CN114364802A - 通过靶向lama1基因来治疗肌营养不良症的方法 - Google Patents
通过靶向lama1基因来治疗肌营养不良症的方法 Download PDFInfo
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Abstract
本发明旨在提供一种人类肌营养不良症(特别是MDC1A)的新的治疗方法。本发明提供了一种多核苷酸,其包含下述碱基序列:(a)编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列,和(b)编码靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA的碱基序列:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
Description
技术领域
本发明涉及一种通过靶向层粘连蛋白-α1链(LAMA1)基因等来治疗肌营养不良症、特别是分区蛋白(Merosin)缺陷性先天性肌营养不良症(MDC1A)的方法。更具体来说,本发明涉及一种用于治疗或预防肌营养不良症的方法,所述方法包括通过使用靶向人类LAMA1基因的特定序列的指导RNA和转录激活因子与CRISPR效应蛋白的融合蛋白和治疗或预防肌营养不良症的药剂等,通过上调在肌肉组织中非固有表达的人类LAMA1基因的表达来补充LAMA2或其因突变而缺失的功能。
背景技术
肌营养不良症是具有进行性肌肉萎缩和肌肉力量丧失的遗传性疾病的总称。目前,肌营养不良症尚无有效的基础治疗药物,仅给予对症治疗。作为一种类型的肌营养不良症,常染色体隐性遗传病分区蛋白缺陷性先天性肌营养不良症(MDC1A)是已知的。
MDC1A是一种西方类型的没有智力迟钝的先天性肌营养不良症,并由骨骼肌基底膜组分中分区蛋白的缺乏引起。分区蛋白是由通过糖链结构结合到α-营养不良蛋白聚糖的层粘连蛋白链组成的异源三聚体。当它缺失时,细胞骨架和细胞外基质之间通过肌营养不良蛋白糖蛋白复合体的连接被破坏。它是欧美地区发病率最高的先天性肌营养不良症(约50%)。它由6q22.33处的层粘连蛋白α2链基因(LAMA2基因)中的突变引起。
Cohn等人报告了一种在MDC1A dy2J/dy2J小鼠模型中通过系统性递送具有CRISPR/Cas9基因组编辑组分的腺相关病毒(AAV),来校正导致LAMA2基因突变的剪接位点突变的方法。所述dy2J/dy2J小鼠在治疗后显示出肌肉组织病理学和功能的实质性改善,并且没有麻痹的迹象(NPL 1)。
此外,Bassi显示LAMA1基因可能是用于MDC1A的疾病改良基因。LAMA1基因编码与层粘连蛋白α2链结构相似的层粘连蛋白α1链蛋白。具体来说,使用小鼠的实验已显示出金黄色葡萄球菌(S.aureus)的CRISPR/Cas9系统可用于上调LAMA1的表达并补偿层粘连蛋白α2链的缺乏的可能性(NPL 2、NPL 3)。
[引文列表]
[非专利文献]
[NPL 1]Kemaladewi,D.U.,Maino,E.,Hyatt,E.,Hou,H.,Ding,M.,Place,K.M.,Zhu,X.,Bassi,P.,Baghestani,Z.,Deshwar,A.G.,Merico,D.,Xiong,H.Y.,Frey,B.J.,Wilson,M.D.,Ivakine,E.A.,Cohn,R.D.Nat Medicine.23:8.2017。
[NPL 2]Prabhpreet Singh Bassi,符合多伦多大学分子遗传学系理学硕士学位要求而提交的论文,2017:“评估CRISPR/Cas9介导的基因调节在1A型分区蛋白缺陷性先天性肌营养不良症中的治疗潜力”(Assessing the Therapeutic Potential of CRISPR/Cas9-Mediated Gene Modulation in Assessing the Therapeutic Potential ofCRISPR/Cas9-Mediated Gene Modulation in Merosin-Deficient Congenital MuscularDystrophy Type 1A)。
[NPL 3]Dwi U.Kemaladewi,Prabhpreet S.Bassi,Steven erwood,Dhekra Al-Basha,Kinga I.Gawlik,Kyle Lindsay,elzbieta Hyatt,rebekah Kember,Kara M.Place,ryan M.Marks,Madeleine Durbeej,Steven A.Prescott,evgueni A.Ivakine&ronaldD.Cohn,Nature 572,p125,2019:“通过改良物基因的上调治疗肌营养不良症的不依赖于突变的方法”(A mutation-independent approach for muscular dystrophy viaupregulation of a modifier gene)。
发明内容
[技术问题]
本发明旨在提供一种用于人类肌营养不良症(特别是MDC1A)的新的治疗方法。
[技术解决方案]
本发明人对上述问题进行了深入研究,并发现通过使用靶向人类LAMA1基因(基因ID:284217)的特定序列的指导RNA和转录激活因子与缺少核酸酶活性的CRISPR效应蛋白的融合蛋白,可以在肌细胞中上调人类LAMA1基因的表达。在这些发现的基础上,本发明人完成了本发明。
本发明可以包括下述发明。
[1]一种多核苷酸,其包含下述碱基序列:
(a)编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列,和
(b)编码靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA的碱基序列:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[2]上述[1]所述的多核苷酸,其中编码指导RNA的碱基序列包含:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的碱基序列,
(ii)在SEQ ID NO:124中阐述的碱基序列,
(iii)在SEQ ID NO:178、193或195中阐述的碱基序列,
或其中缺失、替换、插入和/或添加了1至3个碱基的所述碱基序列。
[3]上述[1]或[2]所述的多核苷酸,其中所述转录激活因子选自VP64、VP160、VPH、VPR、VP64-miniRTA(miniVR)和microVR、其具有转录激活能力的变体。
[4]上述[3]所述的多核苷酸,其中所述转录激活因子是miniVR。
[5]上述[1]至[4]中的任一项所述的多核苷酸,其中所述核酸酶缺陷型CRISPR效应蛋白是dCas9。
[6]上述[5]所述的多核苷酸,其中所述dCas9源自于金黄色葡萄球菌(Staphylococcus aureus)。
[7]上述[1]至[6]中的任一项所述的多核苷酸,其还包含用于编码指导RNA的碱基序列的启动子序列和/或用于所述编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列的启动子序列。
[8]上述[7]所述的多核苷酸,其中所述用于编码指导RNA的碱基序列的启动子序列选自U6启动子、SNR6启动子、SNR52启动子、SCR1启动子、RPR1启动子、U3启动子和H1启动子。
[9]上述[8]所述的多核苷酸,其中所述用于编码指导RNA的碱基序列的启动子序列是U6启动子。
[10]上述[7]至[9]中的任一项所述的多核苷酸,其中用于所述编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列的启动子序列是遍在启动子或肌肉特异性启动子。
[11]上述[10]所述的多核苷酸,其中所述遍在启动子选自EFS启动子、CMV启动子和CAG启动子。
[12]上述[10]所述的多核苷酸,其中所述肌肉特异性启动子选自CK8启动子、肌球蛋白重链激酶(MHCK)启动子、肌肉肌酸激酶(MCK)启动子、合成C5-12(Syn)启动子和unc45b启动子。
[13]一种载体,其包含上述[1]至[12]中的任一项所述的多核苷酸。
[14]上述[13]所述的载体,其中所述载体是质粒载体或病毒载体。
[15]上述[14]所述的载体,其中所述病毒载体选自腺相关病毒(AAV)载体、腺病毒载体和慢病毒载体。
[16]上述[15]所述的载体,其中所述AAV载体选自AAV1、AAV2、AAV6、AAV7、AAV8、AAV9及其变体。
[17]一种用于治疗或预防MDC1A的药剂,其包含上述[1]至[12]中的任一项所述的多核苷酸或上述[13]至[16]中的任一项所述的载体。
[18]一种用于治疗或预防MDC1A的方法,所述方法包括向需要的对象给药上述[1]至[12]中的任一项所述的多核苷酸或上述[13]至[16]中的任一项所述的载体。
[19]上述[1]至[12]中的任一项所述的多核苷酸或上述[13]至[16]中的任一项所述的载体用于治疗或预防MDC1A的用途。
[20]上述[1]至[12]中的任一项所述的多核苷酸或上述[13]至[16]中的任一项所述的载体在制备用于治疗或预防MDC1A的药物组合物中的用途。
[21]一种用于上调细胞中人类LAMA1基因的表达的方法,所述方法包括在上述细胞中表达
(c)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,和
(d)靶向人类LAMA1的表达调控区中的下述连续区域的指导RNA:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[22]一种核糖核蛋白,其包含:
(c)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,和
(d)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA:(i)在SEQ IDNO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[23]一种用于上调人类LAMA1基因的表达的试剂盒,其包含:
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[24]一种用于治疗或预防MDC1A的方法,所述方法包括给药下述(e)和(f):
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[25]下述(e)和(f)在制备用于治疗或预防MDC1A的药物组合物中的用途:
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
[有利效果]
根据本发明,可以上调人类LAMA1基因的表达,作为其结果,预期本发明能够治疗MDC1A。
附图说明
[图1]图1示出了人类LAMA1基因中被靶向的基因组区域的位置。
[图2]图2示出了在源自于3号供体的原代骨骼肌成肌细胞(HSMM细胞)中,使用含有由SEQ ID NO:1至16中示出的靶向序列编码的crRNA的sgRNA和mini-VR,对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了含有由每种靶向序列编码的crRNA的sgRNA,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图3]图3示出了在源自于5号供体的原代HSMM细胞中,使用含有由SEQ ID NO:1至16中示出的靶向序列编码的crRNA的sgRNA和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了含有由每种靶向序列编码的crRNA的sgRNA,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图4]图4示出了在源自于3号供体的原代HSMM细胞中,使用含有由SEQ ID NO:10、11、15、17-61中示出的靶向序列编码的crRNA的sgRNA和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了含有由每种靶向序列编码的crRNA的sgRNA,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图5]图5示出了在源自于3号供体的原代HSMM细胞中,使用含有由位于R1和R2区中的靶向序列编码的crRNA的sgRNA和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了含有由每种靶向序列编码的crRNA的sgRNA,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图6]图6示出了在原代HSMM细胞(源自于3号、121号、368号、617号供体)中,使用含有由SEQ ID NO:130-221中示出的靶向序列编码的crRNA的sgRNA和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了含有由每种靶向序列编码的crRNA的sgRNA,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图7A]图7A示出了在原代HSMM细胞(源自于3号、121号供体)中,使用含有由SEQID NO:178、193或195中示出的靶向序列编码的crRNA的sgRNA(sgLAMA1-155、sgLAMA1-170、sgLAMA-172)和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了每种条件,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。实验被重复三次,并且示出了平均值和SD。
[图7B]图7B示出了在原代HSMM细胞(源自于368号、617号供体)中,使用含有由SEQID NO:178、193或195中示出的靶向序列编码的crRNA的sgRNA(sgLAMA1-155、sgLAMA1-170、sgLAMA-172)和mini-VR对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了每种条件,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。实验被重复三次,并且示出了平均值和SD。
[图8]图8示出了在原代HSMM细胞(源自于3号、121号、368号、617号供体)中对人类LAMA1基因的表达水平的评估结果。水平轴示出了供体号,竖直轴示出了在使用HPRT对照时的表达水平。
[图9]图9示出了在原代HSMM细胞(源自于3号供体)中,使用含有由SEQ ID NO:178、193或195中示出的靶向序列编码的crRNA的sgRNA(sgLAMA1-155、sgLAMA1-170、sgLAMA-172)和各种不同的激活组成部分对人类LAMA1基因的表达增强作用的评估结果。水平轴示出了每种条件,并且竖直轴示出了在使用每种sgRNA时LAMA1基因的表达水平与使用对照sgRNA时为1的表达水平的比率。
[图10]图10示出了在原代HSMM细胞(源自于3号、617号供体)中,使用含有由SEQID NO:178、193或195中示出的靶向序列编码的crRNA的sgRNA和microVR对人类LAMA1基因在蛋白质水平上的表达增强作用的评估结果。
具体实施方式
在下文中详细解释本发明的实施方式。
1.多核苷酸
本发明提供了一种包含下述碱基序列的多核苷酸(在后文中有时也被称为“本发明的多核苷酸”):
(a)编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列,和
(b)编码靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA的碱基序列:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,
(ii)在SEQ ID NO:124中阐述的连续区域,或
(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
本发明的多核苷酸被引入到所需细胞中并转录,以产生核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白和靶向人类LAMA1基因的表达调控区的特定区域的指导RNA。这些融合蛋白和指导RNA形成复合体(在后文中所述复合体有时被称为“核糖核蛋白;RNP”)并协同作用于上述特定区域,从而激活人类LAMA1基因的转录。
(1)定义
在本说明书中,“人类层粘连蛋白-α1链(LAMA1)基因的表达调控区”意味着可以通过与RNP结合而激活人类LAMA1基因的表达的任何区域。也就是说,所述人类LAMA1基因的表达调控区可以存在于人类LAMA1基因的任何区域例如启动子区、增强子区、内含子和外显子中,只要人类LAMA1基因的表达被RNP的结合所激活即可。在本说明书中,当表达调控区用特定序列示出时,所述表达调控区在概念上包括正义链序列和反义链序列两者。
在本发明中,核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白被指导RNA召集到所述人类LAMA1基因的表达调控区中的特定区域中。在本说明书中,“靶向……的指导RNA”意味着“将融合蛋白召集到……中的指导RNA”。
在本说明书中,“指导RNA(也被称为“gRNA”)”是包含基因组特异性CRISPR-RNA(也被称为“crRNA”)的RNA。crRNA是与靶向序列(在后文描述)的互补序列结合的RNA。当使用Cpf1作为CRISPR效应蛋白时,“指导RNA”是指包含由crRNA和附连到其5’-端的特定序列的RNA(例如在FnCpf 1的情况下,SEQ ID NO:65中阐述的RNA序列)构成的RNA。当使用Cas9作为CRISPR效应蛋白时,“指导RNA”是指包含crRNA和附连到其3’-端的反式激活crRNA(被称为“tracrRNA”)的嵌合RNA(也被称为“单一指导RNA(sgRNA)”)(参见例如Zhang F.等,HumMol Genet.2014年9月15日;23(R1):R40-6和Zetsche B.等,Cell.2015年10月22日;163(3):759-71,其整体通过参考并入本文)。
在本说明书中,与所述人类LAMA1基因的表达调控区中crRNA所结合的序列互补的序列被称为“靶向序列”。也就是说,在本说明书中,“靶向序列”是存在于人类LAMA1基因的表达调控区中并与PAM(前间区序列邻近基序)相邻的DNA序列。当使用Cpf1作为CRISPR效应蛋白时,PAM与所述靶向序列的5’-侧相邻。当使用Cas9作为CRISPR效应蛋白时,PAM与所述靶向序列的3’-侧相邻。所述靶向序列可以存在于所述人类LAMA1基因的表达调控区的正义链序列侧或反义链序列侧上(参见例如上述Zhang F.等,Hum Mol Genet.2014年9月15日;23(R1):R40-6和Zetsche B.等,Cell.2015年10月22日;163(3):759-71,其整体通过参考并入本文)。
(2)核酸酶缺陷型CRISPR效应蛋白
在本发明中,使用核酸酶缺陷型CRISPR效应蛋白,与其融合的转录激活因子被召集到所述人类LAMA1基因的表达调控区。在本发明中使用的核酸酶缺陷型CRISPR效应蛋白(在后文中被简称为“CRISPR效应蛋白”)没有特别限制,只要它与gRNA形成复合体并被召集到所述人类LAMA1基因的表达调控区即可。例如,可以包括核酸酶缺陷型Cas9(在后文中有时也被称为“dCas9”)或核酸酶缺陷型Cpf1(在后文中有时也被称为“dCpf1”)。
