JP2022188202A - 細胞並びにその使用方法及び製造方法 - Google Patents
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Abstract
Description
本出願は、その全体が参照により本明細書に組み込まれる2017年3月20日出願の米国仮出願第62/473,564号の優先権を主張する。
適用なし
本開示の一部である配列表は、本発明のヌクレオチド及び/又はアミノ酸配列を含むコンピュータ読み取り可能な形態を含む。配列表の主題は、その全体が参照により本明細書に組み込まれる。
本開示は、概して、細胞療法に関する。
壊滅的な感染症に対するワクチンは、人類の最大の医学的ブレークスルーのいくつかを象徴する。ワクチンの基本原理は、生の感染が誘発し得る全身ダメージを与えることなく、天然の病原体を模倣する弱毒化又は不活性化したベクターを用いる免疫の確立である。そのため、これまでに成功した全ワクチンの前提条件は、ヒト免疫系が、天然の生の感染に直面したとき、最終的に適応免疫をもたらすことが本質的に可能でなければならないということである。ポリオのような場合では、適応免疫が天然ウイルスを制御できる前にもたらされるダメージは受け入れられない。それにもかかわらず、持続的な免疫が最終的に達成され、その後の感染を防ぐ。
本開示は、(1)移植可能な抗体又は酵素を分泌する形質細胞へのヒト多能性幹細胞の分化、並びに(2)NKG2Dのリガンドをコードする遺伝子における変異(例えば、CRISPR/Cas9を用いる)(ナチュラルキラー細胞の認識を回避し、移植のための実質的に非免疫原性又は最小限の免疫原性のヒト多能性幹細胞をもたらす)及び補体沈着を防ぐ遺伝子の発現、がヒト多能性幹細胞から免疫原性の主要な決定因子を排除できるという発見に少なくとも部分的に基づく。まとめると、これらは、自己免疫疾患、神経変性疾患、癌、及び感染症に対する拡張可能な既製の療法、並びに免疫拒絶反応を回避するように変更された細胞を用いるES細胞ベースの治療の一般的な適用を可能にする。
最小限の免疫原性の「ユニバーサルな」ドナーhES細胞株の作製は、再生医療の多くの分野の目標であった。数十年の移植の研究は、生着に対する免疫学的障壁が相当あることを明らかにし、本当に「ユニバーサルな」株を達成するための最善の方法は完全には明らかにされなかった。
本開示は、既製の療法の拡張可能な供給源の生成を提供し、その適用は、免疫療法、膵臓β細胞の交換、又は多発性硬化症のためのオリゴデンドロサイトの回復に及ぶ。
ヒト組織を再生するために使用できる、安価で簡単に操作できる幹細胞が必要である。本明細書には、最小限に免疫原性であり「ユニバーサルな」ドナーとみなされる幹細胞株(例えば、遺伝子操作された)が記載される。これらの細胞は、再生医療のための既製の治療の供給源として、宿主免疫抑制なしに使用できる。
多能性幹細胞を用いる抗体媒介性免疫の作製が、本明細書に記載される。このトピックについての先行論文は存在せず、又は多能性幹細胞を用いて抗体媒介性免疫を追求する他の場所での他の進行中の研究プロジェクトはないと考えられている。
本明細書に記載されるように、形質細胞は、感染症のための予防として使用できる。例えば、hES細胞の内因性遺伝子座にノックインされたインフルエンザ抗体遺伝子が記載された(例えば、実施例1、図3参照)。これらの抗体は、インフルエンザウイルスの保存された部分に結合し、ほぼ全てのflu株を中和する(例えば、実施例1参照)。別の例として、形質細胞は、HIVなどの進行中の慢性感染症の治療に使用できる(例えば、実施例1参照)。別の例として、形質細胞は、ハーラー症候群などの酵素欠損症(例えば、実施例1参照)又は第IX因子欠損症に関連する疾患のための酵素補充療法に使用できる。別の例として、形質細胞は、癌の治療に使用できる(例えば、実施例1参照)。別の例として、形質細胞は、自己免疫疾患の治療に使用できる(例えば、実施例1参照)。別の例として、形質細胞は、アルツハイマー病の治療に使用できる(例えば、実施例1参照)。別の例として、抗体を発現する形質細胞は、(例えば、免疫療法剤での)抗体療法を必要とする対象の治療に使用できる。例えば、免疫療法剤は、抗体であり得る。一例として、免疫療法剤は、リツキサン、エクリジマブ、又はアデュカヌマブであり得る。
