JPWO2020081843A5 - - Google Patents
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- JPWO2020081843A5 JPWO2020081843A5 JP2021521116A JP2021521116A JPWO2020081843A5 JP WO2020081843 A5 JPWO2020081843 A5 JP WO2020081843A5 JP 2021521116 A JP2021521116 A JP 2021521116A JP 2021521116 A JP2021521116 A JP 2021521116A JP WO2020081843 A5 JPWO2020081843 A5 JP WO2020081843A5
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Description
本明細書で提供される開示のいくつかの実施形態は、以下の非限定的な実施例によってさらに説明される。
本開示は、例えば、以下に関する。
[1]
システムであって、
デオキシリボ核酸(DNA)エンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
配列番号22、21、28、30、18~20、23~27、29、31~44、および104のいずれか1つからのスペーサ配列を含むガイドRNA(gRNA)、または前記gRNAをコードする核酸と、
関心対象の遺伝子(GOI)またはその機能的誘導体をコードする核酸配列を含むドナーテンプレートと、を含む、システム。
[2]
前記gRNAは、配列番号22、21、28、および30のいずれか1つからのスペーサ配列を含む、前記[1]に記載のシステム。
[3]
前記gRNAは、配列番号22からのスペーサ配列を含む、前記[2]に記載のシステム。
[4]
前記gRNAは、配列番号21からのスペーサ配列を含む、前記[2]に記載のシステム。
[5]
前記gRNAは、配列番号28からのスペーサ配列を含む、前記[2]に記載のシステム。
[6]
前記gRNAは、配列番号30からのスペーサ配列を含む、前記[2]に記載のシステム。
[7]
前記DNAエンドヌクレアーゼは、配列NGGまたはNNGGを有するプロトスペーサ隣接モチーフ(PAM)を認識し、Nは、任意のヌクレオチドまたはその機能的誘導体である、前記[1]~[6]のいずれか一項に記載のシステム。
[8]
前記DNAエンドヌクレアーゼは、II型Casエンドヌクレアーゼまたはその機能的誘導体である、前記[1]~[7]のいずれか一項に記載のシステム。
[9]
前記DNAエンドヌクレアーゼは、Cas9である、前記[1]~[8]のいずれか一項に記載のシステム。
[10]
前記DNAエンドヌクレアーゼをコードする前記核酸は、宿主細胞における発現のためにコドン最適化されている、前記[1]~[9]のいずれか一項に記載のシステム。
[11]
前記GOIまたはその機能的誘導体をコードする前記核酸配列は、宿主細胞における発現のためにコドン最適化されている、前記[1]~[10]のいずれか一項に記載のシステム。
[12]
前記GOIは、治療用ポリペプチドおよび予防用ポリペプチドからなる群から選択されるポリペプチドをコードする、前記[1]~[11]のいずれか一項に記載のシステム。
[13]
前記GOIは、第VIII因子(FVIII)タンパク質、第IX因子(FIX)タンパク質、アルファ-1-アンチトリプシン、第XIII因子(FXIII)タンパク質、第VII因子(FVII)タンパク質、第X因子(FX)タンパク質、プロテインC、セリンプロテアーゼ阻害剤G1(セルピンG1)、またはそれらのいずれかの機能的誘導体からなる群から選択されるタンパク質をコードする、前記[1]~[11]のいずれか一項に記載のシステム。
[14]
前記GOIは、FVIIIタンパク質またはそのいずれかの機能的誘導体をコードする、前記[13]に記載のシステム。
[15]
前記GOIは、FIXタンパク質またはそのいずれかの機能的誘導体をコードする、前記[13]に記載のシステム。
[16]
前記GOIは、セルピンG1タンパク質またはそのいずれかの機能的誘導体をコードする、前記[13]に記載のシステム。
[17]
前記DNAエンドヌクレアーゼをコードする前記核酸は、デオキシリボ核酸(DNA)である、前記[1]~[16]のいずれか一項に記載のシステム。
[18]
前記DNAエンドヌクレアーゼをコードする前記核酸は、リボ核酸(RNA)である、前記[1]~[16]のいずれか一項に記載のシステム。
[19]
前記DNAエンドヌクレアーゼをコードする前記RNAは、mRNAである、前記[18]に記載のシステム。
[20]
前記ドナーテンプレートは、AAVベクターにコードされている、前記[1]~[19]のいずれか一項に記載のシステム。
[21]
前記ドナーテンプレートは、前記GOIまたは機能的誘導体をコードする前記核酸配列を含むドナーカセットを含み、前記ドナーカセットは、片側または両側でgRNA標的部位によって隣接されている、前記[20]に記載のシステム。
[22]
前記ドナーカセットは、両側でgRNA標的部位によって隣接されている、前記[21]に記載のシステム。
[23]
前記gRNA標的部位は、前記システムにおけるgRNAのための標的部位である、前記[21]または[22]に記載のシステム。
[24]
前記ドナーテンプレートの前記gRNA標的部位は、前記システムにおけるgRNAのためのゲノムgRNA標的部位の逆相補体である、前記[23]に記載のシステム。
[25]
前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、リポソームまたは脂質ナノ粒子に製剤化される、前記[1]~[24]のいずれか一項に記載のシステム。
[26]
前記リポソームまたは脂質ナノ粒子は、前記gRNAも含む、前記[25]に記載のシステム。
[27]