上述dCas9的实例包括但不限于化脓性链球菌(Streptococcus pyogenes)来源的Cas9(SpCas9;PAM序列:NGG(N是A、G、T或C,后文中同样如此))、嗜热链球菌(Streptococcusthermophilus)来源的Cas9(StCas9;PAM序列:NNAGAAW(W是A或T,后文中同样如此))、脑膜炎奈瑟氏菌(Neisseria meningitidis)来源的Cas9(NmCas9;PAM序列:NNNNGATT)或金黄色葡萄球菌(Staphylococcus aureus)来源的Cas9(SaCas9;PAM序列:NNGRRT(R是A或G,后文中同样如此))等的核酸酶缺陷型变体(参见例如Nishimasu等,Cell.2014年2月27日;156(5):935-49;Esvelt KM等,Nat Methods.2013年11月;10(11):1116-21;Zhang Y.MolCell.2015年10月15日;60(2):242-55和Friedland AE等,Genome Biol.2015年11月24日;16:257,其整体通过参考并入本文)。例如,在SpCas9的情况下,可以使用其中第10位Asp残基被转变成Ala残基并且第840位His残基被转变成Ala残基的双重突变体(有时被称为“dSpCas9”)(参见例如上述Nishimasu等,Cell.2014)。或者,在SaCas9的情况下,可以使用其中第10位Asp残基被转变成Ala残基并且第580位Asn残基被转变成Ala残基的双重突变体(SEQ ID NO:66)或其中第10位Asp残基被转变成Ala残基并且第557位His残基被转变成Ala残基的双重突变体(SEQ ID NO:67)(在后文中任何这些双重突变体有时被称为“dSaCas9”)(参见例如上述Friedland AE等,Genome Biol.2015,其整体通过参考并入本文)。
此外,在本发明的一个实施方式中,也可以使用通过将上述与gRNA形成复合体并被召集到人类LAMA1基因的表达调控区的dCas9的一部分氨基酸进行修饰而获得的变体作为dCas9。此类变体的实例包括具有部分缺失的氨基酸序列的截短变体。在本发明的一个实施方式中,可以使用在整体通过参考并入本文的美国临时专利申请号62/682,244和62/749,855中公开的变体作为dCas9。具体来说,也可以使用通过从作为其中第10位Asp残基被转变成Ala残基并且第580位Asn残基被转变成Ala残基的双重突变体的dSaCas9中缺失第721位至第745位氨基酸而获得的dSaCas9(SEQ ID NO:68),或其中所述缺失的部分被肽连接物替换的dSaCas9(例如其中所述缺失的部分被GGSGGS连接物(SEQ ID NO:69)替换的dSaCas9被阐述在SEQ ID NO:70中),或通过缺失作为上述双重突变体的dSaCas9的第482位至第648位氨基酸而获得的dSaCas9(SEQ ID NO:71),或其中所述缺失的部分被肽连接物替换的dSaCas9(例如其中所述缺失的部分被GGSGGS连接物替换的dSaCas9被阐述在SEQ IDNO:72中)。
上述dCpf1的实例包括但不限于新凶手弗朗西斯菌(Francisella novicida)来源的Cpf1(FnCpf1;PAM序列:NTT)、氨基酸球菌(Acidaminococcus sp.)来源的Cpf1(AsCpf1;PAM序列:NTTT)或毛螺菌科(Lachnospiraceae)细菌来源的Cpf1(LbCpf1;PAM序列:NTTT)等的核酸酶缺陷型变体(参见例如Zetsche B.等,Cell.2015年10月22日;163(3):759-71;Yamano T等,Cell.2016年5月5日;165(4):949-62和Yamano T等,Mol Cell.2017年8月17日;67(4):633-45,其整体通过参考并入本文)。例如,在FnCpf1的情况下,可以使用其中第917位Asp残基被转变成Ala残基并且第1006位Glu残基被转变成Ala残基的双重突变体(参见例如上述Zetsche B等,Cell.2015,其整体通过参考并入本文)。在本发明的一个实施方式中,也可以使用通过将上述与gRNA形成复合体并被召集到人类LAMA1基因的表达调控区的dCpf1的一部分氨基酸进行修饰而获得的变体作为dCpf1。
在本发明的一个实施方式中,dCas9被用作CRISPR效应蛋白,并且在特定实施方式中,使用dSaCas9。
包含编码CRISPR效应蛋白的碱基序列的多核苷酸可以通过例如下述步骤来克隆:在cDNA序列信息的基础上合成覆盖编码蛋白质的所需部分的区域的寡聚DNA引物,并使用从产生所述蛋白质的细胞制备的总RNA或mRNA级分作为模板,通过PCR方法扩增所述多核苷酸。此外,包含编码CRISPR效应蛋白的碱基序列的多核苷酸可以通过下述步骤获得:通过已知的定点突变方法在编码被克隆的CRISPR效应蛋白的核苷酸序列中引入突变,以将对DNA切割活性来说重要的位点处的氨基酸残基(例如可以包括但不限于:在SaCas9的情况下第10位的Asp残基、第557位的His残基和第580位的Asn残基;在FnCpf1的情况下第917位的Asp残基和第1006位的Glu残基)转变成其他氨基酸。
或者,包含编码CRISPR效应蛋白的碱基序列的多核苷酸可以在cDNA序列信息的基础上,通过化学合成或化学合成与PCR方法或Gibson组装方法的组合来获得,并且也可以被进一步构建成经历密码子优化以提供适合于在人类中表达的密码子的碱基序列。
(3)转录激活因子
在本发明中,人类LAMA1基因表达被与所述CRISPR效应蛋白融合的转录激活因子的作用激活。在本说明书中,“转录激活因子”意味着具有激活人类LAMA1基因或其保留了功能的肽片段的基因转录的能力的蛋白质。在本发明中使用的转录激活因子没有特别限制,只要它可以激活人类LAMA1基因的表达即可。例如,它包括VP64、VP160、VPH、VPR、miniVR和microVR、其具有转录激活能力的变体等。VP64用SEQ ID NO:73中阐述的由50个氨基酸组成的肽示例。VP160用SEQ ID NO:84中阐述的由131个氨基酸组成的肽示例。VPH是VP64、p65和HSF1的融合蛋白,具体来说用SEQ ID NO:74中阐述的由376个氨基酸组成的肽示例。VPR是VP64、p65和Epstein-Barr病毒的复制和转录激活因子(RTA)的融合蛋白,具体来说用SEQID NO:75中阐述的由523个氨基酸组成的肽示例。VP64、VPH和VPR是已知的,并详细公开在例如整体通过参考并入本文的Chavez A.等,Nat Methods.2016年7月;13(7):563-7和Chavez A.等,Nat Methods.2015年4月;12(4):326-8中。MiniVR和microVR是包含VP64和RTA的转录激活结构域的肽。RTA的转录激活结构域是已知的,并公开在例如整体通过参考并入本文的J Virol.1992年9月;66(9):5500-8等中。具体来说,miniVR用SEQ ID NO:76中阐述的由167个氨基酸组成的肽示例,而microVR用SEQ ID NO:77中阐述的由140个氨基酸组成的肽示例。SEQ ID NO:76中阐述的氨基酸序列由其中使用G-S-G-S连接物(SEQ ID NO:78)将RTA的第493-605位的氨基酸残基与VP64相连的氨基酸序列构成。SEQ ID NO:77中阐述的氨基酸序列由其中使用G-S-G-S连接物将RTA的第520-605位的氨基酸残基与VP64相连的氨基酸序列构成。miniVR和microVR的详细情况描述在整体通过参考并入本文的美国临时专利申请号62/715,432中。上述转录激活因子中的任一者可以经历任何修饰和/或改变,只要它维持其转录激活能力即可。
包含编码转录激活因子的碱基序列的多核苷酸可以通过化学合成或化学合成与PCR方法或Gibson组装方法的组合来构建。此外,包含编码转录激活因子的碱基序列的多核苷酸也可以被构建成密码子优化的DNA序列,其具有适合于在人类中表达的密码子。
包含编码转录激活因子与CRISPR效应蛋白的融合蛋白的碱基序列的多核苷酸可以如下制备:将编码CRISPR效应蛋白的碱基序列直接地或在添加编码连接物、NLS(核定位信号)和/或标签的碱基序列后,连接到编码转录激活因子的碱基序列。在本发明中,所述转录激活因子可以与N-端或C-端融合。作为连接物,可以使用具有约2至50的氨基酸数目的连接物,其具体实例包括但不限于其中甘氨酸(G)和丝氨酸(S)被交替连接的G-S-G-S连接物等。
(4)指导RNA
在本发明中,CRISPR效应蛋白与转录激活因子的融合蛋白可以被指导RNA召集到所述人类LAMA1基因的表达调控区。正如在上述“(1)定义”中所描述的,指导RNA包含crRNA,并且所述crRNA与所述靶向序列的互补序列结合。crRNA可以不与所述靶向序列的互补序列完全互补,只要所述指导RNA可以将所述融合蛋白召集到所述靶区域即可,并且可以是其中缺失、替换、插入和/或添加了至少1至3个碱基的序列。
例如,当使用dCas9作为CRISPR效应蛋白时,所述靶向序列可以使用已发表的gRNA设计网站(CRISPR设计工具、CRISPR direct等)来确定。具体来说,从所述目标基因(即人类LAMA1基因)的序列,列出PAM(例如在SaCas9的情况下是NNGRRT)与其3’-侧相邻的长度为约20个核苷酸的候选靶向序列,并且可以使用这些候选靶向序列中在人类基因组中具有少量脱靶位点的序列作为靶向序列。所述靶向序列的碱基长度为18至24个核苷酸长,优选为20至23个核苷酸长,更优选为21至23个核苷酸长。作为用于预测脱靶位点数目的初筛,大量生物信息学工具是已知且可公开获得的,并且可用于预测具有最低脱靶效应的靶向序列。其实例包括生物信息学工具例如Benchling(https://benchling.com)和COSMID(具有错配、插入和缺失的CRISPR脱靶位点)(可以在因特网上的https://crispr.bme.gatech.edu网站获得)。使用这些工具,可以总结出与被gRNA靶向的碱基序列的相似性。当使用的gRNA设计软件不具有搜索靶基因组的脱靶位点的功能时,所述脱靶位点可以例如通过针对所述候选靶向序列3’-侧上的8至12个核苷酸(具有被靶向的核苷酸序列的高度分辨能力的种子序列)对靶基因组进行Blast搜索来搜索。
在本发明的一个实施方式中,在人类18号染色体(Chr 18)的GRCh38.p13位置中存在的区域中,下述区域可以是人类LAMA1基因的表达调控区。通过组蛋白修饰模式,强烈地建议该区域是表达调控区。因此,在本发明的一个实施方式中,所述靶向序列可以是人类18号染色体(Chr 18)的GRCh38.p13位置中存在的下述区域中的至少一个区域中的18至24个核苷酸长、优选地20至23个核苷酸长、更优选地21至23个核苷酸长的序列:
(1)7,115,000-7,118,000。
在本发明的一个实施方式中,所述靶向序列可以是SEQ ID NO:15、20、25、50、56或61中阐述的碱基序列。
在本发明的一个实施方式中,所述靶向序列可以是人类18号染色体(Chr 18)的GRCh38.p13位置中存在的下述区域中的至少一个区域中的18至24个核苷酸长、优选地20至23个核苷酸长、更优选地21至23个核苷酸长的序列:
(2)7,036,000-7,042,000;
(3)7,083,000-7,087,000。
在本发明的一个实施方式中,所述靶向序列可以是SEQ ID NO:124中阐述的碱基序列。
在本发明的一个实施方式中,所述靶向序列可以是人类18号染色体(Chr 18)的GRCh38.p13位置中存在的下述区域中的至少一个区域中的18至24个核苷酸长、优选地20至23个核苷酸长、更优选地21至23个核苷酸长的序列:
(4)7,118,000-7,133,000。
在本发明的一个实施方式中,所述靶向序列可以是SEQ ID NO:178、193或195中阐述的碱基序列。在本发明的一个实施方式中,编码crRNA的碱基序列可以是与所述靶向序列相同的碱基序列。例如,当SEQ ID NO:15中阐述的靶向序列(TCTCGCCTCCGCCGCCACTCG)作为编码crRNA的碱基序列被引入到细胞中时,从所述序列转录的crRNA是UCUCGCCUCCGCCGCCACUCG(SEQ ID NO:79),并与CGAGTGGCGGCGGAGGCGAGA(SEQ ID NO:80)结合,后者是与SEQ ID NO:15中阐述的碱基序列互补的序列并存在于所述人类LAMA1基因的表达调控区中。在另一个实施方式中,可以使用作为其中缺失、替换、插入和/或添加了至少1至3个碱基的靶向序列的碱基序列作为编码crRNA的碱基序列,只要指导RNA可以将融合蛋白召集到所述靶区域即可。因此,在本发明的一个实施方式中,作为编码crRNA的碱基序列,可以使用SEQ ID NO:15、20、25、50、56或61中阐述的碱基序列或其中缺失、替换、插入和/或添加了1至3个碱基的此类序列。在本发明的另一个实施方式中,作为编码crRNA的碱基序列,可以使用SEQ ID NO:124中阐述的碱基序列或其中缺失、替换、插入和/或添加了1至3个碱基的此类序列。在本发明的另一个实施方式中,作为编码crRNA的碱基序列,可以使用SEQID NO:178、193或195中阐述的碱基序列或其中缺失、替换、插入和/或添加了1至3个碱基的此类序列。
当使用dCpf1作为CRISPR效应蛋白时,编码gRNA的碱基序列可以被设计成编码在5’-端附连有特定RNA的crRNA的DNA序列。附连到crRNA的5’-端的RNA和编码所述RNA的DNA序列可以由本领域普通技术人员根据待使用的dCpf1适合地选择。例如,当使用dFnCpf1时,可以使用其中SEQ ID NO:81:AATTTCTACTGTTGTAGAT被附连到所述靶向序列的5’-侧的碱基序列作为编码gRNA的碱基序列(当转录成RNA时,下划线部分的序列形成碱基对以形成茎环结构)。所述待添加到5’-端的序列可以是其中缺失、替换、插入和/或添加了至少1至6个碱基的常用于各种不同Cpf1蛋白的序列,只要gRNA在转录后可以将融合蛋白召集到所述表达调控区即可。
当使用dCas9作为CRISPR效应蛋白时,编码gRNA的碱基序列可以被设计成其中编码已知tracrRNA的DNA序列被连接到编码crRNA的DNA序列的3’-端的DNA序列。此类tracrRNA和编码所述tracrRNA的DNA序列可以由本领域普通技术人员根据待使用的dCas9适合地选择。例如,当使用dSaCas9时,使用在SEQ ID NO:82中阐述的碱基序列作为编码tracrRNA的DNA序列。所述编码tracrRNA的DNA序列可以是其中缺失、替换、插入和/或添加了至少1至6个碱基的常用于各种不同Cas9蛋白的编码tracrRNA的碱基序列,只要gRNA在转录后可以将融合蛋白召集到所述表达调控区即可。
包含编码以这种方式设计的gRNA的碱基序列的多核苷酸,可以使用已知的DNA合成方法化学合成。
在本发明的另一个实施方式中,本发明的多核苷酸可以包含两种或更多种具有不同crRNA的gRNA。
(5)启动子序列
在本发明的一个实施方式中,启动子序列可以被可操作连接到编码CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列和/或编码gRNA的碱基序列中的每一者的上游。可能连接的启动子没有特别限制,只要它在靶细胞中显示出启动子活性即可。可能连接到所述编码融合蛋白的碱基序列上游的启动子序列的实例包括但不限于EFS启动子、CMV(巨细胞病毒)启动子、CK8启动子、MHC启动子、MYOD启动子、hTERT启动子、SRα启动子、SV40启动子、LTR启动子、CAG启动子、RSV(劳斯肉瘤病毒)启动子等。可能连接到所述编码gRNA的碱基序列上游的启动子序列的实例包括但不限于作为pol III启动子的U6启动子、SNR6启动子、SNR52启动子、SCR1启动子、RPR1启动子、U3启动子、H1启动子和tRNA启动子等。在本发明的一个实施方式中,可以使用肌肉特异性启动子作为连接到编码上述融合蛋白的碱基序列上游的启动子序列。所述肌肉特异性启动子的实例包括但不限于CK8启动子、CK6启动子、CK1启动子、CK7启动子、CK9启动子、心肌肌钙蛋白C启动子、α-肌动蛋白启动子、肌球蛋白重链激酶(MHCK)启动子、肌球蛋白轻链2A启动子、肌营养不良蛋白启动子、肌肉肌酸激酶启动子、dMCK启动子、tMCK启动子、enh348 MCK启动子、合成C5-12(Syn)启动子、unc45b启动子、Myf5启动子、MLC1/3f启动子、MYOD启动子、Myog启动子、Pax7启动子等(肌肉特异性启动子的详细情况参见例如整体通过参考并入本文的US2011/0212529A;McCarthy JJ等,Skeletal Muscle.2012年5月;2(1):8;Wang B.等,Gene Ther.2008年11月;15(22):1489-99等)。
(6)其他碱基序列
此外,除了上面提到的序列之外,本发明的多核苷酸还可以包含已知的序列例如多腺苷化信号、Kozak共有序列等,用于提高由编码CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列转录而产生的mRNA的翻译效率的目的。此外,本发明的多核苷酸可以包含编码连接物序列的碱基序列、编码NLS的碱基序列和/或编码标签的碱基序列。
2.载体
本发明提供了包含本发明的多核苷酸的载体(在后文中有时被称为“本发明的载体”)。本发明的载体可以是质粒载体或病毒载体。
当本发明的载体是质粒载体时,所使用的质粒载体没有特别限制,并且可以是任何质粒载体例如克隆质粒载体和表达质粒载体。所述质粒载体通过用已知方法将本发明的多核苷酸插入到质粒载体中来制备。
当本发明的载体是病毒载体时,所使用的病毒载体没有特别限制,其实例包括但不限于腺病毒载体、腺相关病毒(AAV)载体、慢病毒载体、反转录病毒载体、仙台病毒载体等。在本说明书中,“病毒载体”还包括其衍生物。考虑到在基因疗法中的使用,优选地使用AAV载体,因为它可以长时间表达转入基因,并且它源自于非致病性病毒且具有高安全性。
包含本发明的多核苷酸的病毒载体可以通过已知方法来制备。简单来说,制备其中插入有本发明的多核苷酸的用于病毒表达的质粒载体,将所述载体转染到适合的宿主细胞中以允许包含本发明的多核苷酸的表达载体的瞬时生产,并收集所述病毒载体。
在本发明的一个实施方式中,在使用AAV载体时,所述AAV载体的血清型没有特别限制,只要可以激活靶细胞中人类LAMA1基因的表达即可,并且可以使用AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10及其变体等中的任一者(对于AAV的各种不同血清型,参见例如整体通过参考并入本文的WO 2005/033321)。AAV的变体的实例包括但不限于具有修饰的衣壳的新血清型(例如整体通过参考并入本文的WO 2012/057363)等。
在制备AAV载体的一个实例中,首先制备载体质粒,其包含在野生型AAV基因组序列的两端处的反向末端重复序列(ITR)和插入的本发明的多核苷酸以代替编码Rep蛋白和衣壳蛋白的DNA。另一方面,形成病毒粒子所必需的编码Rep蛋白和衣壳蛋白的DNA被插入到其他质粒中。此外,作为腺病毒辅助质粒,制备包含负责AAV增殖所必需的腺病毒辅助作用的基因(E1A、E1B、E2A、VA和E4orf6)的质粒。将这三种质粒共转染到宿主细胞中导致在所述细胞中产生重组AAV(即AAV载体)。作为宿主细胞,优选地使用能够供应负责上述辅助作用的基因的一部分基因产物(蛋白质)的细胞(例如293细胞等)。当使用此类细胞时,在上述腺病毒辅助质粒中不必携带编码可以从所述宿主细胞供应的蛋白质的基因。产生的AAV载体存在于细胞核中。因此,通过使用冻融来破坏所述宿主细胞,收集病毒,并通过使用氯化铯的密度梯度超速离心方法、柱方法等对所述病毒级分进行分离和纯化,来制备所需的AAV载体。
AAV载体在安全性、基因转导效率等方面具有极大优势,并被用于基因疗法中。然而,已知可以被包装的多核苷酸的大小有限。例如,包括作为本发明的一个实施方式的包含编码dSaCas9与miniVR或microVR的融合蛋白的碱基序列、编码靶向人类LAMA1基因的表达调控区的gRNA的碱基序列和作为启动子序列的EFS启动子序列和U6启动子序列的多核苷酸的碱基长度和ITR部分在内的总长度约为4.85kb,并且它们可以被包装在单一AAV载体中。
3.用于治疗或预防MDC1A的药剂
本发明还提供了一种包含本发明的多核苷酸或本发明的载体的用于治疗或预防MDC1A的药剂(在后文中有时被称为“本发明的药剂”)。
