CN112011576A - Crispr基因编辑技术在治疗地中海贫血中的应用 - Google Patents
Crispr基因编辑技术在治疗地中海贫血中的应用 Download PDFInfo
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Abstract
本发明提供了一种CRISPR基因编辑技术在治疗地中海贫血中的应用,该应用中的CRISPR系统包括至少一种核酸酶和至少一种sgRNA,所述sgRNA能够靶向HBG(γ珠蛋白基因)启动子的抑制元件,所述核酸酶能够切割HBG启动子的抑制元件,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列包括SEQ ID No.1所示序列或SEQ ID No.1的互补序列。通过电转的方法将所述核酸酶和sgRNA的复合物转到细胞中,可以敲除HBG(γ珠蛋白基因)启动子上的抑制元件,提高细胞中HBG mRNA相对含量,相较于传统的慢病毒感染技术,免除了由于病毒导致的外源DNA随机整合,提高了临床应用的前景。
Description
技术领域
本申请涉及基因编辑技术领域,尤其涉及CRISPR基因编辑技术在治疗地中海贫血中的应用。
背景技术
β型地中海贫血是由β珠蛋白基因发生突变所导致的血液类遗传疾病,目前该基因已知的致病突变类型大约有300多种。人体的血红蛋白是由α和β两种珠蛋白组成的异源四聚体。当β珠蛋白发生突变无法表达或功能缺失,就会造成红细胞中聚积过多的α珠蛋白,导致红细胞无法正常形成,其前体过早凋亡。所以患有β地中海贫血的病人必须不断地输血来维持体内的β珠蛋白含量是红细胞能够正常形成。
长期的输血会导致体内铁元素过多的聚积,造成铁中毒,因而患者必须定期接受除铁治疗。少数的病人得到了珍贵的造血干细胞或骨髓的成功配对得到了彻底根治这种疾病的机会,但是即使配对成功异体移植仍然存在着很大的免疫排斥风险,患者必须定期服用免疫抑制药物来降低发生排斥的几率。
在寻找其他替代疗法时,有研究者发现补充大量的γ珠蛋白能够在一定程度上缓解地中海贫血疾病。γ珠蛋白在结构上与β珠蛋白类似,前者主要在婴儿时期表达,随着年龄的增长其表达逐渐被BCL11A复合物抑制。为了能够在成年患者体内大量表达γ珠蛋白,人们开始寻找各种化学小分子类药物,尝试刺激γ珠蛋白的表达。不过在利用小分子类药物的研究当中,不同患者对于药物的敏感度有着相当大的差异,所以科学家仍然在寻找一种更为高效持久的药物,即使不能根治疾病也至少可以降低地贫患者需要接受输血的频率以及高昂的治疗费用,尤其对于平穷的国家,由于缺乏产前诊断和较高的地贫携带着基数,这些地区的地贫患者正在逐年增加。在另一方面移民也使得本来并非地中海贫血流行区的国家发病率有所升高,地中海贫血的治疗面临着巨大的挑战。
针对γ珠蛋白基因的研究,目前采用的技术手段是敲除造血干细胞HBG(γ珠蛋白基因)启动子上的抑制元件,通过上调HBG上调进而缓解症状。在临床的案例中,已经发现有些地贫患者由于天生在HBG启动子抑制元件处有碱基缺失造成地贫症状大大缓解的病例。
CRISPR/Cas系统具有加工产生CRISPR RNA(crRNA)和切割双链DNA功能。crRNA(CRISPR-derived RNA)通过碱基配对与tracrRNA(trans-activating RNA)结合形成tracrRNA/crRNA复合体,此复合体一旦形成就能引导核酸酶在与crRNA配对的序列靶位点剪切双链DNA。而tracrRNA/crRNA复合体可通过人工设计,融合crRNA与tracrRNA形成sgRNA(single-guided RNA),sgRNA足以引导核酸酶对DNA的定点切割。sgRNA可以通过载体表达或者化学合成后与核酸酶共同进入细胞,对特异DNA序列剪切,从而促使DNA发生NHEJ(nonhomologous end-joining)导致的基因缺失或同源重组,实现基因敲除。
利用质粒递送Cas9/sgRNA在临床上暂时还不能实现。首先质粒递送系统的效率非常低,相对地毒性却非常大,暂时不可能满足足够的编辑效率进行后期的移植达到治疗目的。利用慢病毒感染造血干细胞递送Cas9/sgRNA是常用的的方式,但是,需要感染相当长的时间(大于72小时)才能达到一个相对较高的效率;利用慢病毒的方案本身就存在外源DNA随机整合的致癌风险,体外感染较长时间后那些真正在移植中起到自我更新作用的长时造血干细胞开始分化,干性减弱,这对后期的干细胞移植成功率有很大影响;另外,慢病毒感染仍然不能达到80%以上的编辑效率。
发明内容
为了提高CRISPR基因编辑技术在地中海贫血治疗中的应用,本发明对于CRISPR系统进行了改进,尤其是针对sgRNA的选择。
一方面,本发明提供了一种CRISPR系统,所述系统包括该系统至少一种核酸酶和至少一种sgRNA(指导RNA),所述sgRNA能够靶向HBG(γ珠蛋白基因)启动子的抑制元件,所述核酸酶能够切割HBG启动子的抑制元件。
进一步的,所述核酸酶选自Cas蛋白或Cpf1蛋白,可以选自CRISPR系统中天然存在的野生型的Cas蛋白或Cpf1蛋白,也可以选自突变型的Cas蛋白或Cpf1蛋白;在一个优选的实施方式中,所述Cas蛋白为Cas9;优选的,所述Cas9可以选自Streptococcus pyogenes、Staphylococcus aureus或N.meningitidis来源的Cas9;更优选的,所述Cas9的氨基酸序列如SEQ ID No.5所示。