前記gRNAと予め複合体化されて、リボ核タンパク質(RNP)複合体を形成する前記DNAエンドヌクレアーゼを含む、前記[1]~[26]のいずれか一項に記載のシステム。
[28]
細胞においてゲノムを編集する方法であって、
前記細胞に、以下:
(a)配列番号22、21、28、30、18~20、23~27、29、31~44、および104のいずれか1つからのスペーサ配列を含むgRNA、または前記gRNAをコードする核酸と、
(b)DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
(c)関心対象の遺伝子(GOI)または機能的誘導体をコードする核酸配列を含むドナーテンプレートと、を提供することを含む、方法。
[29]
前記gRNAは、配列番号22、21、28、および30のいずれか1つからのスペーサ配列を含む、前記[28]に記載の方法。
[30]
前記gRNAは、配列番号21からのスペーサ配列を含む、前記[29]に記載の方法。
[31]
前記gRNAは、配列番号22からのスペーサ配列を含む、前記[30]に記載の方法。
[32]
前記gRNAは、配列番号28からのスペーサ配列を含む、前記[29]に記載の方法。
[33]
前記gRNAは、配列番号30からのスペーサ配列を含む、前記[29]に記載の方法。
[34]
前記DNAエンドヌクレアーゼは、配列NGGまたはNNGGを有するプロトスペーサ隣接モチーフ(PAM)を認識し、Nは、任意のヌクレオチドまたはその機能的誘導体である、前記[28]~[33]のいずれか一項に記載の方法。
[35]
前記DNAエンドヌクレアーゼは、II型Casエンドヌクレアーゼまたはその機能的誘導体である、前記[28]~[34]のいずれか一項に記載の方法。
[36]
前記DNAエンドヌクレアーゼは、Cas9である、前記[28]~[35]のいずれか一項に記載の方法。
[37]
前記DNAエンドヌクレアーゼをコードする前記核酸は、前記細胞における発現のためにコドン最適化されている、前記[28]~[36]のいずれか一項に記載の方法。
[38]
前記GOIまたはその機能的誘導体をコードする前記核酸配列は、前記細胞における発現のためにコドン最適化されている、前記[28]~[37]のいずれか一項に記載の方法。
[39]
前記GOIは、治療用ポリペプチドおよび予防用ポリペプチドからなる群から選択されるポリペプチドをコードする、前記[28]~[38]のいずれか一項に記載の方法。
[40]
前記GOIは、FVIIIタンパク質、FIXタンパク質、アルファ-1-アンチトリプシン、FXIIIタンパク質、FVIIタンパク質、FXタンパク質、プロテインC、セルピンG1、またはそれらのいずれかの機能的誘導体からなる群から選択されるタンパク質をコードする、前記[28]~[38]のいずれか一項に記載の方法。
[41]
前記DNAエンドヌクレアーゼをコードする前記核酸は、デオキシリボ核酸(DNA)である、前記[28]~[40]のいずれか一項に記載の方法。
[42]
前記DNAエンドヌクレアーゼをコードする前記核酸は、リボ核酸(RNA)である、前記[28]~[40]のいずれか一項に記載の方法。
[43]
前記DNAエンドヌクレアーゼをコードする前記RNAは、mRNAである、前記[42]に記載の方法。
[44]
前記ドナーテンプレートは、AAVベクターにコードされている、前記[28]~[43]のいずれか一項に記載の方法。
[45]
前記ドナーテンプレートは、前記GOIまたは機能的誘導体をコードする前記核酸配列を含むドナーカセットを含み、前記ドナーカセットは、片側または両側でgRNA標的部位によって隣接されている、前記[28]~[44]のいずれか一項に記載の方法。
[46]
前記ドナーカセットは、両側でgRNA標的部位によって隣接されている、前記[45]に記載の方法。
[47]
前記gRNA標的部位は、(a)の前記gRNAのための標的部位である、前記[45]または[46]に記載の方法。
[48]
前記ドナーテンプレートの前記gRNA標的部位は、(a)の前記gRNAのための前記細胞ゲノムにおけるgRNA標的部位の逆相補体である、前記[47]に記載の方法。
[49]
前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、リポソームまたは脂質ナノ粒子に製剤化される、前記[28]~[48]のいずれか一項に記載の方法。
[50]
前記リポソームまたは脂質ナノ粒子は、前記gRNAも含む、前記[49]に記載の方法。
[51]
前記細胞に、前記gRNAと予め複合体化された前記DNAエンドヌクレアーゼを提供し、RNP複合体を形成することを含む、前記[28]~[50]のいずれか一項に記載の方法。
[52]
(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、(c)の前記ドナーテンプレートが前記細胞に提供されてから4日を超えた後に、前記細胞に提供される、前記[28]~[51]のいずれか一項に記載の方法。
[53]
(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、(c)が前記細胞に提供されてから少なくとも14日後に、前記細胞に提供される、前記[28]~[52]のいずれか一項に記載の方法。
[54]
1つ以上の追加用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、第1の用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸に続いて、前記細胞に提供される、前記[52]または[53]に記載の方法。
[55]
1つ以上の追加用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、前記GOIもしくは機能的誘導体をコードする前記核酸配列の標的化された組み込みの標的レベル、および/または前記GOIもしくは機能的誘導体をコードする前記核酸配列の発現の標的レベルが達成されるまで、前記第1の用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸に続いて、前記細胞に提供される、前記[54]に記載の方法。