本发明的药剂包含本发明的多核苷酸或本发明的载体作为活性成分,并且可以被制备成包含此类活性成分(即本发明的多核苷酸或本发明的载体)并通常包含可药用载体的制剂。
本发明的药剂被肠胃外给药,并且可以局部或系统性给药。本发明的药剂可以通过例如但不限于静脉内给药、动脉内给药、皮下给药、腹膜内给药或肌肉内给药来给药。
给药到对象的本发明的药剂的剂量没有特别限制,只要它是治疗和/或预防的有效量即可。它可以根据活性成分、剂型、对象的年龄和体重、给药时间表、给药方法等适合地优化。
在本发明的一个实施方式中,本发明的药剂不仅可以给药到患有MDC1A的对象,而且可以预防性给药到根据遗传背景分析等在将来可能发生MDC1A的对象。在本说明书中,除了疾病的治愈之外,术语“治疗”还包括疾病的缓解。此外,除了预防疾病的发作之外,术语“预防”还可以包括延迟疾病的发作。本发明的药剂也可以被称为“本发明的药物组合物”等。
4.治疗或预防MDC1A的方法
本发明还提供了一种用于治疗或预防MDC1A的方法,所述方法包括向需要的对象给药本发明的多核苷酸或本发明的载体(在后文中有时被称为“本发明的方法”)。此外,本发明包括本发明的多核苷酸或本发明的载体,其用于治疗或预防MDC1A。此外,本发明包括本发明的多核苷酸或本发明的载体在制备用于治疗或预防MDC1A的药物组合物中的用途。
本发明的方法可以通过向患有MDC1A的对象给药上述本发明的药剂来实践,并且剂量、给药途径、对象等与上文描述的相同。
症状的测量可以在使用本发明的方法的治疗开始之前和所述治疗之后的任何时间进行,以确定所述对象对所述治疗的反应。
本发明的方法可以改善所述对象的骨骼肌和/或心肌的功能。功能待改善的肌肉没有特别限制,实例是任何肌肉或肌肉群。
5.核糖核蛋白
本发明提供了一种包含下述组分的核糖核蛋白(在后文中有时被称为“本发明的RNP”):
(c)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,和
(d)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域;
(ii)在SEQ ID NO:124中阐述的连续区域;或
(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
作为包含在本发明的RNP中的CRISPR效应蛋白、转录激活因子和指导RNA,可以使用在上述“1.多核苷酸”章节中详细解释的CRISPR效应蛋白、转录激活因子和指导RNA。包含在本发明的RNP中的CRISPR效应蛋白与转录激活因子的融合蛋白可以通过例如将编码所述融合蛋白的多核苷酸引入到细胞、细菌或其他生物体中以允许表达,或通过使用所述多核苷酸的体外翻译系统来生产。此外,包含在本发明的RNP中的指导RNA可以通过例如化学合成或通过使用编码所述指导RNA的多核苷酸的体外转录系统来生产。将由此制备的CRISPR效应蛋白与指导RNA混合,以制备本发明的RNP。在必要时,可以混合其他物质例如金粒子。为了将本发明的RNP直接递送到靶细胞、组织等,可以通过已知方法将所述RNP包封在脂质纳米粒子(LNP)中。本发明的RNP可以通过已知方法引入到所述靶细胞、组织等中。例如,对于在LNP中的包封和引入方法,可以参考整体通过参考并入本文的Lee K.等,Nat BiomedEng.2017;1:889-901;WO 2016/153012等。
在本发明的一个实施方式中,包含在本发明的RNP中的指导RNA靶向人类18号染色体(Chr 18)的GRCh38.p13位置中存在的下述区域中的至少一个区域中长度为18至24个连续核苷酸、优选地长度为20至23个连续核苷酸、更优选地长度为21至23个连续核苷酸:
(1)7,115,000-7,118,000。
在一个实施方式中,所述指导RNA靶向包含SEQ ID NO:15、20、25、50、56或61中阐述的序列的全部或一部分的区域。
(2)7,036,000-7,042,000;
(3)7,083,000-7,087,000。
在一个实施方式中,所述指导RNA靶向包含SEQ ID NO:124中阐述的序列的全部或一部分的区域。
(4)7,118,000-7,133,000。
在一个实施方式中,所述指导RNA靶向包含SEQ ID NO:178、193或195中阐述的序列的全部或一部分的区域。
6.其他
本发明还提供了一种用于激活人类LAMA1基因的表达的组合物或试剂盒,其包含下述组分:
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域;
(ii)在SEQ ID NO:124中阐述的连续区域;或
(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
本发明还提供了一种用于治疗或预防MDC1A的方法,所述方法包括给药下述(e)和(f):
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域;
(ii)在SEQ ID NO:124中阐述的连续区域;或
(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
作为本发明中的CRISPR效应蛋白、转录激活因子、指导RNA以及编码它们的多核苷酸和其中带有它们的载体,可以使用在上述“1.多核苷酸”、“2.载体”和“5.核糖核蛋白”章节中详细解释的那些。上述(e)和(f)的剂量、给药途径、对象、制剂等,与在“3.用于治疗或预防MDC1A的药剂”章节中解释的相同。
在下面的示例性实施方式的描述过程中,本发明的其他特点将变得显而易见,提供所述描述是为了说明本发明,并且不打算限制它。
实施例
实验方法
LAMA1靶向序列的选择
基于人类骨骼肌细胞中基因组的H3K4me3、H3K27Ac模式,扫描了人类LAMA1基因的另外两个推测的基因调控区(R1和R2)中在本文中被定义为靶向序列的可以被无催化活性的SaCas9(D10A和N580A突变体;与gRNA复合的dSaCas9)靶向的序列。被靶向的基因组区域相对于LAMA1基因的位置被描绘在图1中,它们的坐标如下所示:
1. 18号染色体:GRCh38/hg38;7,036,000-7,042,000->~6kb(R1)
2. 18号染色体:GRCh38/hg38;7,083,000-7,087,000->~4kb(R2)
靶向序列由与具有序列NNGRRT的前间区序列邻近基序(PAM)相邻的21个核苷酸的区段指定(5’-21nt靶向序列-NNGRRT-3’)(表1)。
此外,我们还扫描了人类LAMA1 TSS位点上游接近15kb的区域,并且只选择与食蟹猴((Macaca fascicularis)基因组的相应区域完全匹配的靶向序列和PAM序列。被靶向的基因组区域相对于LAMA1基因的位置被描绘在图1中,它们的坐标如下所示:
18号染色体:GRCh38/hg38;7,118,000-7,133,000->~15kb(与食蟹猴匹配的)
表1用于筛选LAMA1基因的表达调控区的靶向序列
[表1-1]
[表1-2]
[表1-3]
[表1-4]
[表1-5]
[表1-6]
[表1-7]
[表1-8]
在表1中,“位置”指示在使用SaCas9时所有示出的gRNA的潜在SaCas9切割位点。
SEQ ID NO:1-61位于TSS区中,SEQ ID NO:85-113位于R1区中,SEQ ID NO:114-129位于R2区中,并且SEQ ID NO:130-221位于食蟹猴匹配区中(图1)。
慢病毒转移质粒(pED176和衍生质粒)的构建
pLentiCRISPR v2购自Genscript(https://www.genscript.com),并做出了下述修饰:将SpCas9 gRNA支架序列用SaCas9 gRNA支架序列代替;将SpCas9-FLAG用与密码子优化的VP64-miniRTA(也被称为mini-VR)融合的dSaCas9代替。VP64-miniRTA转录激活结构域在定位到启动子时可以通过激活转录来激活基因表达。VP64-miniRTA被连接到dSaCas9(D10A和N580A突变体)的C-端,其在后文中被称为dSaCas9-VR,并且被靶向序列指导而靶向人类LAMA1基因调控区(表1,图1)。产生的骨架质粒被命名为pED176。通过将mini-VR用其他激活结构域VP64-EBNA2、VP160、VP64-nanoRTA、VP64-microRTA代替,我们还产生了衍生质粒。
gRNA克隆
将三种对照非靶向性靶向序列和164种靶向序列(表1)克隆到pED176中。正向和反向寡聚物由Integrated DNA Technologies以下述格式合成:正向:5’CACC(G)-20个碱基对的靶向序列-3’,和反向:5’AAAC-19-21个碱基对的反向互补靶向序列-(C)-3’,其中如果靶不始于G,则添加括号中的碱基。将寡聚物以100μM重悬浮在Tris-EDTA缓冲液(pH 8.0)中。将1μl每种互补的寡聚物合并在NE缓冲液3.1(NEB目录号:B7203S)中的10μl反应中。将反应在热循环仪中加热至95℃并允许其冷却至25℃,由此将具有与克隆到pED176相容的粘性末端突出部的寡聚物退火。将退火的寡聚物与已用BsmBI消化并凝胶纯化的慢病毒转移质粒pED176合并,并用T4 DNA连接酶(NEB目录号:M0202S)按照制造商的方案连接。将2μl连接反应液按照制造商的方案转化到10μl NEB稳定感受态细胞(NEB目录号:C3040I)中。得到的构建物通过U6启动子驱动包含与tracrRNA(SEQ ID NO:83)融合的由各个靶向序列编码的crRNA的sgRNA的表达。
慢病毒产生
将HEK293TA细胞以0.75x106个细胞/孔的密度接种在6孔细胞培养板(VWR目录号:10062-892)中的2ml生长培养基(增补有10%FBS和2mM新鲜L-谷氨酰胺、1mM丙酮酸钠和非必需氨基酸的DMEM培养基)中,并在37℃/5%CO2下温育24小时。第二天,按照制造商的方案建立TransIT-VirusGEN转染反应,使用了1.5μg包装质粒混合物[1μg包装质粒(参见pCMVdelta R8.2;addgene#12263)和0.5μg包膜表达质粒(参见pCMV-VSV-G;addgene#8454)]和1μg含有编码dSaCas9-VR和指定sgRNA的序列的转移质粒。在转染后48小时,通过将培养基上清液通过0.45μM PES滤器(VWR目录号:10218-488)来收获慢病毒。在即将使用之前,将纯化并分装的慢病毒储存在-80℃冰箱中。
HSMM细胞的转导
来自于5位年龄为0-26岁不等的不同人类供体(分别被称为3号供体、5号供体、121号供体、368号供体、617号供体)的原代骨骼肌成肌细胞细胞(HSMM)从Lonza Inc获得。将细胞在原代骨骼肌细胞生长培养基[SkGM-2骨骼肌生长BulletKit培养基(Lonza#CC-3244和CC-3246)]中培养。为了转导,将细胞以0.125-0.33x106个细胞/孔的密度接种在含有生长培养基的6孔细胞培养板(VWR目录号:10062-894)中,并在37℃/5%CO2温育24小时。第二天,向每个孔添加1.5ml生长培养基,其增补有8μg/ml Polybrene(Sigma目录号:TR-1003-G)和1.0ml对应于包含由各个靶向序列(表1)编码的crRNA和tracrRNA的每个sgRNA的慢病毒上清液(参见上文)。将细胞与慢病毒温育6小时,然后除去病毒培养基并用新鲜生长培养基代替。在转导后72小时,将细胞用选择培养基[增补有0.5μg/ml嘌呤霉素(Sigma Aldrich目录号:P8833)的生长培养基]饲养。每2-3天向细胞提供新鲜的选择培养基。细胞在选择培养基中7-10天后,收获细胞并按照制造商的指导用RNeasy 96试剂盒(Qiagen目录号:74182)提取RNA。
基因表达分析
对于基因表达分析来说,按照大容量cDNA反转录试剂盒(Applied Biosystems;ThermoFisher目录号:4368813)的流程,在10μl体积中从~0.5-0.8μg总RNA产生cDNA。将cDNA稀释10倍,并使用Taqman Fast Advanced主混合物,按照制造商的方案进行分析。Taqman探针(LAMA1:测定Id Hs01074489_m1 FAM;HPRT:测定Id Hs99999909_m1 VIC_PL)从Life Technologies获得。基于Taqman探针的实时PCR反应按照Taqman Fast Advanced主混合物方案的指导,通过QuantStudio 5实时PCR系统进行处理和分析。
在嘌呤霉素选择下7天后,按照制造商的指导使用QIAGEN Allprep蛋白质/RNA试剂盒(Qiagen#80404)从转导的HSMM细胞提取总蛋白,然后定量并归一化到1μg/μL的终浓度。将20μg每种蛋白质溶液在NuPAGE Tris-乙酸盐3-8%微型凝胶(FisherSci EA0375BOX)上分离,然后在35V和4C下转移70分钟到PVDF膜(Bio-Rad)上。然后将膜在RT下在SuperBlock T20(PBS)阻断缓冲液(LifeTech 37516)中温育1hr,以阻断非特异性相互作用位点。然后将膜在4℃下与抗LAMA1抗体(1:100)(Santa Cruz Bio sc-74417)或抗b-肌动蛋白抗体(1:10000)(LifeTech MA1-140)温育过夜。将膜在清洗缓冲液(1XTBS和0.05%吐温20)中清洗3次,每次晃动10min,以除去过量的或非特异性结合后松散结合的抗体。将在阻断溶液中1:10,000稀释的与辣根过氧化物酶(HRP;LifeTech)偶联的山羊抗小鼠免疫球蛋白抗体在RT下在膜上温育1hr,伴随晃动。进行另外一系列的三次清洗,然后将膜在SuperSignal West Femto极高灵敏度底物(LifeTech 34094)中浸泡1min。结果通过AzureC400可视化。
数据分析
对于每个样品和三个对照来说,通过从HPRT探针的3个技术平行样的平均Ct值中减去LAMA1探针的平均Ct值(平均Ct LAMA1-平均Ct HPRT),计算出ΔCt值。使用公式2-(ΔCt)确定每个样品的表达值。然后将每个实验的样品表达值归一化到3个对照表达值的平均值,以确定每个样品的相对LAMA1表达。
结果
LAMA1基因表达被dSaCas9-VR:sgRNA的激活
产生了将用于VP64-miniRTA和用于每个靶向序列的sgRNA的表达盒递送到原代HSMM细胞的慢病毒。选择对嘌呤霉素具有抗性的转导的细胞,并使用Taqman测定法对LAMA1表达进行定量。将来自于每个样品的表达值归一化到用对照sgRNA转导的细胞中LAMA1表达的平均值。
如图2中所示,在16个测试的序列中,3个靶向序列在3号供体HSMM细胞中显示出LAMA1 mRNA表达的~5-7倍的上调(图2),同样的3个序列在5号供体细胞中显示出~11-16倍的上调(图3)。
在从使用16种sgRNA(SEQ ID No.1-16)的第一次筛选中观察到有希望的上调结果后,我们继续设计并筛选了同一区域中的另外45种sgRNA(SEQ ID No.17-61),并鉴定到效能几乎为sgRNA 15的两倍的新的高效sgRNA,例如sgRNA 25和sgRNA 50(图4)。
如图5中所示,在R1和R2中的40个测试的序列中,只有gRNA#101在3号供体HSMM细胞中显示出LAMA1 mRNA表达的超过3倍的上调。
如图6中所示,在位于LAMA1 TSS上游的92个测试的指导序列中,少数的这些指导序列能够将LAMA1表达水平上调到2倍或更高。三个最有效的指导序列即gRNA#155、gRNA#170和gRNA#172,被包括在下述使用4种不同来源的原代HSMM细胞测试的验证实验中,每种处理条件包括三个生物学平行样:1.无病毒转导的;2.仅转导dSaCas9-VR,不转导sgRNA的;3.非靶向性sgRNA和dSaCas9-VR一起转导的;4.gRNA#155和dSaCas9-VR一起转导的;5.gRNA#170和dSaCas9-VR一起转导的;6.gRNA#172和dSaCas9-VR一起转导的。如图7中所示,在所有4种不同来源的原代HSMM细胞中,所有三种sgRNA都能一致地将LAMA1表达水平上调到更高水平(至少3.5倍)。并且我们在不同HSMM来源之间观察到可变的上调效能(例如在121号供体中~3.5倍,相比于在368号供体中>35倍),这可能是由LAMA1的不同基础表达水平造成的(图8)。
接下来,我们继续测试这些sgRNA是否可以使用不同的激活组成部分来上调LAMA1水平。如图9中所示,VP160、nanoVR、microVR和miniVR都能将LAMA1表达上调超过3倍,VP64-MyoD能够将LAMA1表达上调2倍左右。同时,为了检查LAMA1 mRNA水平的上调是否能够转变成蛋白质水平升高,我们从使用microVR的样品提取了总蛋白并进行了western印迹测定。如图10中所示,在两个独立的HSMM细胞来源中,所有三种sgRNA都能将LAMA1蛋白质水平提高至少1.7倍。
上述所有专利和其他参考文献均通过该参考文献整个并入本文,如同详细阐述一样。
[工业实用性]
根据本发明,源自于MDC1A患者的肌细胞中LAMA1基因的表达可以被上调。因此,预期本发明对MDC1A的治疗和/或预防极为有用。
本申请是基于均在美国提交的美国临时专利申请号62/887,863(提交日期:2019年8月16日)和美国临时专利申请号63/008,059(提交日期:2020年4月10日),所述临时申请的内容整个并入本文。
序列表
<110> 摩大力斯医疗株式会社(Modalis Therapeutics Corporation)
<120> 通过靶向LAMA1基因来治疗肌营养不良症的方法
<130> 093060
<150> US62/887,863
<151> 2019-08-16
<150> US63/008,059
<151> 2020-04-10
<160> 221
<170> PatentIn version 3.5
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<212> DNA
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tctccgggct gcaggcagga g 21
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<212> DNA
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<212> DNA
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<210> 17
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<212> DNA
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<212> DNA
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<210> 19
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<212> DNA
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<210> 20
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<212> DNA
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<210> 21
<211> 21
<212> DNA
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<210> 22
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<212> DNA
