JP2021521838A - ブルトン型チロシンキナーゼに対するtalenベースのおよびcrispr/casベースのゲノム編集 - Google Patents
ブルトン型チロシンキナーゼに対するtalenベースのおよびcrispr/casベースのゲノム編集 Download PDFInfo
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Abstract
Description
本願は、2018年4月27日に出願された米国仮出願第62/664,035号の優先権を主張し、その全体が、参照により本明細書中に組み込まれる。
本明細書とともに電子的に提出されたテキストファイルの内容は、その全体が参照により本明細書に組み込まれる:配列表のコンピュータ読み取り可能なフォーマットの写し(ファイル名:SECH_001_01WO_ST25.txt、記録された日:2019年4月26日、ファイルサイズ75キロバイト)。
技術分野
本開示は、改善されたゲノム編集組成物に関する。より具体的には、本開示は、ブルトン型チロシンキナーゼ(BTK)遺伝子を編集するための、TALENベースのおよびCRISPR/Casベースのゲノム編集組成物および該ゲノム編集組成物を使用する方法に関する。
X連鎖無ガンマグロブリン血症は、ブルトン型チロシンキナーゼ(BTK)遺伝子中の変異によって引き起こされる稀な免疫不全である。BTK遺伝子中の600を超える異なる変異が、X連鎖無ガンマグロブリン血症と関連付けられている。これらの変異の多くは、BTKタンパク質の不存在をもたらす。他の変異は単一のタンパク質構成要素(アミノ酸)を変化させ、これは、細胞中で急速に分解される異常なBTKタンパク質の産生を引き起こし得る。BTKは、正常なB成熟および活性化のために、BCRを介したシグナル伝達のために、および骨髄系細胞中のいくつかのシグナル伝達経路のために必要とされる。機能的なBTKを欠如する被験体は、主に未成熟なB細胞、最小の抗体産生を有し、反復する生命を脅かす感染症に罹りやすい。
一般的には、本開示は、1つには、ヒトBTK遺伝子のゲノム編集を媒介するTALENベースのまたはCRISPRベースのゲノム編集システムおよびこれを使用する方法に関する。
a)T1−F RVD HD NG HD NN NI HD NG NI NG NN NI NI NI NI HD NG;
b)T1−R RVD HD NG NI NI NN NN HD HD NI NI NN NG HD HD NG;
c)T2−F RVD NI NG HD NI NI NN NN NI HD NG NG NN NN HD HD NG;
d)T2−R RVD NI HD HD NI NI HD NN NI NI NI NI NG NG NG NI HD HD NG;
e)T3−F RVD NI NG NG NG HD HD NG NI NN HD HD NG NI NG NI NI HD NG;
f)T3−R RVD NN NN HD NG NG HD NG NG NI NN NN NI HD HD NG NG NG;
g)T4−F RVD HD HD NI NG NG NG NN NI NI NI HD NG NI NN NN NG;および
h)T4−R RVD HD HD NG HD NI NG HD HD HD NG HD NG NG NN NN NG NG;
を含む群から選択されるRVDを有するTALエフェクタードメインを含み、TALエフェクタードメインは標的部位T1、T2、T3またはT4を結合することができる。
配列番号1〜8は、ヒトBTK遺伝子の第一および第二のイントロン中のTALEN標的部位である。
A.概要
一般的には、本開示は、1つには、改善されたゲノム編集組成物およびその使用の方法に関する。いずれかの特定の理論に拘泥することを望むものではないが、本明細書中で想定されるゲノム編集組成物は、X連鎖無ガンマグロブリン血症(XLA)と関連する症候を処置、予防または軽減するために、細胞中のブルトン型チロシンキナーゼ(BTK)の量を増加させるために使用される。従って、本明細書において想定される組成物は、XLAを有する被験体に、根治的となり得る解決手段を与える。いずれかの特定の理論に拘泥することを望むものではないが、XLAをもたらす1またはそれを超える変異および/または欠失を有するBTK遺伝子中に機能的なBTKタンパク質をコードするポリヌクレオチドを導入するゲノム編集アプローチがXLAによって引き起こされる免疫的および機能的欠損を救出し、根治的となり得る治療を与えると想定される。
B.定義
C.TALENベースの系
表1:標的部位
D.CRISPR/Casベースの系
Casタンパク質
a)ニッカーゼ活性、すなわち、核酸分子の一本鎖、例えば、非相補鎖または相補鎖を切断する能力;
b)一実施形態において、2つのニッカーゼ活性の存在である二本鎖ヌクレアーゼ活性、すなわち、二本鎖核酸の両方の鎖を切断し、二本鎖切断を作出する能力;
c)エンドヌクレアーゼ活性;
d)エキソヌクレアーゼ活性;および/または