[56]
前記GOIまたは機能的誘導体をコードする前記核酸配列は、内因性アルブミンプロモーターの制御下で発現される、前記[28]~[55]のいずれか一項に記載の方法。
[57]
前記細胞は、肝細胞である、前記[28]~[56]のいずれか一項に記載の方法。
[58]
遺伝子改変細胞であって、前記細胞のゲノムは、前記[28]~[57]のいずれか一項に記載の方法によって編集されている、遺伝子改変細胞。
[59]
前記GOIまたは機能的誘導体をコードする前記核酸配列は、前記内因性アルブミンプロモーターの前記制御下で発現される、前記[58]に記載の遺伝子改変細胞。
[60]
前記GOIまたはその機能的誘導体をコードする前記核酸配列は、前記細胞における発現のためにコドン最適化されている、前記[58]または[59]に記載の遺伝子改変細胞。
[61]
前記細胞は、肝細胞である、前記[58]~[60]のいずれか一項に記載の遺伝子改変細胞。
[62]
対象における障害または健康状態を治療する方法であって、
前記対象における細胞に、以下:
(a)配列番号22、21、28、30、18~20、23~27、29、31~44、および104のいずれか1つからのスペーサ配列を含むgRNA、または前記gRNAをコードする核酸と、
(b)DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
(c)関心対象の遺伝子(GOI)または機能的誘導体をコードする核酸配列を含むドナーテンプレートと、を提供することを含む、方法。
[63]
前記gRNAは、配列番号22、21、28、および30のいずれか1つからのスペーサ配列を含む、前記[62]に記載の方法。
[64]
前記gRNAは、配列番号22からのスペーサ配列を含む、前記[63]に記載の方法。
[65]
前記gRNAは、配列番号21からのスペーサ配列を含む、前記[63]に記載の方法。
[66]
前記gRNAは、配列番号28からのスペーサ配列を含む、前記[63]に記載の方法。
[67]
前記gRNAは、配列番号30からのスペーサ配列を含む、前記[63]に記載の方法。
[68]
前記GOIは、治療用ポリペプチドおよび予防用ポリペプチドからなる群から選択されるポリペプチドをコードする、前記[62]~[67]のいずれか一項に記載の方法。
[69]
前記GOIは、FVIIIタンパク質、FIXタンパク質、アルファ-1-アンチトリプシン、FXIIIタンパク質、FVIIタンパク質、FXタンパク質、プロテインC、セルピンG1、またはそれらのそのいずれかの機能的誘導体からなる群から選択されるタンパク質をコードする、前記[62]~[67]のいずれか一項に記載の方法。
[70]
前記GOIは、FVIIIタンパク質またはそのいずれかの機能的誘導体をコードする、前記[69]に記載の方法。
[71]
前記GOIは、FIXタンパク質またはそのいずれかの機能的誘導体をコードする、前記[69]に記載の方法。
[72]
前記GOIは、セルピンG1またはそのいずれかの機能的誘導体をコードする、前記[69]に記載の方法。
[73]
前記対象は、血友病A、血友病B、MPS II、MPS1H、アルファ-1-アンチトリプシン欠乏症、FXIII欠乏症、FVII欠乏症、FX欠乏症、プロテインC欠乏症、およびHAEからなる群から選択される障害もしくは健康状態を有するか、または有することが疑われる患者である、前記[62]~[72]のいずれか一項に記載の方法。
[74]
前記対象は、血友病Aを有するか、または有することが疑われる患者である、前記[73]に記載の方法。
[75]
前記対象は、血友病Bを有するか、または有することが疑われる患者である、前記[73]に記載の方法。
[76]
前記対象は、HAEを有するか、または有することが疑われる患者である、前記[73]に記載の方法。
[77]
前記対象は、血友病A、血友病B、MPS II、MPS1H、アルファ-1-アンチトリプシン欠乏症、FXIII欠乏症、FVII欠乏症、FX欠乏症、プロテインC欠乏症、およびHAEからなる群から選択される障害または健康状態のリスクを有すると診断されている、前記[62]~[72]のいずれか一項に記載の方法。
[78]
前記対象は、血友病Aのリスクを有すると診断されている患者である、前記[77]に記載の方法。
[79]
前記対象は、血友病Bのリスクを有すると診断されている患者である、前記[77]に記載の方法。
[80]
前記対象は、HAEのリスクを有すると診断されている患者である、前記[77]に記載の方法。
[81]
前記DNAエンドヌクレアーゼは、配列NGGまたはNNGGを有するプロトスペーサ隣接モチーフ(PAM)を認識し、Nは、任意のヌクレオチドまたはその機能的誘導体である、前記[62]~[80]のいずれか一項に記載の方法。
[82]
前記DNAエンドヌクレアーゼは、II型Casエンドヌクレアーゼまたはその機能的誘導体である、前記[62]~[81]のいずれか一項に記載の方法。
[83]
前記DNAエンドヌクレアーゼは、Cas9である、前記[62]~[82]のいずれか一項に記載の方法。
[84]
前記DNAエンドヌクレアーゼをコードする前記核酸は、前記細胞における発現のためにコドン最適化されている、前記[62]~[83]のいずれか一項に記載の方法。
[85]
前記GOIまたはその機能的誘導体をコードする前記核酸配列は、前記細胞における発現のためにコドン最適化されている、前記[62]~[84]のいずれか一項に記載の方法。
[86]
前記DNAエンドヌクレアーゼをコードする前記核酸は、デオキシリボ核酸(DNA)である、前記[62]~[85]のいずれか一項に記載の方法。
[87]
前記DNAエンドヌクレアーゼをコードする前記核酸は、リボ核酸(RNA)である、前記[62]~[85]のいずれか一項に記載の方法。
[88]
前記DNAエンドヌクレアーゼをコードする前記RNAは、mRNAである、前記[87]に記載の方法。
[89]