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accttcagca gcctgataga c 21
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<212> DNA
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<210> 24
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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<210> 25
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<212> DNA
<213> 智人(Homo sapiens)
<400> 25
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<210> 26
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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<212> DNA
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gcttccatca tgaatgcttg a 21
<210> 28
<211> 21
<212> DNA
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aacgtgtgtt tgggcattgt g 21
<210> 29
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<212> DNA
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<210> 30
<211> 21
<212> DNA
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<210> 31
<211> 21
<212> DNA
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<210> 32
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<212> DNA
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<210> 33
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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tctaggggtg gcgtgggtga c 21
<210> 34
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<212> DNA
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<210> 35
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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<212> DNA
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caaacccgct cattcactgc g 21
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<212> DNA
<213> 智人(Homo sapiens)
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tcaatcccgc gcagtgaatg a 21
<210> 38
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<212> DNA
<213> 智人(Homo sapiens)
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ttcgcctatt gcacaaaaag c 21
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<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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gcttggctgc caggggcccc g 21
<210> 40
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 40
ggtcgcggcg gccgggaaag g 21
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<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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ctcattgtcc ggctgcgcaa g 21
<210> 42
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<212> DNA
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atgaatggag aaagagctct c 21
<210> 43
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<212> DNA
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<210> 44
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 44
gggcgcccgg agcggggcgc c 21
<210> 45
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 45
gccatctacg cgagcagtgc t 21
<210> 46
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 46
ctgctcgcgt agatggcgct c 21
<210> 47
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 47
tcccgcgctt gccggggagg g 21
<210> 48
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 48
cggagtgggt gtctcggcca c 21
<210> 49
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 49
ggccgagaca cccactccga g 21
<210> 50
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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cgcatcctga tccacctcgg a 21
<210> 51
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 51
gacacccact ccgaggtgga t 21
<210> 52
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 52
agcccgtcgc gttggggctg c 21
<210> 53
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 53
aggtgagccc ggcccgggtc c 21
<210> 54
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 54
cggcagagag gtgagcccgg c 21
<210> 55
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 55
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<210> 56
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
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gcctggaacg ctccacggga c 21
<210> 57
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 57
gggcggggcg gggcgcagcc g 21
<210> 58
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 58
gggcgccccc gggggagggg t 21
<210> 59
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 59
caagctgggc gcccccgggg g 21
<210> 60
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 60
cgggggcgcc cagcttggcc t 21
<210> 61
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 61
gtcagcccgg cctccccgac t 21
<210> 62
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 对照非靶向性靶向序列
<400> 62
acggaggcta agcgtcgcaa 20
<210> 63
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 对照非靶向性靶向序列
<400> 63
cgcttccgcg gcccgttcaa 20
<210> 64
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 对照非靶向性靶向序列
<400> 64
gtaggcgcgc cgctctctac 20
<210> 65
<211> 19
<212> RNA
<213> 新凶手弗朗西斯菌(Francisella novicid)
<220>
<221> misc_structure
<222> (1)..(19)
<223> crRNA的5'-柄
<400> 65
aauuucuacu guuguagau
<210> 66
<211> 1053
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<220>
<221> 变体
<222> (580)..(580)
<223> Asn残基转变成Ala残基
<400> 66
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
485 490 495
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
500 505 510
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
515 520 525
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
530 535 540
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
545 550 555 560
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
565 570 575
Gln Glu Glu Ala Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
580 585 590
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
595 600 605
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
610 615 620
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
625 630 635 640
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
645 650 655
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
660 665 670
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
675 680 685
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
690 695 700
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
705 710 715 720
Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys
725 730 735
Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu
740 745 750
Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp
755 760 765
Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile
770 775 780
Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu
785 790 795 800
Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu
805 810 815
Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His
820 825 830
Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly
835 840 845
Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr
850 855 860
Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile
865 870 875 880
Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp
885 890 895
Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr
900 905 910
Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val
915 920 925
Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser
930 935 940
Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala
945 950 955 960
Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly
965 970 975
Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile
980 985 990
Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn Met
995 1000 1005
Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser Lys
1010 1015 1020
Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn Leu
1025 1030 1035
Tyr Glu Val Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys Gly
1040 1045 1050
<210> 67
<211> 1053
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<220>
<221> 变体
<222> (557)..(557)
<223> His残基转变成Ala残基
<400> 67
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
485 490 495
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
500 505 510
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
515 520 525
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
530 535 540
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp Ala Ile Ile Pro
545 550 555 560
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
565 570 575
Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
580 585 590
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
595 600 605
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
610 615 620
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
625 630 635 640
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
645 650 655
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
660 665 670
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
675 680 685
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
690 695 700
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