本明細書に記載されるように、遺伝子操作された多能性幹細胞株を、細胞が免疫系のいくつかの治療群による認識を回避するように改変した。そのような遺伝子における変更は典型的には、遺伝子及び標的のグループにて予め形成され、そのうちのいくつかは先行技術に記載されている。従来技術の改変に加えられる、本発明の重要な新規特徴は、当業者には容易に明らかであろう。
本開示は、β2ミクログロブリン及びTAP1コード遺伝子における遺伝子改変を提供する。これは、HLA-I発現を排除し、同種CD8+T細胞による直接認識を防ぐ。本明細書に記載するように、遺伝子改変は不活性化変異であり得る。
本開示はさらに、ナチュラルキラー(NK)細胞認識を回避するように、NKG2Dのリガンドをコードする遺伝子中に生成される変異を提供する。NK細胞は、多くの異なる認識様式を有し、NKG2Dは全てのNK細胞上で発現することが知られている唯一の活性化受容体である。NKG2Dリガンドの消失はこのように、従来技術で説明される他の代替戦略とは対照的に、全てのNK細胞による反応性を消失させる。
本開示はさらに、ヒトES細胞中のAAVS遺伝子座に送達される構築物の設計及び検証を提供する。これらの構築物は、補体固定(例えば、CD46/Crry、CD55、及びCD59)の回避をもたらす遺伝子をコードする。細胞上での古典的及び代替的補体沈着を防止するためのCD46/Crry、CD55、及びCD59発現の使用が、本明細書に記載される(例えば、実施例2参照)。古典的及び代替的補体沈着の防止は、抗体依存的免疫拒絶の防止に重要であると考えられている。
以下の定義及び方法は、本発明をより良く定義するため及び、本発明の実施において当業者を導くために提供される。特に断りのない限り、用語は、従来の用法に従って、関連技術分野の当業者によって理解されるべきである。
本明細書に記載の薬剤及び組成物は、例えば、レミントンの薬学(A.R.Gennaro,編)、第21版、参照によりその全体が本明細書に組み込まれるISBN:0781746736(2005)に記載の1以上の薬学的に許容される担体又は賦形剤を使用して、任意の従来の方法により製剤化できる。そのような製剤は、対象への適切な投与のための形態を提供するように適切な量の担体と共に、精製形態であり得る、治療有効量の本明細書に記載の生物学的活性剤を含有する。
また提供されるのは、ナチュラルキラー細胞の認識を回避しながら多能性幹細胞で疾患(例えば、病原体、感染症)を治療するために、それを必要とする対象における疾患(例えば、自己免疫疾患、自己免疫疾患によって破壊された組織、病原体、癌、酵素欠損症、又は神経変性疾患)を細胞ベースの療法(例えば、遺伝子操作幹細胞の分化した子孫)及び治療有効量の細胞ベースの治療剤の投与で治療するプロセスである。
本明細書に記載の薬剤及び組成物は、当技術分野で公知の様々な手段で本明細書に記載の方法に従って投与できる。薬剤及び組成物は、外因性の物質又は内因性物質のいずれかとして治療的に使用できる。外因性の薬剤は、体外で生成又は製造され、身体に投与されるものである。内因性剤は、体内の他の臓器の内部への又は他の臓器への送達用のいくつかの種類の(生物学的又は他の)装置によって体内で生成又は製造されるものである。