(a)の前記gRNA、(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸、および(c)の前記ドナーテンプレート、のうちの1つ以上は、リポソームまたは脂質ナノ粒子に製剤化される、前記[62]~[88]のいずれか一項に記載の方法。
[90]
前記ドナーテンプレートは、AAVベクターにコードされている、前記[62]~[89]のいずれか一項に記載の方法。
[91]
前記ドナーテンプレートは、前記GOIまたは機能的誘導体をコードする前記核酸配列を含むドナーカセットを含み、前記ドナーカセットは、片側または両側でgRNA標的部位によって隣接されている、前記[62]~[90]のいずれか一項に記載の方法。
[92]
前記ドナーカセットは、両側でgRNA標的部位によって隣接されている、前記[91]に記載の方法。
[93]
前記gRNA標的部位は、(a)の前記gRNAのための標的部位である、前記[91]または[92]に記載の方法。
[94]
前記ドナーテンプレートの前記gRNA標的部位は、(a)の前記gRNAのための前記細胞ゲノムにおける前記gRNA標的部位の逆相補体である、前記[93]に記載の方法。
[95]
前記ドナーテンプレートを前記細胞に提供することは、前記ドナーテンプレートを前記対象に投与することを含む、前記[62]~[94]のいずれか一項に記載の方法。
[96]
前記投与は、静脈内経路を介する、前記[95]に記載の方法。
[97]
前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、リポソームまたは脂質ナノ粒子に製剤化される、前記[62]~[96]のいずれか一項に記載の方法。
[98]
前記リポソームまたは脂質ナノ粒子は、前記gRNAも含む、前記[97]に記載の方法。
[99]
前記gRNAおよび前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸を前記細胞に提供することは、前記リポソームまたは脂質ナノ粒子を前記対象に投与することを含む、前記[98]に記載の方法。
[100]
前記投与は、静脈内経路を介する、前記[99]に記載の方法。
[101]
前記細胞に、前記gRNAと予め複合体化された前記DNAエンドヌクレアーゼを提供し、RNP複合体を形成することを含む、前記[62]~[100]のいずれか一項に記載の方法。
[102]
(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、(c)の前記ドナーテンプレートが前記細胞に提供されてから4日を超えた後に、前記細胞に提供される、前記[62]~[101]のいずれか一項に記載の方法。
[103]
(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、(c)の前記ドナーテンプレートが前記細胞に提供されてから少なくとも14日後に、前記細胞に提供される、前記[62]~[102]のいずれか一項に記載の方法。
[104]
1つ以上の追加用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、前記第1の用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸に続いて、前記細胞に提供される、前記[102]または[103]に記載の方法。
[105]
1つ以上の追加用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸は、前記GOIまたは機能的誘導体をコードする前記核酸配列の標的化された組み込みの標的レベルおよび/または前記GOIタンパク質または機能的誘導体をコードする前記核酸配列の発現の標的レベルが達成されるまで、前記第1の用量の、(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸に続いて、前記細胞に提供される、前記[104]に記載の方法。
[106]
(a)の前記gRNAおよび(b)の前記DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸を前記細胞に提供することは、前記対象に前記DNAエンドヌクレアーゼをコードする核酸および前記gRNAを含む脂質ナノ粒子を投与することを含む、前記[102]~[105]のいずれか一項に記載の方法。
[107]
(c)の前記ドナーテンプレートを前記細胞に提供することは、前記対象に、AAVベクターにコードされた前記ドナーテンプレートを投与することを含む、前記[102]~[106]のいずれか一項に記載の方法。
[108]
前記GOIまたは機能的誘導体をコードする前記核酸配列は、前記内因性アルブミンプロモーターの制御下で発現される、前記[62]~[107]のいずれか一項に記載の方法。
[109]
前記細胞は、肝細胞である、前記[62]~[108]のいずれか一項に記載の方法。
[110]
前記GOIまたは機能的誘導体をコードする前記核酸配列は、前記対象の前記肝臓において発現される、前記[62]~[109]のいずれか一項に記載の方法。
[111]
対象における血友病A、血友病B、または遺伝性血管浮腫を治療する方法であって、
前記[58]~[61]のいずれか一項に記載の遺伝子改変細胞を前記対象に投与することを含む、方法。
[112]
前記遺伝子改変細胞は、前記対象に対して自家である、前記[111]に記載の方法。
[113]
前記対象からの生物学的試料を得ることをさらに含み、前記生物学的試料は、肝細胞の細胞を含み、前記遺伝子改変細胞は、前記肝細胞から調製される、前記[111]または[112]に記載の方法。
[114]
前記[1]~[27]のいずれか一項に記載のシステムの1つ以上の要素を含み、かつ使用のための説明書をさらに含む、キット。
Some embodiments of the disclosure provided herein are further illustrated by the following non-limiting examples.