进一步的,所述sgRNA的靶向序列位于HBG启动子上游约-114bp处;优选的,位于启动子上游-99bp~-118bp处;所述HBG可以为HBG1或HBG2,在优选的实施方式中,所述HBG为HBG1。
在优选的实施方式中,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列为SEQ ID No.1所示序列或SEQ ID No.1的互补序列。所述sgRNA还包括骨架序列;优选的,所述sgRNA包括5’端到3’端依次连接的靶向序列和骨架序列;更优选的,所述骨架序列为SEQ ID No.2所示序列。
另一方面,本发明提供了一种包含核酸酶和sgRNA的复合物;优选的,所述核酸酶为Cas9或Cpf1,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列包括SEQ ID No.1所示序列或SEQ ID No.1的互补序列。
在一个实施方式中,所述sgRNA包括碱基的化学修饰。在优选的实施方式中,所述sgRNA包括5’末端第1-n位碱基的任意一个或任意几个碱基的化学修饰,和/或3’末端第1至n位碱基的任意一个或任意几个碱基的化学修饰;所述n选自2、3、4、5、6、7、8、9或10。优选的,sgRNA包括5’末端一个、两个、三个、四个或五个碱基的化学修饰,和/或3’末端一个、两个、三个、四个或五个碱基的化学修饰。例如,在sgRNA的5’末端第1位碱基、第2位碱基、第3位碱基、第4位碱基、第5位碱基或第1-2位碱基、第1-3位碱基、第1-4位碱基、第1-5位碱基进行化学修饰;和/或,在sgRNA的3’末端第1位碱基、第2位碱基、第3位碱基、第4位碱基、第5位个碱基或第1-2位碱基、第1-3位碱基、第1-4位碱基、第1-5位碱基进行化学修饰。在优选的实施方式中,所述化学修饰为甲基化修饰、氟化修饰或硫代修饰中的一种或任意几种。
另一方面,本发明提供了一种改变HBG基因表达的方法,所述方法包括向细胞中引入上述包含核酸酶和sgRNA的复合物的步骤。
进一步的,本发明所述改变HBG基因表达的方法为上调HBG基因的表达。
在优选的实施方式中,采用电转化的方法向细胞中引入包含核酸酶和sgRNA的复合物;优选的,所述细胞为造血干细胞。
进一步的,所述核酸酶和sgRNA的质量比为1-10:1,优选的,2-5:1,更优选3:1。
进一步的,所述核酸酶和sgRNA通过温育形成复合物;优选的,所述温育的温度为20-50℃,优选,25-45℃;优选的,所述温育的时间为2-30分钟,优选,5-20分钟。
进一步的,所述包含核酸酶和sgRNA的复合物与细胞的用量比例为1μg复合物:(1×102-1×106个)细胞,优选的,为1μg复合物:(1×103-1×105个)细胞。
另一方面,本发明还提供了包含核酸酶和sgRNA的复合物在制备治疗地中海贫血的试剂中的应用;优选的,所述核酸酶为Cas9或Cpf1,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列为5’CTTGTCAAGGCTATTGGTCA3’。
优选的,所述地中海贫血为β地中海贫血。
进一步的,所述应用包括将包含核酸酶和sgRNA的复合物引入到细胞中的步骤,所述引入优选为电转化。
有益效果:
本发明利用cas9蛋白和体外合成的sgRNA先在体外孵育形成复合物,然后通过电转的方法敲除造血干细胞HBG(γ珠蛋白基因)启动子上的抑制元件。相较于传统的慢病毒感染技术具有以下优势:
1.不需要利用病毒感染,免除了由于病毒导致的外源DNA随机整合。2.相较于病毒感染的方式,提高了临床应用的前景;利用病毒感染CRISPR/Cas9进行HBG启动子抑制元件的敲除需要进行长时间感染(大于72小时),此时体内取出的造血干细胞的干性已经大大降低,将会导致移植的成功率大大下降,并不真正适用于临床治疗。
附图说明
此处所说明的附图用来提供对本申请的进一步理解,构成本申请的一部分,本申请的示意性实施例及其说明用于解释本申请,并不构成对本申请的不当限定。在附图中:
图1为Cas9/sgRNA基因编辑方法流程图。
图2为Cas9/sgRNA体外形成复合物示意图。
图3为Cas9/sgRNA复合物编辑造血干细胞HBG位点示意图。
图4为sg-HBG1和sg-HBG2在细胞中的编辑效率。
图5为条件优化后在HUDEP2和HSPC细胞中的基因编辑效率。
图6为利用Cas9蛋白和sgRNA复合物编辑后检测编辑效率图。
图7为基因编辑后HBG mRNA基因含量检测结果。
图8为对比例1的sgRNA进行基因编辑后的检测结果,左图为编辑效率检测结果,右图为HBG的mRNA含量检测结果。
图9为采用电转质粒(P),AAV6感染CRISPR/Cas9系统(A),与电转Cas9/sgRNA复合物(C)编辑效率和HBG表达量结果检测图;左图为基因编辑效率检测结果,右图为HBG表达量检测结果。
具体实施方式
为了更清楚的阐释本申请的整体构思,下面以实施例的方式进行详细说明。在下文的描述中,给出了大量具体的细节以便提供对本申请更为彻底的理解。然而,对于本领域技术人员来说显而易见的是,本申请可以无需一个或多个这些细节而得以实施。在其他的例子中,为了避免与本申请发生混淆,对于本领域公知的一些技术特征未进行描述。
实施例1sgRNA的设计以及编辑效率的验证
本实施例中采用Cas9与sgRNA复合物通过电转化的方法在人类造血干细胞中引入该复合物,所述Cas9的氨基酸序列如SEQ ID No.5所示。方法流程如图1所示。具体的,如图2-3所示,Cas9和sgRNA在体外孵育可以形成复合物,电转进入造血干细胞后,可以靶向HBG1的基因上游元件进行切割从而上调HBG的表达。
