCCCCAGCAG(配列番号612)、およびR2:TCTAAAAACATGGCCCCAGC(配列番号613)。細胞の遺伝子を編集し、遺伝子編集効率を実施例38に従って測定した(図41)。さらに、細胞を、ターゲティング配列L1およびR1を標的とする遺伝子編集タンパク質、ならびに配列:cccctccaggccgtgcataaggctgtgctgaccatcgacgtcaaagggactgaagctgctggggccatgtttttagaggcc(配列番号614)を含む修復テンプレートで共トランスフェクションし、AatII酵素を用いて、実施例38に従って遺伝子修復効率を測定した(図42)。別の細胞試料を、A1AT遺伝子中の以下の配列を標的とする遺伝子編集タンパク質でトランスフェクトした:L2:TGCCTGGTCCCTGTCTCCCT(配列番号615)およびR3:TGTCTTCTGGGCAGCATCTC(配列番号616)。遺伝子編集効率を実施例38に従って測定した(図43)。
次の配列:L:TAAGGCTGTGCTGACCATCG(配列番号611)およびR:TAAAAACATGGCCCCAGCAG(配列番号612)ならびに配列:RT:cccctccaggccgtgcataaggctgtgctgaccatcgacgagaaagggactgaagctgctggggccatgtttttagaggcc(配列番号617)を含む修復テンプレートを標的とする遺伝子編集タンパク質をコードするRNAを、本発明の方法に従ってビークルと配合し、A1AT欠損症を罹患している対象に投与し、対象の肝臓細胞中のZ変異の修正、対象の肝臓細胞中の重合Zタンパク質の蓄積の減少、機能的A1ATの分泌および血清レベルの増大、ならびに1つまたは複数の対象の症状の改善がもたらされた。
FXNA(配列番号582)において、1つまたは複数の二本鎖切断を生成可能な1つまたは複数の遺伝子編集タンパク質をコードするRNA、およびFXNB(配列番号583)において、1つまたは複数の二本鎖切断を生成可能な1つまたは複数の遺伝子編集タンパク質をコードする合成RNAを、実施例1に従って合成した。RNAを本発明の方法に従って配合し、カテーテルを用いてフリードライヒ運動失調症の患者の心臓に投与した。標的配列ペアは、ペア1:TCCCACACGTGTTATTTGGC(配列番号618)およびTGGCAACCAATCCCAAAGTT(配列番号619);ペア2:TAATAAATAAAAATAAAAAA(配列番号620)およびTTGCCTATTTTTCCAGAGAT(配列番号621)から選択される。
A1AT_A(配列番号584)において、1つまたは複数の二本鎖切断を生成可能な1つまたは複数の遺伝子編集タンパク質をコードするRNAを、実施例1に従って合成した。RNAを本発明の方法に従って配合し、門脈内注入によりA1AT欠損症の患者の肝臓に投与した。
A1AT_B(配列番号585)において、1つまたは複数の二本鎖切断を生成可能な1つまたは複数の遺伝子編集タンパク質をコードするRNAを、実施例1に従って合成した。RNAおよび配列:A1AT_RT(配列番号586)を含む一本鎖単鎖DNAを本発明の方法に従って配合し、門脈内注入によりA1AT欠損症の患者の肝臓に投与した。
2つ以上の反復配列、次に:BASE_EDIT_FRONT(配列番号587)、その次に次記のいずれか:BASE_EDIT_ADA1(配列番号588)、BASE_EDIT_ADA2(配列番号589)、BASE_EDIT_ADA3(配列番号590)、BASE_EDIT_ADA4(配列番号591)、BASE_EDIT_CDA1(配列番号592)およびBASE_EDIT_CDA2(配列番号593)、を含む遺伝子編集タンパク質をコードするRNAを、実施例1に従って合成した。遺伝子編集タンパク質は、標的配列の下流にある1~50塩基内の1つまたは複数の変異を修正できる。
図49に示すように、約100,000個の初代ヒト新生児表皮ケラチノサイトを、EpiLife+サプリメントS7に播種した。細胞を、実施例3に従って、2μgのhGDF15をコードするRNAでトランスフェクトした。トランスフェクション後、種々の時点で培地をサンプリングし、ELISA(R&DDGD150)を用いて、製造業者の説明書に従って、hGDF15のレベルを分析した。図49は、トランスフェクション後、hGDF15レベルが時間依存的に上方制御されたことを示す。
hGDF15をコードするRNAの投与に対するズッカー肥満(ZDF)ラットの応答を評価する試験を実施した。ズッカー肥満ラット(ZDF)は、ヒト疾患の多くの状況を模倣するよく研究された肥満モデルである。具体的には、8~10週齢の雄のラットをこの試験に使用した。全部で15匹のZDFおよび15匹の野生型対照スプラーグドーリーラットを試験し、動物を試験グループに割り当て、以下の表に示すように治療した:
当業者は、本明細書で具体的に記載された特定の実施形態に対する多数の等価物を、ルーチン実験のみを用いて認識し、確認できるであろう。このような等価物は、次の請求項の範囲内に包含されることが意図されている。
本明細書で引用されている全ての特許および刊行物は、参照によりその全体が本明細書に組み込まれる。
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- 明細書または図面に実質的に記載された発明。
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