The present disclosure relates to, for example, the following.
[1]
a system,
a deoxyribonucleic acid (DNA) endonuclease or a nucleic acid encoding said DNA endonuclease;
a guide RNA (gRNA) comprising a spacer sequence from any one of SEQ ID NOs: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA When,
a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or a functional derivative thereof.
[2]
The system of [1] above, wherein the gRNA comprises a spacer sequence from any one of SEQ ID NOs: 22, 21, 28, and 30.
[3]
The system according to [2] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:22.
[4]
The system according to [2] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:21.
[5]
The system of [2] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:28.
[6]
The system according to [2] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:30.
[7]
Any one of [1] to [6] above, wherein the DNA endonuclease recognizes a protospacer adjacent motif (PAM) having the sequence NGG or NNGG, and N is any nucleotide or functional derivative thereof. The system described in .
[8]
The system according to any one of [1] to [7] above, wherein the DNA endonuclease is a type II Cas endonuclease or a functional derivative thereof.
[9]
The system according to any one of [1] to [8], wherein the DNA endonuclease is Cas9.
[10]
The system according to any one of [1] to [9] above, wherein the nucleic acid encoding the DNA endonuclease is codon-optimized for expression in a host cell.
[11]
The system according to any one of [1] to [10] above, wherein the nucleic acid sequence encoding the GOI or a functional derivative thereof is codon-optimized for expression in a host cell.
[12]
The system according to any one of [1] to [11] above, wherein the GOI encodes a polypeptide selected from the group consisting of therapeutic polypeptides and prophylactic polypeptides.
[13]
The GOI is Factor VIII (FVIII) protein, Factor IX (FIX) protein, alpha-1-antitrypsin, Factor XIII (FXIII) protein, Factor VII (FVII) protein, Factor X (FX) protein , protein C, serine protease inhibitor G1 (serpin G1), or any functional derivative thereof, according to any one of [1] to [11] above, which encodes a protein selected from the group consisting of system.
[14]
The system of [13] above, wherein the GOI encodes a FVIII protein or any functional derivative thereof.
[15]
The system of [13] above, wherein the GOI encodes a FIX protein or any functional derivative thereof.
[16]
The system of [13] above, wherein the GOI encodes a serpin G1 protein or any functional derivative thereof.
[17]
The system according to any one of [1] to [16] above, wherein the nucleic acid encoding the DNA endonuclease is deoxyribonucleic acid (DNA).
[18]
The system according to any one of [1] to [16] above, wherein the nucleic acid encoding the DNA endonuclease is ribonucleic acid (RNA).
[19]
The system according to [18] above, wherein the RNA encoding the DNA endonuclease is mRNA.
[20]
The system according to any one of [1] to [19] above, wherein the donor template is encoded in an AAV vector.
[21]
The system of [20] above, wherein said donor template comprises a donor cassette comprising said nucleic acid sequence encoding said GOI or functional derivative, said donor cassette being flanked on one or both sides by gRNA target sites. .
[22]
The system of [21] above, wherein the donor cassette is flanked on both sides by gRNA target sites.
[23]
The system of [21] or [22] above, wherein the gRNA target site is a target site for a gRNA in the system.
[24]
The system of [23] above, wherein the gRNA target site of the donor template is the reverse complement of a genomic gRNA target site for the gRNA in the system.
[25]
The system according to any one of [1] to [24] above, wherein the DNA endonuclease or the nucleic acid encoding the DNA endonuclease is formulated in a liposome or lipid nanoparticle.
[26]
The system according to [25] above, wherein the liposome or lipid nanoparticle also contains the gRNA.
[27]
The system according to any one of [1] to [26] above, comprising the DNA endonuclease pre-complexed with the gRNA to form a ribonucleoprotein (RNP) complex.
[28]
A method of editing a genome in a cell comprising:
In said cells:
(a) a gRNA comprising a spacer sequence from any one of SEQ ID NOS: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA; ,
(b) a DNA endonuclease or a nucleic acid encoding said DNA endonuclease;
(c) a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or functional derivative.
[29]
The method of [28] above, wherein the gRNA comprises a spacer sequence from any one of SEQ ID NOS: 22, 21, 28, and 30.