また、提供されるのは、キットである。そのようなキットは、本明細書に記載の薬剤又は組成物、特定の実施形態において、投与のための説明書を含んでよい。そのようなキットは、本明細書に記載の方法の実行を容易にすることができる。キットとして供給される場合、組成物又は組成物を作製するための異なる成分は、別々の容器に包装され、使用直前に混合できる。成分は、前駆細胞、ユニバーサル多能性幹細胞の子孫、及びIL-4、IFNγ、BMP4、bFGF、VEGF、IL-6、IGF1、IL-11、SCF、又はEPOなどのインビトロで治療用細胞を作製するのに使用される試薬を含むが、これらに限定されない。成分のそのような別々の包装は、所望であれば、組成物を含有する1以上の単位剤形を含有し得るパック又はディスペンサー装置で提供できる。パックは、例えば、金属又はブリスターパックなどのプラスチックホイルを含み得る。成分のそのような別々の包装はまた、特定の場合において、成分の活性を失うことなく長期保存を可能にし得る。
以下の非限定的な例は、本開示をさらに例示するために提供される。以下の実施例に開示される技術は、本発明者らが本開示の実施において十分に機能することを見出した手法を表し、ひいては、その実施のための形態の例を構成すると考えることができることは、当業者によって理解されるべきである。しかしながら、当業者は、本開示に照らして、開示される特定の実施形態において多くの変更が行われ、さらに、本開示の趣旨及び範囲から逸脱することなく同様又は類似の結果を得ることができることを理解すべきである。
以下の実施例は、広範な中和抗体を生成する移植可能な形質細胞へのヒトES細胞の分化を説明する。
最も臨床的に使用されるワクチンは、中和抗体の生成及び維持に依存する。その結果、ワクチン接種後の保護の主要な相関は、免疫化によって誘発される形質細胞由来の抗体の量、親和性、エピトープ特異性、及び持続時間である。形質細胞は、毎秒数千個の抗体分子を分泌しそのトランスクリプトームのほぼ70%を抗体合成に費やす最終的に分化したBリンパ球である。T細胞依存性抗体応答の最初の数日の間、形質細胞は数日間のみ生存しその後アポトーシスを受ける。徐々により高い親和性の抗体を発現する他の形質細胞は、その後、胚中心反応から作製される。これらの親和性成熟形質細胞は、最高で数十年存続し、主に骨髄に存在し得る。これらの長命形質細胞は、抗原の存在に関わらず、かつ細胞分裂せずに抗体を構成的に分泌し、体液性免疫の主要な決定因子である。それらの多産の抗体分泌速度のために、わずか約3つの抗原特異的長命形質細胞由来の抗体に対応する免疫血清のたった1μlが、特に致死的な西ナイルウイルス感染からナイーブマウスを保護するのに十分であることが示された。本明細書に記載のデータは、これらの細胞が中和抗体を発現する場合の、それらの保護効力を実証する。
抗原特異的な移植可能長命形質細胞の拡張可能な供給源を開発するために、H1ヒト胚性幹細胞を利用した。これらは、最もよく特徴付けられたヒトES細胞であり、最小の系統バイアスを有し、かつ容易に造血細胞を作製する。造血は、少なくとも2つの別々の波:一次及び二次で生じる。一次造血は、赤血球及び骨髄系統の制限されたセットを作製する。これとは対照的に、二次造血は最終的に、リンパ球を含む成人型の血液細胞を生じさせる。そのため、hES細胞の機能の主要な治療目標は、二次造血前駆体を作製することであった。H1 hES細胞を使用する、二次造血細胞前駆体である二次造血内皮を再生可能に作製する方法は、Sturgeonら,Nat Biotech,2014に記載されるように最適化された。方法は、プロセスの2日目に標準Wntシグナル伝達活性化の重要な工程を含む、胚葉誘導中のシグナルの連続操作を用いる(例えば、図1A参照)。これは最終的に、本来はこの可能性を欠く多能性株によってでさえ、T細胞の作製を可能にする(例えば、図1B参照)。重要なことに、これらの分化は定義された無血清条件下で行われ、それにより再現性を最大限にし容易なトラブル解決作業を可能にする。