e)ヘリカーゼ活性、すなわち、二本鎖核酸のらせん構造を巻き戻す能力。
Cas変異体
gRNA
a)非連結ホスフェート酸素および/またはホスホジエステル骨格結合中の連結ホスフェート酸素の1もしくはそれより多くの一方または両方の改変、例えば、置換;
b)リボース糖の、例えば、リボース糖上の2’ヒドロキシルの構成要素の改変、例えば、置換;
c)「デホスホ」リンカーによるホスフェート部分の大規模な置換;
d)天然に存在する核酸塩基の修飾または置換
e)リボース−ホスフェート骨格の置換または修飾;
f)オリゴヌクレオチドの3’末端または5’末端の修飾、例えば、末端ホスフェート基の除去、修飾もしくは置換または部分の抱合;および
g)糖の修飾。
末端プロセシング酵素
E.標的部位
F.ドナー修復テンプレート
G.ポリペプチド
表1−アミノ酸コドン
I.ゲノム編集された細胞
J.組成物および製剤
K.ゲノム編集された細胞治療
それぞれの個別の刊行物、特許出願または発行済み特許が参照によって組み込まれることが具体的にかつ個別的に示されているごとく、参照によって本明細書に組み込まれる。
ヒトBTK遺伝子のイントロン2中の標的部位におけるTALENベースのゲノム編集
ヒトBTK遺伝子のイントロン2中の標的部位におけるCRISPR/Casゲノム編集
Cas9タンパク質と単一のガイドRNAのリボ核タンパク質複合体(RNP)およびAAVドナーの同時送達による初代T細胞中でのCRISPR/Casゲノム編集
CRISPR/CasまたはTALENベースの系によるCD34+T細胞中でのゲノム編集
AAV標的化ベクター配列
#DT(#1177)(配列番号19)
DT−Del(#1233)(配列番号20)
DT−PAM 1254(配列番号21)
DT−PAM mut(#1251)(配列番号22)
ATG−DT−Del(#1375)(配列番号23)
ATG−BTK DT−DEL(#1379)(配列番号24)
CRISPR/CasまたはTALENベースを有するCD34+T細胞中のHDR:NHEJ比
要約
結果
表6
Claims (43)
- ヒトブルトン型チロシンキナーゼ(BTK)遺伝子中の標的部位を切断するTALENを含むゲノム編集組成物。
- TALENが、
i)T1−F RVD HD NG HD NN NI HD NG NI NG NN NI NI NI NI HD NG;
j)T1−R RVD HD NG NI NI NN NN HD HD NI NI NN NG HD HD NG;
k)T2−F RVD NI NG HD NI NI NN NN NI HD NG NG NN NN HD HD NG;
l)T2−R RVD NI HD HD NI NI HD NN NI NI NI NI NG NG NG NI HD HD NG;
m)T3−F RVD NI NG NG NG HD HD NG NI NN HD HD NG NI NG NI NI HD NG;
n)T3−R RVD NN NN HD NG NG HD NG NG NI NN NN NI HD HD NG NG NG;
o)T4−F RVD HD HD NI NG NG NG NN NI NI NI HD NG NI NN NN NG;および
p)T4−R RVD HD HD NG HD NI NG HD HD HD NG HD NG NG NN NN NG NG;
を含む群から選択されるRVDを有するTALエフェクタードメインを含み、
前記TALエフェクタードメインが、標的部位T1、T2、T3またはT4を結合することができる、
請求項1に記載のゲノム編集組成物。 - ゲノム編集組成物であって、
a)Casタンパク質またはCasタンパク質をコードするポリヌクレオチド;
b)ガイドRNA(gRNA);および
c)機能的BTK遺伝子またはその断片を含む修復テンプレート;
を含み、
ゲノム編集システムが、B細胞中の内在性BTK遺伝子を修復することができるか、またはB細胞のゲノム中への機能的BTK遺伝子を挿入することができる、ゲノム編集組成物。 - gRNAが配列番号9〜17に記載されているヌクレオチド配列を含む、請求項3に記載のゲノム編集組成物。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物をコードするポリヌクレオチド。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物をコードするmRNA。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物をコードするcDNA。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物をコードするポリヌクレオチドを含むベクター。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物を含む細胞。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物をコードするポリヌクレオチドを含む細胞。