[30]
The method of [29] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:21.
[31]
The method of [30] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:22.
[32]
The method of [29] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:28.
[33]
The method of [29] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:30.
[34]
Any one of [28] to [33] above, wherein the DNA endonuclease recognizes a protospacer adjacent motif (PAM) having the sequence NGG or NNGG, and N is any nucleotide or functional derivative thereof. The method described in .
[35]
The method according to any one of [28] to [34] above, wherein the DNA endonuclease is a type II Cas endonuclease or a functional derivative thereof.
[36]
The method according to any one of [28] to [35] above, wherein the DNA endonuclease is Cas9.
[37]
The method of any one of [28]-[36] above, wherein the nucleic acid encoding the DNA endonuclease is codon-optimized for expression in the cell.
[38]
The method of any one of [28]-[37] above, wherein said nucleic acid sequence encoding said GOI or a functional derivative thereof is codon-optimized for expression in said cell.
[39]
The method of any one of [28]-[38] above, wherein the GOI encodes a polypeptide selected from the group consisting of therapeutic polypeptides and prophylactic polypeptides.
[40]
The GOI comprises a protein selected from the group consisting of FVIII protein, FIX protein, alpha-1-antitrypsin, FXIII protein, FVII protein, FX protein, protein C, serpin G1, or any functional derivative thereof. The method according to any one of [28] to [38] above, wherein the coding is performed.
[41]
The method according to any one of [28] to [40] above, wherein the nucleic acid encoding the DNA endonuclease is deoxyribonucleic acid (DNA).
[42]
The method according to any one of [28] to [40] above, wherein the nucleic acid encoding the DNA endonuclease is ribonucleic acid (RNA).
[43]
The method according to [42] above, wherein the RNA encoding the DNA endonuclease is mRNA.
[44]
The method of any one of [28]-[43] above, wherein the donor template is encoded in an AAV vector.
[45]
said donor template comprises a donor cassette comprising said nucleic acid sequence encoding said GOI or functional derivative, said donor cassette being flanked on one or both sides by gRNA target sites, said [28]-[44] The method according to any one of .
[46]
The method of [45] above, wherein the donor cassette is flanked on both sides by gRNA target sites.
[47]
The method of [45] or [46] above, wherein the gRNA target site is the target site for the gRNA of (a).
[48]
The method of [47] above, wherein the gRNA target site of the donor template is the reverse complement of a gRNA target site in the cellular genome for the gRNA of (a).
[49]
The method of any one of [28] to [48] above, wherein the DNA endonuclease or the nucleic acid encoding the DNA endonuclease is formulated in a liposome or lipid nanoparticle.
[50]
The method of [49] above, wherein the liposome or lipid nanoparticle also contains the gRNA.
[51]
The method of any one of [28] to [50] above, comprising providing the cell with the DNA endonuclease pre-complexed with the gRNA to form an RNP complex.
[52]
The gRNA of (a) and the DNA endonuclease of (b) or a nucleic acid encoding the DNA endonuclease is added to the cell more than 4 days after the donor template of (c) is provided to the cell. The method according to any one of [28] to [51], provided in
[53]
wherein the gRNA of (a) and the DNA endonuclease of (b) or a nucleic acid encoding the DNA endonuclease are provided to the cell at least 14 days after (c) is provided to the cell; [28] The method according to any one of [52].
[54]
one or more additional doses of said gRNA of (a) and said DNA endonuclease of (b) or a nucleic acid encoding said DNA endonuclease is combined with said first dose of said gRNA of (a) and (b) or the nucleic acid encoding the DNA endonuclease of is subsequently provided to the cell.
[55]
One or more additional doses of said gRNA of (a) and said DNA endonuclease of (b) or a nucleic acid encoding said DNA endonuclease are targeted to said nucleic acid sequence encoding said GOI or functional derivative. of said first dose of said gRNA of (a) and (b) until a target level of integration and/or target level of expression of said nucleic acid sequence encoding said GOI or functional derivative is achieved. The method of [54] above, wherein the DNA endonuclease or a nucleic acid encoding the DNA endonuclease is subsequently provided to the cell.
[56]
The method of any one of [28]-[55] above, wherein said nucleic acid sequence encoding said GOI or functional derivative is expressed under the control of the endogenous albumin promoter.
[57]
The method according to any one of [28] to [56] above, wherein the cells are hepatocytes.
[58]
A genetically modified cell, wherein the genome of said cell has been edited by the method of any one of [28] to [57] above.
[59]
The genetically modified cell of [58] above, wherein said nucleic acid sequence encoding said GOI or functional derivative is expressed under said control of said endogenous albumin promoter.
[60]
The genetically modified cell of [58] or [59] above, wherein said nucleic acid sequence encoding said GOI or a functional derivative thereof is codon-optimized for expression in said cell.
[61]
The genetically modified cell according to any one of [58] to [60] above, wherein the cell is a hepatocyte.
[62]
A method of treating a disorder or condition in a subject comprising:
Cells in said subject to:
(a) a gRNA comprising a spacer sequence from any one of SEQ ID NOS: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA; ,
(b) a DNA endonuclease or a nucleic acid encoding said DNA endonuclease;
(c) a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or functional derivative.