705 710 715 720
Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys
725 730 735
Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu
740 745 750
Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp
755 760 765
Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile
770 775 780
Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu
785 790 795 800
Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu
805 810 815
Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His
820 825 830
Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly
835 840 845
Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr
850 855 860
Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile
865 870 875 880
Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp
885 890 895
Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr
900 905 910
Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val
915 920 925
Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser
930 935 940
Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala
945 950 955 960
Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly
965 970 975
Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile
980 985 990
Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn Met
995 1000 1005
Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser Lys
1010 1015 1020
Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn Leu
1025 1030 1035
Tyr Glu Val Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys Gly
1040 1045 1050
<210> 68
<211> 1028
<212> PRT
<213> 人工序列
<220>
<223> 氨基酸残基(dSaCas9的第721至745位的氨基酸残基)缺失突变体
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<220>
<221> 变体
<222> (580)..(580)
<223> Asn残基转变成Ala残基
<400> 68
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
485 490 495
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
500 505 510
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
515 520 525
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
530 535 540
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
545 550 555 560
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
565 570 575
Gln Glu Glu Ala Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
580 585 590
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
595 600 605
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
610 615 620
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
625 630 635 640
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
645 650 655
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
660 665 670
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
675 680 685
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
690 695 700
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
705 710 715 720
Thr Glu Gln Glu Tyr Lys Glu Ile Phe Ile Thr Pro His Gln Ile Lys
725 730 735
His Ile Lys Asp Phe Lys Asp Tyr Lys Tyr Ser His Arg Val Asp Lys
740 745 750
Lys Pro Asn Arg Glu Leu Ile Asn Asp Thr Leu Tyr Ser Thr Arg Lys
755 760 765
Asp Asp Lys Gly Asn Thr Leu Ile Val Asn Asn Leu Asn Gly Leu Tyr
770 775 780
Asp Lys Asp Asn Asp Lys Leu Lys Lys Leu Ile Asn Lys Ser Pro Glu
785 790 795 800
Lys Leu Leu Met Tyr His His Asp Pro Gln Thr Tyr Gln Lys Leu Lys
805 810 815
Leu Ile Met Glu Gln Tyr Gly Asp Glu Lys Asn Pro Leu Tyr Lys Tyr
820 825 830
Tyr Glu Glu Thr Gly Asn Tyr Leu Thr Lys Tyr Ser Lys Lys Asp Asn
835 840 845
Gly Pro Val Ile Lys Lys Ile Lys Tyr Tyr Gly Asn Lys Leu Asn Ala
850 855 860
His Leu Asp Ile Thr Asp Asp Tyr Pro Asn Ser Arg Asn Lys Val Val
865 870 875 880
Lys Leu Ser Leu Lys Pro Tyr Arg Phe Asp Val Tyr Leu Asp Asn Gly
885 890 895
Val Tyr Lys Phe Val Thr Val Lys Asn Leu Asp Val Ile Lys Lys Glu
900 905 910
Asn Tyr Tyr Glu Val Asn Ser Lys Cys Tyr Glu Glu Ala Lys Lys Leu
915 920 925
Lys Lys Ile Ser Asn Gln Ala Glu Phe Ile Ala Ser Phe Tyr Asn Asn
930 935 940
Asp Leu Ile Lys Ile Asn Gly Glu Leu Tyr Arg Val Ile Gly Val Asn
945 950 955 960
Asn Asp Leu Leu Asn Arg Ile Glu Val Asn Met Ile Asp Ile Thr Tyr
965 970 975
Arg Glu Tyr Leu Glu Asn Met Asn Asp Lys Arg Pro Pro Arg Ile Ile
980 985 990
Lys Thr Ile Ala Ser Lys Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp
995 1000 1005
Ile Leu Gly Asn Leu Tyr Glu Val Lys Ser Lys Lys His Pro Gln
1010 1015 1020
Ile Ile Lys Lys Gly
1025
<210> 69
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> GGSGGS连接物
<400> 69
Gly Gly Ser Gly Gly Ser
1 5
<210> 70
<211> 1034
<212> PRT
<213> 人工序列
<220>
<223> 带有GGSGGS连接物的氨基酸残基(dSaCas9的第721至745位的氨基酸残基)缺失突变体
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<220>
<221> 变体
<222> (580)..(580)
<223> Asn残基转变成Ala残基
<220>
<221> MISC_FEATURE
<222> (721)..(726)
<223> GGSGGS连接物
<400> 70
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
485 490 495
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
500 505 510
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
515 520 525
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
530 535 540
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
545 550 555 560
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
565 570 575
Gln Glu Glu Ala Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
580 585 590
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
595 600 605
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
610 615 620
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
625 630 635 640
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
645 650 655
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
660 665 670
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
675 680 685
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
690 695 700
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
705 710 715 720
Gly Gly Ser Gly Gly Ser Thr Glu Gln Glu Tyr Lys Glu Ile Phe Ile
725 730 735
Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp Tyr Lys Tyr
740 745 750
Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile Asn Asp Thr
755 760 765
Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu Ile Val Asn
770 775 780
Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu Lys Lys Leu
785 790 795 800
Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His Asp Pro Gln
805 810 815
Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly Asp Glu Lys
820 825 830
Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr Leu Thr Lys
835 840 845
Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile Lys Tyr Tyr
850 855 860
Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp Tyr Pro Asn
865 870 875 880
Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr Arg Phe Asp
885 890 895
Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val Lys Asn Leu
900 905 910
Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser Lys Cys Tyr
915 920 925
Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala Glu Phe Ile
930 935 940
Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly Glu Leu Tyr
945 950 955 960
Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile Glu Val Asn
965 970 975
Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn Met Asn Asp Lys
980 985 990
Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser Lys Thr Gln Ser Ile
995 1000 1005
Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn Leu Tyr Glu Val Lys
1010 1015 1020
Ser Lys Lys His Pro Gln Ile Ile Lys Lys Gly
1025 1030
<210> 71
<211> 886
<212> PRT
<213> 人工序列
<220>
<223> 氨基酸残基(dSaCas9的第482至648位的氨基酸残基)缺失突变体
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<400> 71
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Thr Arg Tyr Ala Thr Arg Gly Leu Met Asn Leu Leu Arg Ser Tyr
485 490 495
Phe Arg Val Asn Asn Leu Asp Val Lys Val Lys Ser Ile Asn Gly Gly
500 505 510
Phe Thr Ser Phe Leu Arg Arg Lys Trp Lys Phe Lys Lys Glu Arg Asn
515 520 525
Lys Gly Tyr Lys His His Ala Glu Asp Ala Leu Ile Ile Ala Asn Ala
530 535 540
Asp Phe Ile Phe Lys Glu Trp Lys Lys Leu Asp Lys Ala Lys Lys Val
545 550 555 560
Met Glu Asn Gln Met Phe Glu Glu Lys Gln Ala Glu Ser Met Pro Glu
565 570 575
Ile Glu Thr Glu Gln Glu Tyr Lys Glu Ile Phe Ile Thr Pro His Gln
580 585 590
Ile Lys His Ile Lys Asp Phe Lys Asp Tyr Lys Tyr Ser His Arg Val
595 600 605
Asp Lys Lys Pro Asn Arg Glu Leu Ile Asn Asp Thr Leu Tyr Ser Thr
610 615 620
Arg Lys Asp Asp Lys Gly Asn Thr Leu Ile Val Asn Asn Leu Asn Gly
625 630 635 640
Leu Tyr Asp Lys Asp Asn Asp Lys Leu Lys Lys Leu Ile Asn Lys Ser
645 650 655
Pro Glu Lys Leu Leu Met Tyr His His Asp Pro Gln Thr Tyr Gln Lys
660 665 670
Leu Lys Leu Ile Met Glu Gln Tyr Gly Asp Glu Lys Asn Pro Leu Tyr
675 680 685
Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr Leu Thr Lys Tyr Ser Lys Lys
690 695 700
Asp Asn Gly Pro Val Ile Lys Lys Ile Lys Tyr Tyr Gly Asn Lys Leu
705 710 715 720
Asn Ala His Leu Asp Ile Thr Asp Asp Tyr Pro Asn Ser Arg Asn Lys
725 730 735
Val Val Lys Leu Ser Leu Lys Pro Tyr Arg Phe Asp Val Tyr Leu Asp
740 745 750