在本实施方式中设计了两条sgRNA,sg-HBG1和sg-HBG2,sg-HBG1靶向序列为CTTGTCAAGGCTATTGGTCA,sg-HBG2靶向序列为CTTGACCAATAGCCTTGACA。体外分别合成两个对应位点化学修饰和未修饰的sgRNA。此处,化学修饰是指在sgRNA靶向序列的5’端第1位、第1-2位或第1-3位碱基,和/或3’端第1位、第1-2位或第1-3位碱基进行甲基化修饰。具体的,此实施例中的化学修饰为在sgRNA的5’末端第1-3位碱基以及3’末端第1-3位碱基进行甲基化修饰。
将sgRNA与Cas9混合后在37℃继续孵育10min电转HSPC细胞。此实施例中所用的Cas9浓度为5μM。最后将造血干细胞重悬在1ml stemspan培养基中。电转24小时后提取细胞基因组。将细胞以300g离心,利用酚氯仿抽提的方法获得实验组和对照组基因组DNA,取500ng基因组DNA,利用正向引物CCTTAGAAACCACTGCTAACTG和反向引物ATAACCTCAGACGTTCCAGAAGCGAGTGTG进行PCR扩增。扩增条件如下:95℃4min,95℃30s,53℃30s,72℃20s,72℃5min,16℃hold。如图4所示,将扩增产物进行深度测序或sanger测序后分析编辑效率,不管是修饰的还是非修饰的,sg-HBG1位点的编辑效率要始终高于sg-HBG2位点。此外,经过修饰的sg-HBG1的编辑效率要高于非修饰的sg-HBG1。
在具体的基因治疗中,需要将编辑效率提高到80%以上才能够获得很好的治疗效果,否则所表达的γ血红蛋白不足以达到治疗作用。必须对sg-HBG1位点的基因编辑条件进行优化。具体操作时,以1.5μM,2.5μM,5μM,10μM浓度的Cas9蛋白与sgRNA混合电转HUDEP2细胞,所述sgRNA的靶向序列为CTTGTCAAGGCTATTGGTCA;在sgRNA的5’末端第1-3位碱基以及3’末端第1-3位碱基进行甲基化修饰。24小时后取细胞基因组。将细胞以300g离心,利用酚氯仿抽提的方法获得实验组和对照组基因组DNA,取500ng基因组DNA,利用正向引物CCTTAGAAACCACTGCTAACTG和反向引物ATAACCTCAGACGTTCCAGAAGCGAGTGTG进行PCR扩增。扩增条件如下:95℃4min,95℃30s,53℃30s,72℃20s,72℃5min,16℃hold。将PCR产物进行深度测序或sanger测序分析后,如图5左所示在HUDEP2细胞中10μMCas9浓度体现出中最高的编辑效率,1.5μM浓度Cas9编辑效率最低。在原代造血干细胞中HSPC中,以2.5μM,5μM,10μMCas9与sg-HBG1进行混合电转,并提取DNA测序,如图5右所示,结果显示在HSPC细胞中5μMCas9浓度的编辑效率最高。
实施例2在人类造血干细胞中进行HBG启动子位点的编辑
本实施例中采用Cas9与sgRNA复合物通过电转化的方法在人类造血干细胞中引入该复合物,所述Cas9的氨基酸序列如SEQ ID No.5所示;所述sgRNA序列包括靶向序列和骨架序列,所述靶向序列为5’CTTGTCAAGGCTATTGGTCA3’(SEQ ID No.1),所述骨架序列为5’GTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGC3’(SEQ ID No.2);所述sgRNA序列为5’CTTGTCAAGGCTATTGGTCAGTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGC3’(SEQ ID No.3)。
在本实施方式中,在sgRNA(SEQ ID No.3)的5’末端第1-3位碱基以及3’末端第1-3位碱基进行甲基化修饰;在其他的实施方式中,还可以在sgRNA5’末端第1-5位碱基或3’末端第1-5位碱基的任意一个或任意几个碱基进行甲基化修饰,或其他的化学修饰,如,氟化修饰或硫代修饰。
具体而言:将150μg Cas9蛋白与50μg sgRNA在37℃体外孵育10分钟。形成复合物,复合物的体积控制在1-50μl以内,在优选的实施方式中,控制在15μl以内。计数,取1×106-5×106造血干细胞,以300g离心10min沉淀细胞,弃上清,将细胞重悬在100μl,Lonza电转试剂中。电转试剂由82μl solution buffer以及18μl supplement组成。
将上述Cas9蛋白与sgRNA形成的复合物加入到经过重悬的电转试剂中,对照组不加sgRNA只加入Cas9蛋白。在Lonza 4D nucleofector中以EO100程序进行电转。电转后将细胞和Cas9/sgRNA复合物在37℃继续孵育10min。最后将造血干细胞重悬在1ml stemspan培养基中。
将细胞以300g离心,利用酚氯仿抽提的方法获得实验组和对照组基因组DNA,取500ng基因组DNA,利用正向引物5’CCTTAGAAACCACTGCTAACTG3’和反向引物5’ATAACCTCAGACGTTCCAGAAGCGAGTGTG3’进行PCR扩增。扩增条件如下:95℃4min,95℃30s,53℃30s,72℃20s,72℃5min,16℃hold。
如图6所示,将扩增产物进行深度测序或sanger测序后分析编辑效率,在实验组的sanger测序图谱中可以清楚的看到编辑所产生的多峰信号,经过软件分析后所得编辑效率为80%,而对照组几乎没有多峰信号,编辑效率为0.5%(检测背景信号)。
实施例3基因编辑后HBG表达量检测