二次造血前駆体を作製して、これらの前駆体をB細胞に分化させる方法を調査した。ヒトES細胞からの堅牢なB細胞分化を報告した研究は現在までほとんどなく、これらの手法は、成熟B細胞を作製できなかったか、又は1種の特定のiPS株でのみ実行できたかのいずれかであった。これらの手法のいずれも、定義された条件を使用しておらず、現在試験されるhES細胞株のいずれかにこれらの手法を適応することは成功していない。したがって、造血内皮の組み合わせを作製し(例えば、図1参照)、その後に、B系統促進転写因子PAX5の発現を行った。二次造血内皮細胞を、構成的に発現されるrTTA-T2A-GFP、すなわちリボソームスキッピング2A配列によりレポーターに連結されたドキシサイクリン誘導性転写活性化因子、及びドキシサイクリン誘導性プロモーターにより促進されるPAX5をコードするレンチウイルスベクターで形質導入した(例えば、図2A参照)。形質導入細胞はしたがって、rTTA及びGFPを構成的に発現するが、PAX5をドキシサイクリン処理時にのみ発現する。20日間のFlt3L、SCF、IL7、及びMS5間質細胞との共培養後に、B細胞がドキシサイクリン処理時にのみ観察された(例えば、図2B参照)。そのため、定義された転写因子発現は、さもなければ扱いにくい前駆細胞によるBリンパ球生成を促進できる。
hES細胞からB細胞を作製する以前の試みは、表面抗原受容体発現のない未熟リンパ球をもたらした。この問題に対処するために、及び発達するB細胞に病原体特異性を提供するために、広範な中和インフルエンザ特異的抗体であるFI6からのVDJ及びVJ配列を含有する標的化カセット、並びにゼオシン及びハイグロマイシン耐性カセットをそれぞれ作製した(例えば、図3A参照)。これらの標的化カセットを、Cas9及び内因性免疫グロブリン重鎖及びκ軽鎖遺伝子座を標的化するためのガイドRNA(gRNA)と共に、H1 hES細胞にヌクレオフェクトした(ZFN又はTALENも使用できる)。細胞を、ゼオシン及びブラストサイジン耐性について選択し、適切な標的化を確認するためにPCR分析を行った(例えば、図3B参照)。これらの細胞を次いで、Creリコンビナーゼをコードする構築物でトランスフェクトし、薬剤耐性カセットを欠くサブクローンを単離した(例えば、FI6遺伝子でのIgH及びIgκ標的化並びに薬剤耐性カセットの除去のPCR確認を示す図3C参照)。
インビボで、B細胞からの短命ではなく長命の形質細胞の形成を促進する手がかりが最近特定された。長命形質細胞は、それらの短命対応物よりもはるかに多くのブドウ糖を運び込むことが示された。この増強されたグルコース取り込みは、抗体分泌及び呼吸のためのミトコンドリアのピルビン酸の上昇を促進し、長期的な形質細胞永続性に必要とされる。現在、グルコースの取り込みの増強は、長命形質細胞と短命形質細胞の有望な分離を可能にする唯一の既知の特性であると考えられている。外因性因子のインビトロでのスクリーニングを通して、IFNγ及びIL-4がグルコース取り込みを促進することが発見された(例えば、図4参照)。
上記の研究に加えて、いくつかのプロトコルが、インビトロでのヒト形質細胞の長期生存を可能にする方法を報告している。しかしヒト形質細胞用の異種移植モデルの欠如が、インビボでの生存の分析を妨げている。この問題に対処するために、ヒト骨髄からの付着性線維芽細胞/間葉系幹細胞を免疫不全NOD-SCID IL2rγ-/-(NSG)マウスに皮下移植するシステムが開発された。骨に似た小骨が移植後約8週間目に形成され、完全なヒト微小環境を提供する。これらの小骨は、正常ヒト造血及び初代骨髄性悪性腫瘍を堅牢に支持し、そのうちのいくつかは、以前に異種移植片中で増殖したことがなかった。