Asn Gly Val Tyr Lys Phe Val Thr Val Lys Asn Leu Asp Val Ile Lys
755 760 765
Lys Glu Asn Tyr Tyr Glu Val Asn Ser Lys Cys Tyr Glu Glu Ala Lys
770 775 780
Lys Leu Lys Lys Ile Ser Asn Gln Ala Glu Phe Ile Ala Ser Phe Tyr
785 790 795 800
Asn Asn Asp Leu Ile Lys Ile Asn Gly Glu Leu Tyr Arg Val Ile Gly
805 810 815
Val Asn Asn Asp Leu Leu Asn Arg Ile Glu Val Asn Met Ile Asp Ile
820 825 830
Thr Tyr Arg Glu Tyr Leu Glu Asn Met Asn Asp Lys Arg Pro Pro Arg
835 840 845
Ile Ile Lys Thr Ile Ala Ser Lys Thr Gln Ser Ile Lys Lys Tyr Ser
850 855 860
Thr Asp Ile Leu Gly Asn Leu Tyr Glu Val Lys Ser Lys Lys His Pro
865 870 875 880
Gln Ile Ile Lys Lys Gly
885
<210> 72
<211> 892
<212> PRT
<213> 人工序列
<220>
<223> 带有GGSGGS连接物的氨基酸残基(dSaCas9的第482至648位的氨基酸残基)缺失突变体
<220>
<221> 变体
<222> (10)..(10)
<223> Asp残基转变成Ala残基
<220>
<221> MISC_FEATURE
<222> (482)..(487)
<223> GGSGGS连接物
<400> 72
Met Lys Arg Asn Tyr Ile Leu Gly Leu Ala Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Gly Gly Ser Gly Gly Ser Thr Arg Tyr Ala Thr Arg Gly Leu Met
485 490 495
Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys Val
500 505 510
Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp Lys
515 520 525
Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp Ala
530 535 540
Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys Leu
545 550 555 560
Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys Gln
565 570 575
Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu Ile
580 585 590
Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp Tyr
595 600 605
Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile Asn
610 615 620
Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu Ile
625 630 635 640
Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu Lys
645 650 655
Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His Asp
660 665 670
Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly Asp
675 680 685
Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr Leu
690 695 700
Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile Lys
705 710 715 720
Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp Tyr
725 730 735
Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr Arg
740 745 750
Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val Lys
755 760 765
Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser Lys
770 775 780
Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala Glu
785 790 795 800
Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly Glu
805 810 815
Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile Glu
820 825 830
Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn Met Asn
835 840 845
Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser Lys Thr Gln
850 855 860
Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn Leu Tyr Glu Val
865 870 875 880
Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys Gly
885 890
<210> 73
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> VP64
<400> 73
Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
1 5 10 15
Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe
20 25 30
Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp
35 40 45
Met Leu
50
<210> 74
<211> 376
<212> PRT
<213> 人工序列
<220>
<223> VPH
<400> 74
Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
1 5 10 15
Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe
20 25 30
Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp
35 40 45
Met Leu Ser Ser Gly Ser Pro Lys Lys Lys Arg Lys Val Gly Ser Pro
50 55 60
Ser Gly Gln Ile Ser Asn Gln Ala Leu Ala Leu Ala Pro Ser Ser Ala
65 70 75 80
Pro Val Leu Ala Gln Thr Met Val Pro Ser Ser Ala Met Val Pro Leu
85 90 95
Ala Gln Pro Pro Ala Pro Ala Pro Val Leu Thr Pro Gly Pro Pro Gln
100 105 110
Ser Leu Ser Ala Pro Val Pro Lys Ser Thr Gln Ala Gly Glu Gly Thr
115 120 125
Leu Ser Glu Ala Leu Leu His Leu Gln Phe Asp Ala Asp Glu Asp Leu
130 135 140
Gly Ala Leu Leu Gly Asn Ser Thr Asp Pro Gly Val Phe Thr Asp Leu
145 150 155 160
Ala Ser Val Asp Asn Ser Glu Phe Gln Gln Leu Leu Asn Gln Gly Val
165 170 175
Ser Met Ser His Ser Thr Ala Glu Pro Met Leu Met Glu Tyr Pro Glu
180 185 190
Ala Ile Thr Arg Leu Val Thr Gly Ser Gln Arg Pro Pro Asp Pro Ala
195 200 205
Pro Thr Pro Leu Gly Thr Ser Gly Leu Pro Asn Gly Leu Ser Gly Asp
210 215 220
Glu Asp Phe Ser Ser Ile Ala Asp Met Asp Phe Ser Ala Leu Leu Ser
225 230 235 240
Gln Ile Ser Ser Ser Gly Gln Gly Gly Gly Gly Ser Gly Phe Ser Val
245 250 255
Asp Thr Ser Ala Leu Leu Asp Leu Phe Ser Pro Ser Val Thr Val Pro
260 265 270
Asp Met Ser Leu Pro Asp Leu Asp Ser Ser Leu Ala Ser Ile Gln Glu
275 280 285
Leu Leu Ser Pro Gln Glu Pro Pro Arg Pro Pro Glu Ala Glu Asn Ser
290 295 300
Ser Pro Asp Ser Gly Lys Gln Leu Val His Tyr Thr Ala Gln Pro Leu
305 310 315 320
Phe Leu Leu Asp Pro Gly Ser Val Asp Thr Gly Ser Asn Asp Leu Pro
325 330 335
Val Leu Phe Glu Leu Gly Glu Gly Ser Tyr Phe Ser Glu Gly Asp Gly
340 345 350
Phe Ala Glu Asp Pro Thr Ile Ser Leu Leu Thr Gly Ser Glu Pro Pro
355 360 365
Lys Ala Lys Asp Pro Thr Val Ser
370 375
<210> 75
<211> 523
<212> PRT
<213> 人工序列
<220>
<223> VPR
<400> 75
Glu Ala Ser Gly Ser Gly Arg Ala Asp Ala Leu Asp Asp Phe Asp Leu
1 5 10 15
Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu
20 25 30
Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp
35 40 45
Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Ile Asn Ser Arg Ser Ser
50 55 60
Gly Ser Ser Gln Tyr Leu Pro Asp Thr Asp Asp Arg His Arg Ile Glu
65 70 75 80
Glu Lys Arg Lys Arg Thr Tyr Glu Thr Phe Lys Ser Ile Met Lys Lys
85 90 95
Ser Pro Phe Ser Gly Pro Thr Asp Pro Arg Pro Pro Pro Arg Arg Ile
100 105 110
Ala Val Pro Ser Arg Ser Ser Ala Ser Val Pro Lys Pro Ala Pro Gln
115 120 125
Pro Tyr Pro Phe Thr Ser Ser Leu Ser Thr Ile Asn Tyr Asp Glu Phe
130 135 140
Pro Thr Met Val Phe Pro Ser Gly Gln Ile Ser Gln Ala Ser Ala Leu
145 150 155 160
Ala Pro Ala Pro Pro Gln Val Leu Pro Gln Ala Pro Ala Pro Ala Pro
165 170 175
Ala Pro Ala Met Val Ser Ala Leu Ala Gln Ala Pro Ala Pro Val Pro
180 185 190
Val Leu Ala Pro Gly Pro Pro Gln Ala Val Ala Pro Pro Ala Pro Lys
195 200 205
Pro Thr Gln Ala Gly Glu Gly Thr Leu Ser Glu Ala Leu Leu Gln Leu
210 215 220
Gln Phe Asp Asp Glu Asp Leu Gly Ala Leu Leu Gly Asn Ser Thr Asp
225 230 235 240
Pro Ala Val Phe Thr Asp Leu Ala Ser Val Asp Asn Ser Glu Phe Gln
245 250 255
Gln Leu Leu Asn Gln Gly Ile Pro Val Ala Pro His Thr Thr Glu Pro
260 265 270
Met Leu Met Glu Tyr Pro Glu Ala Ile Thr Arg Leu Val Thr Gly Ala
275 280 285
Gln Arg Pro Pro Asp Pro Ala Pro Ala Pro Leu Gly Ala Pro Gly Leu
290 295 300
Pro Asn Gly Leu Leu Ser Gly Asp Glu Asp Phe Ser Ser Ile Ala Asp
305 310 315 320
Met Asp Phe Ser Ala Leu Leu Gly Ser Gly Ser Gly Ser Arg Asp Ser
325 330 335
Arg Glu Gly Met Phe Leu Pro Lys Pro Glu Ala Gly Ser Ala Ile Ser
340 345 350
Asp Val Phe Glu Gly Arg Glu Val Cys Gln Pro Lys Arg Ile Arg Pro
355 360 365
Phe His Pro Pro Gly Ser Pro Trp Ala Asn Arg Pro Leu Pro Ala Ser
370 375 380
Leu Ala Pro Thr Pro Thr Gly Pro Val His Glu Pro Val Gly Ser Leu
385 390 395 400
Thr Pro Ala Pro Val Pro Gln Pro Leu Asp Pro Ala Pro Ala Val Thr
405 410 415
Pro Glu Ala Ser His Leu Leu Glu Asp Pro Asp Glu Glu Thr Ser Gln
420 425 430
Ala Val Lys Ala Leu Arg Glu Met Ala Asp Thr Val Ile Pro Gln Lys
435 440 445
Glu Glu Ala Ala Ile Cys Gly Gln Met Asp Leu Ser His Pro Pro Pro
450 455 460
Arg Gly His Leu Asp Glu Leu Thr Thr Thr Leu Glu Ser Met Thr Glu
465 470 475 480
Asp Leu Asn Leu Asp Ser Pro Leu Thr Pro Glu Leu Asn Glu Ile Leu
485 490 495
Asp Thr Phe Leu Asn Asp Glu Cys Leu Leu His Ala Met His Ile Ser
500 505 510
Thr Gly Leu Ser Ile Phe Asp Thr Ser Leu Phe
515 520
<210> 76
<211> 167
<212> PRT
<213> 人工序列
<220>
<223> MiniVR
<400> 76
Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
1 5 10 15
Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe
20 25 30
Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp
35 40 45
Met Leu Gly Ser Gly Ser Pro Ala Pro Ala Val Thr Pro Glu Ala Ser
50 55 60
His Leu Leu Glu Asp Pro Asp Glu Glu Thr Ser Gln Ala Val Lys Ala
65 70 75 80
Leu Arg Glu Met Ala Asp Thr Val Ile Pro Gln Lys Glu Glu Ala Ala
85 90 95
Ile Cys Gly Gln Met Asp Leu Ser His Pro Pro Pro Arg Gly His Leu
100 105 110
Asp Glu Leu Thr Thr Thr Leu Glu Ser Met Thr Glu Asp Leu Asn Leu
115 120 125
Asp Ser Pro Leu Thr Pro Glu Leu Asn Glu Ile Leu Asp Thr Phe Leu
130 135 140
Asn Asp Glu Cys Leu Leu His Ala Met His Ile Ser Thr Gly Leu Ser
145 150 155 160
Ile Phe Asp Thr Ser Leu Phe
165
<210> 77
<211> 140
<212> PRT
<213> 人工序列
<220>
<223> MicroVR
<400> 77
Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
1 5 10 15
Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe
20 25 30
Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp
35 40 45
Met Leu Gly Ser Gly Ser Arg Glu Met Ala Asp Thr Val Ile Pro Gln
50 55 60
Lys Glu Glu Ala Ala Ile Cys Gly Gln Met Asp Leu Ser His Pro Pro
65 70 75 80
Pro Arg Gly His Leu Asp Glu Leu Thr Thr Thr Leu Glu Ser Met Thr