将实验组和对照组细胞在分化培养基1(stemspan含有:10%FBS,IL-3:10ng/ml,SCF:50ng/ml,EPO:1U/ml)中培养7天,之后300g离心10分种以沉淀细胞,换入分化培养基2(stemspan含有30%FBS,EPO:3U/ml)培养2天。以300g离心细胞。提取总mRNA,进行反转录获得cDNA。
利用HBG基因正向引物5’GATGCCATAAAGCACCTGGATG3’,反向引物5’TTGCAGAATAAAGCCTATCCTTGA3’进行HBG mRNA的QPCR扩增,利用HBB基因正向引物5’TCAAGGGCACCTTTGCCACAC3’反向引物5’TGATAGGCAGCCTGCACTG3’进行QPCR检测HBG mRNA相对于HBB基因的表达含量。如图7所示,经过编辑后HBG mRNA相对于HBB的含量,实验组明显升高。
对比例1采用其他的sgRNA对造血干细胞进行基因编辑
采用其他的sgRNA,序列为:5’ACTGGATACTCTAAGACTATGTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGC3’(SEQ ID No.4);
采用实施例1-2相同的方法进行编辑效率和HBG表达量的检测。
如图8所示,采用上述sgRNA的基因编辑效率高达90%以上,但是,其并无法提高HBG的mRNA含量。
对比例2采用其他方式对造血干细胞进行基因编辑
如图9所示,采用相同的电转方法,利用电转质粒以及电转感染CRISPR/Cas9系统的AAV6,都无法获得与电转Cas9/sgRNA复合物相当的编辑效率以及HBG上调效率。
其中,质粒的制备步骤如下:将实施例1中设计的sgRNA中的靶向序列采用5’CACCCTTGTCAAGGCTATTGGTCA3’和5’AAACTGACCAATAGCCTTGACAAG3’在体外退火后连接入px330质粒中,通过转化转入大肠杆菌进行扩增纯化,用于电转。
AAV6的制备步骤如下:将表达Cas9以及sgRNA的DNA序列连接入AAV表达载体,与AAV6,与AAV-helper质粒共转293T细胞,72小时后,收取转染的细胞,裂解后取上清液,通过密度梯度离心得到纯化后的AAV6病毒,通过超滤将AAV6病毒浓缩,用于感染。
以上所述仅为本申请的实施例而已,并不用于限制本申请。对于本领域技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原理之内所作的任何修改、等同替换、改进等,均应包含在本申请的权利要求范围之内。
SEQUENCE LISTING
<110> 华东师范大学 上海邦耀生物科技有限公司
<120> CRISPR基因编辑技术在治疗地中海贫血中的应用
<130> JH-CNP190438
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> DNA
<213> 人工序列
<400> 1
cttgtcaagg ctattggtca 20
<210> 2
<211> 76
<212> DNA
<213> 人工序列
<400> 2
gttttagagc tagaaatagc aagttaaaat aaggctagtc cgttatcaac ttgaaaaagt 60
ggcaccgagt cggtgc 76
<210> 3
<211> 96
<212> DNA
<213> 人工序列
<400> 3
cttgtcaagg ctattggtca gttttagagc tagaaatagc aagttaaaat aaggctagtc 60
cgttatcaac ttgaaaaagt ggcaccgagt cggtgc 96
<210> 4
<211> 96
<212> DNA
<213> 人工序列
<400> 4
actggatact ctaagactat gttttagagc tagaaatagc aagttaaaat aaggctagtc 60
cgttatcaac ttgaaaaagt ggcaccgagt cggtgc 96
<210> 5
<211> 1367
<212> PRT
<213> 人工序列
<400> 5
Asp Lys Lys Tyr Ser Ile Gly Leu Asp Ile Gly Thr Asn Ser Val Gly
1 5 10 15
Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe Lys
20 25 30
Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile Gly
35 40 45
Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu Lys
50 55 60
Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys Tyr
65 70 75 80
Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser Phe
85 90 95
Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys His
100 105 110
Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr His
115 120 125
Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp Ser
130 135 140
Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His Met
145 150 155 160
Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro Asp
165 170 175
Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr Asn
180 185 190
Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala Lys
195 200 205
Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn Leu
210 215 220
Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn Leu
225 230 235 240
Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe Asp
245 250 255
Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp Asp
260 265 270
Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp Leu
275 280 285
Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp Ile
290 295 300
Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser Met
305 310 315 320
Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys Ala
325 330 335
Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe Asp
340 345 350
Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser Gln
355 360 365
Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp Gly
370 375 380
Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg Lys
385 390 395 400
Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu Gly
405 410 415
Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe Leu
420 425 430
Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile Pro
435 440 445
Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp Met
450 455 460
Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu Val
465 470 475 480
Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr Asn
485 490 495
Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser Leu
500 505 510
Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys Tyr
515 520 525
Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln Lys
530 535 540
Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr Val
545 550 555 560
Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp Ser
565 570 575
Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly Thr
580 585 590
Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp Asn
595 600 605
Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr Leu
610 615 620
Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala His
625 630 635 640
Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr Thr
645 650 655
Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp Lys
660 665 670
Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe Ala
675 680 685
Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe Lys
690 695 700
Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu His
705 710 715 720
Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly Ile
725 730 735
Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly Arg
740 745 750
His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln Thr
755 760 765
Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile Glu
770 775 780
Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro Val
785 790 795 800
Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu Gln
805 810 815
Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg Leu
820 825 830
Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser Phe Leu Lys Asp
835 840 845
Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg Gly
850 855 860
Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys Asn
865 870 875 880
Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys Phe
885 890 895
Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp Lys
900 905 910
Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr Lys
915 920 925
His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp Glu
930 935 940
Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser Lys
945 950 955 960
Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg Glu
965 970 975
Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val Val
980 985 990
Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe Val
995 1000 1005
Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys
1010 1015 1020
Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr
1025 1030 1035
Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala Asn
1040 1045 1050
Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr
1055 1060 1065
Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg
1070 1075 1080
Lys Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu
1085 1090 1095
Val Gln Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg
1100 1105 1110
Asn Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys
1115 1120 1125
Lys Tyr Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu
1130 1135 1140
Val Val Ala Lys Val Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser
1145 1150 1155