これらの小骨も正常な血漿細胞の生存を支持するか否かを試験するために、1~5×106個の初代ヒト骨骨髄CD138+形質細胞を小骨に直接注入した。血清ヒトIgGが移植後2及び4週目に観察され、これらの時点間で抗体濃度は低下しなかった(例えば、図5A参照)。4週目に、形質細胞のフローサイトメトリー分析(例えば、図5B参照)及びELISPOT分析(データ示さず)のために小骨を採取した。抗体分泌細胞が、全ての注入小骨で観察された。これらのデータは、ヒトの小骨が、正常な長命形質細胞の生存及び機能を支持することを実証する。これは、その種のそのような最初のシステムであると考えられる。
定義された転写因子発現を用いて、図2~図3でのようにFI6ノックインhES細胞からのB細胞発達を促進する。ゲノム統合レンチウイルスの使用は、解決の難しい翻訳戦略を提供し得る。因子が分化及び系統の関与に必要とされる時にのみ、それらを一過的に導入するために、改変RNAなどのそのような非組み込み手法を使用できる。これを支持して、PAX5発現は、EBF1と共に正のフィードバックループを媒介してB系統の関与を維持する。そのため、外因性PAX5の一過的発現は、内因性PAX5発現の安定維持を誘発し得る。その間に外因性PAX5発現がB細胞関与を促進するウィンドウを定義するために、ドキシサイクリンを、MS5細胞との共培養のD1~7、D8~14、又はD15~21にのみ投与する。同様の実験を、EBF1をコードするレンチウイルスを用いて実行する。CD19+B細胞をフローサイトメトリーにより特定し、インフルエンザ特異的IgMの発現を、ヘマグルチニンテトラマー試薬を用いて、又は当技術分野で公知の方法及び試薬を用いて確認する。
上記のような成熟B細胞の作製に加えて、初代扁桃ナイーブB細胞を用いて、本発明の方法を用いる長命形質細胞への分化を最適化する。CD20+CD27-B細胞を、ヒトCD40L及びBAFFを発現するNIH 3T3細胞上で選別する。IL-4又はIFNγのいずれかを、1~100ng/mlの濃度で培養物に添加する。6日目に、CD38高CD27高形質芽球/形質細胞を、図5でのようにNSGマウスにおいて静脈内注射するか、又は小骨に直接注射する。血清ヒトIgGを隔週で試料採取する。血清抗体を8~16週にわたって維持する場合、動物を屠殺し、図5でのようにフローサイトメトリー分析及びELISPOT分析のために小骨を収集する。
hES細胞を、長命形質細胞に分化させ、動物モデルにおいてこの方法を検証するために、ヒトの小骨を保有するNOD-SCID-IL2rg(NSG)マウスに移植する。これらの小骨は、ヒト骨髄からの間葉系細胞をマウスに移植した後に形成される(上記のように)。1週間以上(flu特異的抗体濃度の上昇を可能にするのに十分な時間)の後、これらのマウスを、NSGマウスにとって通常は致死であるfluの用量で感染させる。マウスの生存及びインフルエンザウイルスの負荷を次いで測定する。
小骨を形成するために、若いNSGマウスを、臍帯血CD34+細胞(静脈内)及び間葉細胞(上記の)で同時に再構成する。T細胞再構成後、マウスに、ヒトCD4+T細胞を攻撃するためにHIVを次いで感染させ、その後広範な中和HIV特異的形質細胞を移植する。継続的な感染がどの程度抑制されるかを調べるために、HIV力価及び抗体を測定する。Halper-Strombergら 2014 Cell 158(5)989-999に記載されているように、マウスモデルを利用できる。ユニバーサル細胞が発達したら、これをヒト以外の霊長類及びSIVで試験する。