[63]
The method of [62] above, wherein the gRNA comprises a spacer sequence from any one of SEQ ID NOs: 22, 21, 28, and 30.
[64]
The method of [63] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:22.
[65]
The method of [63] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:21.
[66]
The method of [63] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:28.
[67]
The method of [63] above, wherein the gRNA comprises a spacer sequence from SEQ ID NO:30.
[68]
The method of any one of [62]-[67] above, wherein the GOI encodes a polypeptide selected from the group consisting of therapeutic polypeptides and prophylactic polypeptides.
[69]
said GOI is a protein selected from the group consisting of FVIII protein, FIX protein, alpha-1-antitrypsin, FXIII protein, FVII protein, FX protein, protein C, serpin G1, or any functional derivative thereof The method according to any one of [62] to [67] above, which encodes
[70]
The method of [69] above, wherein said GOI encodes a FVIII protein or any functional derivative thereof.
[71]
The method of [69] above, wherein said GOI encodes a FIX protein or any functional derivative thereof.
[72]
The method of [69] above, wherein said GOI encodes Serpin G1 or any functional derivative thereof.
[73]
said subject has a disorder selected from the group consisting of hemophilia A, hemophilia B, MPS II, MPS1H, alpha-1-antitrypsin deficiency, FXIII deficiency, FVII deficiency, FX deficiency, protein C deficiency, and HAE Or the method of any one of the above [62] to [72], wherein the patient has or is suspected of having a medical condition.
[74]
The method of [73] above, wherein the subject is a patient having or suspected of having hemophilia A.
[75]
The method of [73] above, wherein the subject is a patient having or suspected of having hemophilia B.
[76]
The method of [73] above, wherein the subject is a patient having or suspected of having HAE.
[77]
said subject has a disorder selected from the group consisting of hemophilia A, hemophilia B, MPS II, MPS1H, alpha-1-antitrypsin deficiency, FXIII deficiency, FVII deficiency, FX deficiency, protein C deficiency, and HAE Or the method of any one of the above [62] to [72], which has been diagnosed as having a health condition risk.
[78]
The method of [77] above, wherein the subject is a patient diagnosed as having hemophilia A risk.
[79]
The method of [77] above, wherein the subject is a patient diagnosed as having hemophilia B risk.
[80]
The method of [77] above, wherein the subject is a patient diagnosed to be at risk for HAE.
[81]
Any one of [62] to [80] above, wherein the DNA endonuclease recognizes a protospacer adjacent motif (PAM) having the sequence NGG or NNGG, and N is any nucleotide or functional derivative thereof. The method described in .
[82]
The method according to any one of [62] to [81] above, wherein the DNA endonuclease is a type II Cas endonuclease or a functional derivative thereof.
[83]
The method according to any one of [62] to [82], wherein the DNA endonuclease is Cas9.
[84]
The method of any one of [62]-[83] above, wherein the nucleic acid encoding the DNA endonuclease is codon-optimized for expression in the cell.
[85]
The method of any one of [62]-[84] above, wherein said nucleic acid sequence encoding said GOI or a functional derivative thereof is codon-optimized for expression in said cell.
[86]
The method according to any one of [62] to [85] above, wherein the nucleic acid encoding the DNA endonuclease is deoxyribonucleic acid (DNA).
[87]
The method of any one of [62] to [85] above, wherein the nucleic acid encoding the DNA endonuclease is ribonucleic acid (RNA).
[88]
The method of [87] above, wherein the RNA encoding the DNA endonuclease is mRNA.
[89]
one or more of the gRNA of (a), the DNA endonuclease of (b) or a nucleic acid encoding the DNA endonuclease, and the donor template of (c) are formulated in a liposome or lipid nanoparticle. The method according to any one of [62] to [88] above.
[90]
The method of any one of [62]-[89] above, wherein the donor template is encoded in an AAV vector.
[91]
said donor template comprises a donor cassette comprising said nucleic acid sequence encoding said GOI or functional derivative, said donor cassette being flanked on one or both sides by gRNA target sites, said [62]-[90] The method according to any one of .
[92]
The method of [91] above, wherein the donor cassette is flanked on both sides by gRNA target sites.
[93]
The method of [91] or [92] above, wherein the gRNA target site is the target site for the gRNA of (a).
[94]
The method of [93] above, wherein the gRNA target site of the donor template is the reverse complement of the gRNA target site in the cellular genome for the gRNA of (a).
[95]
The method of any one of [62] to [94] above, wherein providing the donor template to the cells comprises administering the donor template to the subject.
[96]
The method of [95] above, wherein the administration is via an intravenous route.
[97]
The method of any one of [62] to [96] above, wherein the DNA endonuclease or the nucleic acid encoding the DNA endonuclease is formulated in a liposome or lipid nanoparticle.
[98]
The method of [97] above, wherein the liposome or lipid nanoparticle also contains the gRNA.
[99]
The method of [98] above, wherein providing the gRNA and the DNA endonuclease or a nucleic acid encoding the DNA endonuclease to the cell comprises administering the liposome or lipid nanoparticle to the subject.