- 請求項8に記載のベクターを含む細胞。
- 請求項1〜4のいずれか一項に記載のゲノム編集組成物によって導入された1またはそれを超えるゲノム修飾を含む細胞。
- 前記細胞が造血細胞である、請求項9〜12のいずれか一項に記載の細胞。
- 前記細胞が造血幹または前駆細胞である、請求項9〜13のいずれか一項に記載の細胞。
- 前記細胞がCD34+細胞である、請求項9〜14のいずれか一項に記載の細胞。
- 前記細胞がCD133+細胞である、請求項9〜15のいずれか一項に記載の細胞。
- 請求項9〜16のいずれか一項に記載の細胞を含む組成物。
- 請求項9〜16のいずれか一項に記載の細胞と生理的に許容され得る担体とを含む組成物。
- 細胞中のBTK遺伝子を編集する方法であって、請求項1〜4のいずれか一項に記載のゲノム編集組成物、請求項5に記載のポリヌクレオチドまたは請求項8に記載のベクターと、ドナー修復テンプレートとを前記細胞中に導入することを含み、前記ゲノム編集組成物の発現がBTK遺伝子中の標的部位に二本鎖切断を作製し、前記ドナー修復テンプレートが、前記二本鎖切断(DSB)の前記部位において、相同組換え修復(HDR)によって前記BTK遺伝子中に取り込まれる、方法。
- 前記BTK遺伝子が、X連鎖無ガンマグロブリン血症(XLA)をもたらす1またはそれを超えるアミノ酸変異または欠失を含む、請求項19に記載の方法。
- 前記細胞が造血細胞である、請求項19または請求項20に記載の方法。
- 前記細胞が造血幹または前駆細胞である、請求項19〜21のいずれか一項に記載の方法。
- 前記細胞がCD34+細胞である、請求項19〜22のいずれか一項に記載の方法。
- 前記細胞がCD133+細胞である、請求項19〜23のいずれか一項に記載の方法。
- ポリペプチドをコードするポリヌクレオチドがmRNAである、請求項19〜24のいずれか一項に記載の方法。
- 5’−3’エキソヌクレアーゼをコードするポリヌクレオチドが前記細胞中に導入される、請求項19〜25のいずれか一項に記載の方法。
- Trex2または生物学的に活性なその断片をコードするポリヌクレオチドが前記細胞中に導入される、請求項19〜26のいずれか一項に記載の方法。
- 前記ドナー修復テンプレートが、DSBの5’のBTK遺伝子配列に相同な5’相同性アームと、ドナーポリヌクレオチドと、DSBの3’のBTK遺伝子配列に相同な3’相同性アームとを含む、請求項19〜27のいずれか一項に記載の方法。
- 前記ドナーポリヌクレオチドが、BTK遺伝子中の1またはそれを超えるアミノ酸変異または欠失を修復するように設計されている、請求項28に記載の方法。
- 前記ドナーポリヌクレオチドが、BTKポリペプチドをコードするcDNAを含む、請求項28に記載の方法。
- 前記ドナーポリヌクレオチドが、BTKポリペプチドをコードするcDNAに動作可能に連結されたプロモーターを含む発現カセットを含む、請求項28に記載の方法。
- 前記5’および3’相同性アームの長さが、約100bp〜約2500bpから独立に選択される、請求項28〜31のいずれか一項に記載の方法。
- 前記5’および3’相同性アームの長さが、約600bp〜約1500bpから独立に選択される、請求項28〜31のいずれか一項に記載の方法。
- 前記5’相同性アームが約1500bpであり、3’相同性アームが約1000bpである、請求項28〜33のいずれか一項に記載の方法。
- 前記5’相同性アームが約600bpであり、3’相同性アームが約600bpである、請求項28〜34のいずれか一項に記載の方法。
- 前記ドナー修復テンプレートを細胞中に導入するためにウイルスベクターが使用される、請求項28〜35のいずれか一項に記載の方法。
- 前記ウイルスベクターが組換えアデノ随伴ウイルスベクター(rAAV)またはレトロウイルスである、請求項36に記載の方法。
- 前記rAAVがAAV2由来の1またはそれを超えるITRを有する、請求項37に記載の方法。
- 前記rAAVが、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9およびAAV10からなる群から選択される血清型を有する、請求項37または請求項38に記載の方法。
- 前記rAAVがAAV2またはAAV6血清型を有する、請求項37〜39のいずれか一項に記載の方法。
- 前記レトロウイルスがレンチウイルスである、請求項36に記載の方法。
- 前記レンチウイルスがインテグラーゼ欠損レンチウイルス(IDLV)である、請求項41に記載の方法。
- X連鎖無ガンマグロブリン血症(XLA)の少なくとも1つの症候またはXLAと関連する症状を処置、予防、または軽減する方法であって、被験体から細胞の集団を採集すること、請求項19〜42のいずれか一項に記載の方法に従って前記細胞の集団を編集すること、および編集された細胞の集団を前記被験体に投与すること、を含む方法。
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