α-L-イズロニダーゼを欠くハーラー症候群のマウスモデル(Clarkら 1997 Science 6(4)503-11)を使用する。全身酵素補充は、ハーラー症候群のための治療である。マウスモデルをNSGに交配して、形成された小骨(上記のように)、及び抗体の代わりにα-L-イズロニダーゼを分泌するように操作された形質細胞(遺伝子置換又はΑβ遺伝子の下流のIRESノックインを通して)を移植する。酵素濃度及び脳の神経病理(例えば、リソソーム膨張(distension))を測定する。
NSG/小骨マウス(上記の)に、原発性非ホジキンリンパ腫を移植し、次いでリツキサンを発現する形質細胞を投与する(Chaoら 2010 Cell 142(5)699-713)。腫瘍の負荷を、組織学的に及びフローサイトメトリーによって定量化する。自殺遺伝子が内蔵される場合は、残存疾患がなくなったときにいつでも、形質細胞を除去できる。
NSG/小骨マウスに、ソリリス/エクリジマブを発現する形質細胞を移植する。これらのマウスを、抗Gq1b抗体で処置し、運動機能及び麻痺を測定する。自己免疫疾患のこのマウスモデルはHalsteadら 2008 131(Pt5)1197-208)に記載されている。
本開示の細胞及び方法は、治療用抗体を必要とする対象の治療で使用できる。例として、治療用抗体は、本明細書に記載するように、改変ES細胞上で過剰発現させることができる。例えば、アルツハイマー病の治療は、Αβプラークの蓄積を避けるためにアデュカヌマブなどの治療用抗体を発現するように本発明の改変ES細胞を操作することによって達成できる。
本明細書に記載のこれらの研究は、改変及び分化のためのオス由来の株のH1(WA01、NIH登録番号0043)細胞を使用する。しかしながら、全てのマウス実験は、オスとメスの両方を利用し、実験に変数として含まれる。さらに、ドナー異種移植片は、オスとメスの両方に由来する。Y染色体PCRを行って匿名のドナーの性別を決定し、再度、これらのデータを分析に変数として含める。
以下の実施例で、免疫原性を低下させるためのヒトES細胞の遺伝子改変を説明する。
堅牢なワークフローを最適化して、ヒトES細胞における標的変異を作製した。Cas9発現構築物及び最大3つの異なるgRNAコードベクターを、H1ヒトES細胞に同時トランスフェクトした。個々のコロニーを手で採取し、標的遺伝子のMiseq分析に供し、非相同末端結合エラーによって導入されたフレームシフト変異を有するクローンを特定した。候補クローンを次いで蛍光活性化細胞選別(FACS)により正確に1細胞/ウェルで播種し、Miseq分析を再び行って変異及びモザイク現象の欠如を確認した(例えば、図6A参照)。次に、クローンを増殖させ、核型を決定し、造血系統に向かうそれらの分化能を確認した。CRISPR/Cas9ベースの標的化変異により、HLA発現を欠く、核型が正常なヒトhES細胞株を作製した。β2mとTAP1の両方の対立遺伝子及びCD74の1つの対立遺伝子に不活性化変異を有する1つのクローンを、標的領域のMiseq分析によって特定した(例えば、図6B参照)。このクローンでは、インターフェロンγ(IFNγ)誘導性HLA-I発現が完全になくなり(例えば、図6C参照)、正常な核型が確認された。このHLA-I欠損株由来の単球は、同種の初代CD8+T細胞増殖を刺激できなかった(例えば、HLA欠損hES細胞子孫はT細胞を刺激しないことを示す図6D参照)。このHLA-I欠損株をその後、CD74の残りの対立遺伝子及びHLA-IIの発現に必要な転写因子であるCIITAの両方の対立遺伝子を除去するために、CRISPRを用いて再標的化した。このクローンもまた、正常な核型を保有することが確認された。その後の分析により、各遺伝子改変後に、細胞が造血能を保持していること、かつ派生単球がHLA-IIの検出可能な発現を欠いていたことが確認された(例えば、HLA-IIはCIITA/CD74欠損細胞により発現されないことを示す図6E参照)。