Val Lys Glu Leu Leu Gly Ile Thr Ile Met Glu Arg Ser Ser Phe
1160 1165 1170
Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala Lys Gly Tyr Lys Glu
1175 1180 1185
Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys Tyr Ser Leu Phe
1190 1195 1200
Glu Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser Ala Gly Glu
1205 1210 1215
Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr Val Asn
1220 1225 1230
Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser Pro
1235 1240 1245
Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His Lys His
1250 1255 1260
Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg
1265 1270 1275
Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala Tyr
1280 1285 1290
Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile
1295 1300 1305
Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe
1310 1315 1320
Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr
1325 1330 1335
Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly
1340 1345 1350
Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1355 1360 1365
Claims (10)
1.一种CRISPR系统,所述系统包括至少一种核酸酶和至少一种sgRNA,所述sgRNA能够靶向HBG启动子的抑制元件,所述核酸酶能够切割HBG启动子的抑制元件,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列包括SEQ ID No.1所示序列或SEQ IDNo.1的互补序列;优选的,所述sgRNA包括碱基的化学修饰;更优选的,所述sgRNA包括5’末端第1-5位碱基的任意一个或任意几个碱基的化学修饰,和/或3’末端第1-5位碱基的任意一个或任意几个碱基的化学修饰;更优选的,所述化学修饰为甲基化修饰、氟化修饰或硫代修饰中的一种或任意几种。
2.根据权利要求1所述的CRISPR系统,其特征在于,所述核酸酶选自Cas蛋白或Cpf1蛋白,更优选的,所述Cas蛋白为Cas9,更优选的,所述Cas9的氨基酸序列如SEQ ID No.5所示。
3.一种包含核酸酶和sgRNA的复合物,其特征在于,所述sgRNA包括靶向HBG启动子的抑制元件的靶向序列,所述靶向序列包括SEQ ID No.1所示序列或SEQ ID No.1的互补序列;优选的,所述核酸酶选自Cas9或Cpf1;更优选的,所述Cas9选自Streptococcus pyogenes、Staphylococcus aureus或Neisseria.meningitidis来源的Cas9;更优选的,所述Cas9的氨基酸序列如SEQ ID No.5所示;优选的,所述sgRNA包括碱基的化学修饰;更优选的,所述sgRNA包括5’末端第1-5位碱基的任意一个或任意几个碱基的化学修饰,和/或3’末端第1-5位碱基的任意一个或任意几个碱基的化学修饰;更优选的,所述化学修饰为甲基化修饰、氟化修饰或硫代修饰中的一种或任意几种。
4.根据权利要求3所述的复合物,其特征在于,所述核酸酶和所述sgRNA的质量比为1-10:1,优选的,2-5:1,更优选3:1。
5.根据权利要求3或4所述的复合物,其特征在于,所述核酸酶和所述sgRNA通过温育形成复合物;优选的,所述温育的温度为20-50℃,优选,25-45℃;优选的,所述温育的时间为2-30分钟,优选,5-20分钟。
6.一种改变HBG基因表达的方法,所述方法包括向细胞中引入权利要求3-5任一所述复合物的步骤;优选的,所述改变HBG基因表达为上调HBG基因表达。
7.根据权利要求6所述的方法,其特征在于,采用电转化的方法向细胞中引入所述复合物;优选的,所述细胞为造血干细胞。
8.根据权利要求7所述的方法,其特征在于,所述复合物与细胞的用量比例为1μg复合物:(1×102-1×106个)细胞,优选的,为1μg复合物:(1×103-1×105个)细胞。
9.权利要求3-5任一所述的复合物在制备治疗地中海贫血的试剂中的应用;优选的,所述地中海贫血为β地中海贫血。
10.根据权利要求9所述的应用,其特征在于,所述应用包括将所述复合物引入到细胞中的步骤;优选的,所述引入选自电转化。
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