85 90 95
Glu Asp Leu Asn Leu Asp Ser Pro Leu Thr Pro Glu Leu Asn Glu Ile
100 105 110
Leu Asp Thr Phe Leu Asn Asp Glu Cys Leu Leu His Ala Met His Ile
115 120 125
Ser Thr Gly Leu Ser Ile Phe Asp Thr Ser Leu Phe
130 135 140
<210> 78
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> GSGS连接物
<400> 78
Gly Ser Gly Ser
<210> 79
<211> 21
<212> RNA
<213> 智人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 对应于靶序列(SEQ ID NO:15)的crRNA
<400> 79
ucucgccucc gccgccacuc g 21
<210> 80
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<220>
<221> misc_feature
<222> (1)..(21)
<223> 与靶序列(SEQ ID NO:15)互补的序列
<400> 80
cgagtggcgg cggaggcgag a 21
<210> 81
<211> 19
<212> DNA
<213> 新凶手弗朗西斯菌(Francisella novicid)
<220>
<221> misc_structure
<222> (1)..(19)
<223> crRNA的5'-柄
<400> 81
aatttctact gttgtagat
<210> 82
<211> 83
<212> DNA
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<220>
<221> misc_feature
<222> (1)..(83)
<223> 编码tracrRNA的序列
<400> 82
gttttagtac tctggaaaca gaatctacta aaacaaggca aaatgccgtg tttatctcgt 60
caacttgttg gcgagatttt ttt 83
<210> 83
<211> 82
<212> RNA
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<220>
<221> misc_feature
<222> (1)..(82)
<223> tracrRNA
<400> 83
guuuuaguac ucuggaaaca gaaucuacua aaacaaggca aaaugccgug uuuaucucgu 60
caacuuguug gcgagauuuu uu 82
<210> 84
<211> 131
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 84
Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu
1 5 10 15
Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe
20 25 30
Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp
35 40 45
Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly
50 55 60
Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala
65 70 75 80
Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp
85 90 95
Phe Asp Leu Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu
100 105 110
Asp Met Leu Gly Ser Asp Ala Leu Asp Asp Phe Asp Leu Asp Met Leu
115 120 125
Tyr Ile Asp
130
<210> 85
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 85
aaaattaaga ttttctttct g 21
<210> 86
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 86
aacttgtttt gtatattttt a 21
<210> 87
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 87
taataattga gatgcattct c 21
<210> 88
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 88
aagctcacat ttaggaacag a 21
<210> 89
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 89
ctatggcaaa ctaaacaaag c 21
<210> 90
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 90
cagaagagca gaagttctta t 21
<210> 91
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 91
catctgagac atcgctacct g 21
<210> 92
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 92
gtttacctta aaaacaaatt c 21
<210> 93
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 93
ctcctggtcc tttacaagtg g 21
<210> 94
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 94
agcagggggc aacgaagaag a 21
<210> 95
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 95
ttctggggtg atgggttcaa c 21
<210> 96
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 96
cccagagggc cgtggggcca t 21
<210> 97
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 97
tttccataga gaaatgtgtg t 21
<210> 98
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 98
tgggaggcgc catctgcgcg g 21
<210> 99
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 99
cctcaacgtt ttcctgtaag t 21
<210> 100
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 100
ctaagatctc cagccttgtt c 21
<210> 101
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 101
tgtgcctaag actgcacagg t 21
<210> 102
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 102
attaaacgca gatatgctat t 21
<210> 103
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 103
tcatagaaaa tacataagca a 21
<210> 104
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 104
aagaagtcac agaaatgcct c 21
<210> 105
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 105
ggcttggaga gaaggggcaa g 21
<210> 106
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 106
gctcatcact ggcactgccc a 21
<210> 107
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 107
taaacctctt ttgccttcat g 21
<210> 108
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 108
ttcttatgaa taaagtttta t 21
<210> 109
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 109
cttcttcaaa atgttaagtt a 21
<210> 110
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 110
caaatgttca tcaactgatg a 21
<210> 111
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 111
atatggttcc atttctaagt t 21
<210> 112
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 112
ttgcaccaat acaccaaaac a 21
<210> 113
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 113
actgctctga gctacagcaa a 21
<210> 114
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 114
tttttgtaat tttagtagag a 21
<210> 115
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 115
actgcactcc agcctgggca a 21
<210> 116
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 116
ctttttgccc agactggtaa a 21
<210> 117
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 117
ttggttttac acataaaaat c 21
<210> 118
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 118
tcttccactc aggacacaca a 21
<210> 119
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 119
tttttcacct aatgtttata a 21
<210> 120
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 120
ggtttttgga tttcttccca g 21
<210> 121
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 121
aacatcacct tgattttgag t 21
<210> 122
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 122
atcagggtgg cttctggtgt t 21
<210> 123
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 123
aaagaagaag aagaagaaaa a 21
<210> 124
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 124
aaaaattagc cgggcttggt g 21
<210> 125
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 125
aaattataga tgttcacttg g 21
<210> 126
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 126
aataccttga tattattatc c 21
<210> 127
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 127
tatgcgtcag aaaaagcggc t 21
<210> 128
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 128
gagaagcttc ttctcaccga t 21
<210> 129
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 129
ggaaggatga atagggcgtg a 21
<210> 130
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 130
cgcctcggcc tcccaaagtg c 21
<210> 131
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 131
ccagcacttt gggaggccga g 21
<210> 132
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 132
cactttggga ggccgaggcg g 21
<210> 133
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 133
gcgggtggat cacttgaggt c 21
<210> 134
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 134
ctacttggga ggctgaggca g 21
<210> 135
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 135
agataatttc ctctcacttg t 21
<210> 136
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 136
cctcagaaaa acaggaattg a 21
<210> 137
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 137
aaaaggatgc aatatagttc a 21
<210> 138
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 138
cattttaaat ttagtactgt a 21
<210> 139
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 139
aggcacatag ctattaaaat g 21
<210> 140
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 140
agatcccaaa agataatcta t 21
<210> 141
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 141
gcattcatat agattatctt t 21
<210> 142
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 142
cgcctcggcc tcccaaagtg c 21
<210> 143
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 143
ccagcacttt gggaggccga g 21
<210> 144
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 144
cactttggga ggccgaggcg g 21
<210> 145
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 145
tttttgtatt tttagtggag a 21
<210> 146
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 146
gctcactgca agctccgcct c 21
<210> 147
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 147
gtcttgctct gtcgcccagg c 21
<210> 148
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 148
cacaaggggt gtccccatat t 21
<210> 149
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 149
ccttatcttt gaactgcaag c 21
<210> 150
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 150
gcagggtttt tagaagatgt g 21
<210> 151
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 151
aatcagaatg tctatgttat t 21
<210> 152
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 152
cgcctcagcc tcccaaagtg c 21
<210> 153
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 153
ccagcacttt gggaggctga g 21
<210> 154
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 154
cactttggga ggctgaggcg g 21
<210> 155
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 155
tttttgtatt tttagtagag a 21
<210> 156
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 156
ccattctcct gcctcagcct c 21
<210> 157