[100]
The method of [99] above, wherein the administration is via an intravenous route.
[101]
The method of any one of [62]-[100] above, comprising providing said cell with said DNA endonuclease pre-complexed with said gRNA to form an RNP complex.
[102]
The gRNA of (a) and the DNA endonuclease of (b) or a nucleic acid encoding the DNA endonuclease is added to the cell more than 4 days after the donor template of (c) is provided to the cell. The method according to any one of [62] to [101], provided in
[103]
said gRNA of (a) and said DNA endonuclease of (b) or nucleic acid encoding said DNA endonuclease is provided to said cell at least 14 days after said donor template of (c) is provided to said cell; The method according to any one of [62] to [102] above.
[104]
one or more additional doses of said gRNA of (a) and said DNA endonuclease of (b) or nucleic acid encoding said DNA endonuclease are combined with said first dose of said gRNA of (a) and (b) ), or the nucleic acid encoding the DNA endonuclease, is provided to the cell subsequently to the method of [102] or [103].
[105]
One or more additional doses of said gRNA of (a) and said DNA endonuclease of (b) or a nucleic acid encoding said DNA endonuclease are targeted to said nucleic acid sequence encoding said GOI or functional derivative. of said first dose of said gRNA of (a) and (b) until a target level of integration and/or target level of expression of said nucleic acid sequence encoding said GOI protein or functional derivative is achieved. The method of [104] above, wherein the DNA endonuclease or a nucleic acid encoding the DNA endonuclease is subsequently provided to the cell.
[106]
Providing said gRNA of (a) and said DNA endonuclease of (b) or a nucleic acid encoding said DNA endonuclease to said cell comprises: The method according to any one of [102] to [105], comprising administering nanoparticles.
[107]
Any one of [102] to [106] above, wherein providing the donor template of (c) to the cell comprises administering to the subject the donor template encoded in an AAV vector. described method.
[108]
The method of any one of [62]-[107] above, wherein said nucleic acid sequence encoding said GOI or functional derivative is expressed under the control of said endogenous albumin promoter.
[109]
The method according to any one of [62] to [108] above, wherein the cells are hepatocytes.
[110]
The method of any one of [62]-[109] above, wherein said nucleic acid sequence encoding said GOI or functional derivative is expressed in said liver of said subject.
[111]
A method of treating hemophilia A, hemophilia B, or hereditary angioedema in a subject, comprising:
A method comprising administering the genetically modified cell of any one of [58] to [61] to the subject.
[112]
The method of [111] above, wherein the genetically modified cell is autologous to the subject.
[113]
Said [111] or [112], further comprising obtaining a biological sample from said subject, said biological sample comprising cells of hepatocytes, said genetically modified cells being prepared from said hepatocytes. ] The method described in .
[114]
A kit comprising one or more elements of the system according to any one of [1] to [27] and further comprising instructions for use.
Claims (114)
デオキシリボ核酸(DNA)エンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
配列番号22、21、28、30、18~20、23~27、29、31~44、および104のいずれか1つからのスペーサ配列を含むガイドRNA(gRNA)、または前記gRNAをコードする核酸と、
関心対象の遺伝子(GOI)またはその機能的誘導体をコードする核酸配列を含むドナーテンプレートと、を含む、システム。 a system,
a deoxyribonucleic acid (DNA) endonuclease or a nucleic acid encoding said DNA endonuclease;
a guide RNA (gRNA) comprising a spacer sequence from any one of SEQ ID NOs: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA When,
a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or a functional derivative thereof.
前記細胞に、以下:
(a)配列番号22、21、28、30、18~20、23~27、29、31~44、および104のいずれか1つからのスペーサ配列を含むgRNA、または前記gRNAをコードする核酸と、
(b)DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
(c)関心対象の遺伝子(GOI)または機能的誘導体をコードする核酸配列を含むドナーテンプレートと、を提供することを含む、方法。 An ex vivo method of genome editing in a cell comprising:
In said cells:
(a) a gRNA comprising a spacer sequence from any one of SEQ ID NOS: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA; ,
(b) a DNA endonuclease or a nucleic acid encoding said DNA endonuclease;
(c) a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or functional derivative.
(b)DNAエンドヌクレアーゼまたは前記DNAエンドヌクレアーゼをコードする核酸と、
(c)関心対象の遺伝子(GOI)または機能的誘導体をコードする核酸配列を含むドナーテンプレートとを含む、対象における障害または健康状態を治療するための薬剤。 ( a) a gRNA comprising a spacer sequence from any one of SEQ ID NOs: 22, 21, 28, 30, 18-20, 23-27, 29, 31-44, and 104, or a nucleic acid encoding said gRNA; ,
(b) a DNA endonuclease or a nucleic acid encoding said DNA endonuclease;
(c) a donor template comprising a nucleic acid sequence encoding a gene of interest (GOI) or functional derivative ; and a medicament for treating a disorder or condition in a subject .
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2019
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- 2019-10-17 AU AU2019362000A patent/AU2019362000A1/en active Pending
- 2019-10-17 KR KR1020217014866A patent/KR20210096088A/en active Search and Examination
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