HLA-I発現の消失は、細胞をNK細胞溶解に感受性にさせると考えられている。活性化受容体NKG2Dのリガンドを消失させた(下記参照)。しかしながら、NKG2D遮断は、NK細胞媒介特異的溶解の約50%のみを除去する。そのため、さらにNK細胞反応性を除去するために、例えば、単鎖三量体を形成するためにペプチド及びβ2mに共有結合されたHLA-E及びHLA-Gの発現を介する、追加の工程を行う。これらの三量体は、内因性HLAとペプチド又はβ2mを交換せず、NKG2A及びILT2発現NK細胞を阻害する。抗体結合、補体沈着及びマクロファージ食作用を含む免疫応答の他の態様も、拒絶反応に寄与し得る。これらの免疫機構のそれぞれに対処しそれらを回避するために、ヒトAAVS遺伝子座を標的化するマルチシストロンベクターのセットを構築した(例えば、図7A、表1参照)。この遺伝子座は、サイレンシングから保護される「セーフハーバー」と考えられている。フローサイトメトリー分析により、HLA欠損hES細胞中の発現が確認された(例えば、図7B参照)。免疫回避及び自殺遺伝子及び標的の概要は、表1で見られ得る。
HLA-Iが存在しないと、標的細胞をNK細胞媒介性細胞溶解に対して感受性にさせることができるので、NKG2Dリガンドを、CRISPR/Cas9を通じて標的化する。これらのうち、RNA配列分析により、MICA及びMICBのみが長命形質細胞で発現されることが実証される。約400個のヌクレオフェクトクローンの予備的な配列決定は、MICAとMICBの間にインフレーム融合を作る、MICA及びMICBの2つの対立遺伝子中のフレームシフト変異及び他の染色体における大きな欠失を保有する1つの株を明らかにした。(図11A)。MICA及びMICBの全4つの対立遺伝子中にフレームシフト変異を有するクローンを作製するために、このMICA/B融合物をCRISPR/Cas9で再標的化した(図11B)。このクローンを、正常な核型について検証した。HLA、MICA/B欠損hES細胞を、以後、HM-KO hESと呼ぶ。
HM-KO hES細胞から始めて、2つのセットのヌクレオフェクションを行った。1つのヌクレオフェクションは、図7Aに示されるヒト免疫回避カセットを用いて行い、別々のヌクレオフェクションは、マウス免疫回避カセットを用いて行った(mAAVS)。これらの構築物を、Cas9発現構築物及びAAVS遺伝子座を標的化するgRNAで同時トランスフェクトした。細胞を、ネオマイシン及びピューロマイシン耐性について選択し、遺伝子の発現をフローサイトメトリーによって確認した(例えば、図7B参照)。
インビボでのヒト免疫回避を試験するために、ヒト化NSG W41マウスを作製した。約2×105個の臍帯血CD34+細胞(セントルイス臍帯血バンクから取得した)を無条件NSG-W41マウスに移植した(例えば、図9A参照)。マウスから採血してヒトの再構成を確認し、改変hESCの各バージョンの100万個の細胞をマトリゲルに包埋し、ヒト化NSG-W41のマウスに皮下移植した。奇形腫の成長を12週間又は腫瘍が20mmの塊に達するまで監視し、その時点でマウスを安楽死させた。HLA欠損細胞を接種したヒト化マウスは奇形腫を形成したが、未改変hES細胞は形成しなかった(例えば、HLA-KO hES細胞はヒト化マウスによる拒絶反応を回避することを示す図9B参照)。ある実験において、マウスをAP1903で処置してiCasp9を活性化し奇形腫の退縮を開始させる。免疫応答のいくつかの態様は、ヒト化NSG-W41マウスでは機能しない。例えば、NK細胞は、このシステムではほとんど形成せず、抗体応答は最小である。したがって、mAAVS構築物を安定に発現するHM-KO細胞を用いて、C57BI6マウスにおける奇形腫アッセイを行う。拒絶反応は、この異種設定で遅延されると予想される。
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