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 157
ctactcagga ggctgaggca g 21
<210> 158
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 158
gctcactgca agctccgcct c 21
<210> 159
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 159
gtgggcagat cacttgagct c 21
<210> 160
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 160
cacctcagcc tcccaaagtg c 21
<210> 161
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 161
agcctcccaa agtgctggaa t 21
<210> 162
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 162
ggatttcaac aggatcaccc a 21
<210> 163
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 163
gaactagaat ctggatttca a 21
<210> 164
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 164
cagggatcca gccacggtgc c 21
<210> 165
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 165
tactagaatt ggttatggtg t 21
<210> 166
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 166
actttgcaga tgtgattaaa t 21
<210> 167
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 167
agagccagct gtaaggacac c 21
<210> 168
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 168
ggtgaaaccc attttggact t 21
<210> 169
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 169
tgtattgtta tcttatagtt c 21
<210> 170
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 170
aatactggaa aaaagagaag g 21
<210> 171
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 171
gaaggaagaa tagaggtctc a 21
<210> 172
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
17288
gaagagagcc ctcaccagaa a 21
<210> 173
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 173
cttacaagaa cacaaatcct a 21
<210> 174
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 174
aagaatgggg ctctgatcca a 21
<210> 175
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 175
tagtatttta catttacata g 21
<210> 176
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 176
atggggatat tttatagtaa a 21
<210> 177
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 177
gcatctccct aaagccaagg a 21
<210> 178
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 178
aggaagagga agccaaattg g 21
<210> 179
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 179
ccagcaggca gggatgtcct g 21
<210> 180
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 180
tctgcaggac atccctgcct g 21
<210> 181
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 181
ctactcggga ggctgaggca g 21
<210> 182
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 182
tgattctcct gcctcagcct c 21
<210> 183
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 183
gctcactgca agctctgcct c 21
<210> 184
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 184
ctactcggga ggctgaggca g 21
<210> 185
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 185
ccattctcct gcctcagcct c 21
<210> 186
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 186
tttttgtatt tttagtagag a 21
<210> 187
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 187
tactaaaaat acaaaaatta g 21
<210> 188
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 188
cactttggga ggccgaggtg g 21
<210> 189
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 189
cacctcggcc tcccaaagtg c 21
<210> 190
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 190
aacctaaagt gtaaaatatt g 21
<210> 191
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 191
cactaagcca atgccaggtt t 21
<210> 192
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 192
gctcactgca acctctgcct c 21
<210> 193
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 193
gtgggcagga gttgaaatga g 21
<210> 194
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 194
ggaaacgcag ctgagctctg a 21
<210> 195
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 195
ccacaaggga gcaagtggtt g 21
<210> 196
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 196
aaacaaaggc aagttaatca g 21
<210> 197
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 197
cagcagggag aatggggatc a 21
<210> 198
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 198
ggcttggaaa acaggaacca a 21
<210> 199
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 199
acatttgaag gtcagacagc t 21
<210> 200
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 200
ggacaggaag agctccacga a 21
<210> 201
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 201
ggtcagttta ctccccatgg g 21
<210> 202
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 202
tctcactaat tgctccatgc a 21
<210> 203
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 203
gtcttgctct gtcacccagg c 21
<210> 204
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 204
ctacttggga ggctgaggca g 21
<210> 205
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 205
tttttgtatt tttagtagag a 21
<210> 206
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 206
cactttggga ggctgaggca g 21
<210> 207
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 207
gaaacatgac ttagtgacta a 21
<210> 208
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 208
cagccacaat ctccatctgt c 21
<210> 209
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 209
gctcactgca acctctgctt c 21
<210> 210
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 210
ctacttggga ggctgaggca g 21
<210> 211
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 211
tgcctcagcc tcccaagtag c 21
<210> 212
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 212
caagcaggtt agccagcctc t 21
<210> 213
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 213
cacagaggct ggctaacctg c 21
<210> 214
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 214
gtcaaaggaa gctgatagat c 21
<210> 215
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 215
attagaaatt taaaacaaaa t 21
<210> 216
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 216
aatcaagatg aatccaggca g 21
<210> 217
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 217
aagcttatta ttggagcagc t 21
<210> 218
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 218
aaagaacctc cccatcctag c 21
<210> 219
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 219
gtaaagttct cattccacac c 21
<210> 220
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 220
aaggttaata tgagaatctg t 21
<210> 221
<211> 21
<212> DNA
<213> 智人(Homo sapiens)
<400> 221
tctttaggtc ctagatacct t 21
Claims (25)
1.一种多核苷酸,其包含下述碱基序列:
(a)编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列,和
(b)编码靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA的碱基序列:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
2.根据权利要求1所述的多核苷酸,其中编码指导RNA的碱基序列包含:
(i)在SEQ ID NO:15、20、25、50、56或61中阐述的碱基序列,
(ii)在SEQ ID NO:124中阐述的碱基序列,
(iii)在SEQ ID NO:178、193或195中阐述的碱基序列,
或其中缺失、替换、插入和/或添加了1至3个碱基的所述碱基序列。
3.根据权利要求1或2所述的多核苷酸,其中所述转录激活因子选自VP64、VP160、VPH、VPR、VP64-miniRTA(miniVR)和microVR、其具有转录激活能力的变体。
4.根据权利要求3所述的多核苷酸,其中所述转录激活因子是miniVR。
5.根据权利要求1至4中的任一项所述的多核苷酸,其中所述核酸酶缺陷型CRISPR效应蛋白是dCas9。
6.根据权利要求5所述的多核苷酸,其中所述dCas9源自于金黄色葡萄球菌(Staphylococcus aureus)。
7.根据权利要求1至6中的任一项所述的多核苷酸,其还包含用于编码指导RNA的碱基序列的启动子序列和/或用于所述编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列的启动子序列。
8.根据权利要求7所述的多核苷酸,其中所述用于编码指导RNA的碱基序列的启动子序列选自U6启动子、SNR6启动子、SNR52启动子、SCR1启动子、RPR1启动子、U3启动子和H1启动子。
9.根据权利要求8所述的多核苷酸,其中所述用于编码指导RNA的碱基序列的启动子序列是U6启动子。
10.根据权利要求7至9中的任一项所述的多核苷酸,其中用于所述编码核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白的碱基序列的启动子序列是遍在启动子或肌肉特异性启动子。
11.根据权利要求10所述的多核苷酸,其中所述遍在启动子选自EFS启动子、CMV启动子和CAG启动子。
12.根据权利要求10所述的多核苷酸,其中所述肌肉特异性启动子选自CK8启动子、肌球蛋白重链激酶(MHCK)启动子、肌肉肌酸激酶(MCK)启动子、合成C5-12(Syn)启动子和unc45b启动子。
13.一种载体,其包含根据权利要求1至12中的任一项所述的多核苷酸。
14.根据权利要求13所述的载体,其中所述载体是质粒载体或病毒载体。
15.根据权利要求14所述的载体,其中所述病毒载体选自腺相关病毒(AAV)载体、腺病毒载体和慢病毒载体。
16.根据权利要求15所述的载体,其中所述AAV载体选自AAV1、AAV2、AAV6、AAV7、AAV8、AAV9及其变体。
17.一种用于治疗或预防MDC1A的药剂,其包含根据权利要求1至12中的任一项所述的多核苷酸或根据权利要求13至16中的任一项所述的载体。
18.一种用于治疗或预防MDC1A的方法,所述方法包括向需要的对象给药根据权利要求1至12中的任一项所述的多核苷酸或根据权利要求13至16中的任一项所述的载体。
19.根据权利要求1至12中的任一项所述的多核苷酸或根据权利要求13至16中的任一项所述的载体用于治疗或预防MDC1A的用途。
20.根据权利要求1至12中的任一项所述的多核苷酸或根据权利要求13至16中的任一项所述的载体在制备用于治疗或预防MDC1A的药物组合物中的用途。
21.一种用于上调细胞中人类LAMA1基因的表达的方法,所述方法包括在上述细胞中表达
(c)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,和
(d)靶向人类LAMA1的表达调控区中的下述连续区域的指导RNA:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
22.一种核糖核蛋白,其包含:
(c)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,和
(d)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ ID NO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
23.一种用于上调人类LAMA1基因的表达的试剂盒,其包含:
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ IDNO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
24.一种用于治疗或预防MDC1A的方法,所述方法包括给药下述(e)和(f):
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ IDNO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
25.下述(e)和(f)在制备用于治疗或预防MDC1A的药物组合物中的用途:
(e)核酸酶缺陷型CRISPR效应蛋白与转录激活因子的融合蛋白,或编码所述融合蛋白的多核苷酸,和
(f)靶向人类LAMA1基因的表达调控区中的下述连续区域的指导RNA或编码所述指导RNA的多核苷酸:(i)在SEQ ID NO:15、20、25、50、56或61中阐述的连续区域,(ii)在SEQ IDNO:124中阐述的连续区域,或(iii)在SEQ ID NO:178、193或195中阐述的连续区域。
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