CN111629786B - 用于编辑rna的组合物和方法 - Google Patents
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- CN111629786B CN111629786B CN201880073848.3A CN201880073848A CN111629786B CN 111629786 B CN111629786 B CN 111629786B CN 201880073848 A CN201880073848 A CN 201880073848A CN 111629786 B CN111629786 B CN 111629786B
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Abstract
提供了用于编辑内源RNA分子的组合物和方法。
Description
本申请在35U.S.C.119(e)下要求2017年10月6日提交的美国临时专利申请号62/569,376的优先权。前述申请并入本文作为参考。
本发明是在National Institutes of Health提供的经费号NS087726的政府支持下进行的。政府对本发明具有一定的权利。
以电子形式提交的文本文件的说明
以电子形式一同提交的文本文件的内容以其全部内容并入本文作为参考:序列表的计算机可读格式拷贝(文件名:SEQLIST.txt;记录日期:2018年10月9日;文件大小:44.6KB)。
技术领域
本发明涉及核酸编辑领域。具体地,公开了用于治疗性编辑RNA、特别是核内的内源RNA的组合物和方法。
背景技术
为了描述本发明所属领域的现有技术水平,在整个说明书中引用了一些出版物和专利文件。这些引用中的每一个以完整说明的一样并入本文作为参考。
在编辑或改变遗传物质的策略中已做出了进步,例如,多种基因编辑技术。然而,仍需要修正导致疾病的突变、特别是神经***中导致疾病的突变的方法。
Rett综合征是转录因子甲基CpG结合蛋白2(MECP2)中的散布性突变(sporadicmutations)所引起的神经发育病症(Amir et al.(1999)Nat.Genet.,23:185-188)。MECP2位于X染色体上。由于哺乳动物中的剂量补偿(dosage compensation)机制,患有Rett综合征的女性是镶嵌型的(mosaic),在野生型细胞和突变细胞之间具有约50:50的分离。具有MECP2突变的女性经历早期发育标志退化,如语言和有目的的手部运动,然后获得严重的运动异常,包括呼吸运动异常,并且平均在40岁死亡(Neul et al.,(2010)Ann.Neurol.,68:944-950;Percy et al.(2010)Ann.Neurol.,68:951-955)。在MECP2中具有突变的男性具有单个X染色体,其具有更加严重的疾病,通常在2岁之前死亡(Schule et al.(2008)Clin.Genet.,74:116-126)。尚无治愈Rett综合征的方法。
发明内容
根据本发明的一个方面,提供了用于编辑细胞中、特别是细胞核中的内源RNA序列的方法。在某些实施方式中,该方法包括向细胞递送:i)编码包含核定位信号和连接至RNA结合域的RNA编辑酶的融合蛋白的核酸分子,和ii)编码一种或多种向导RNA的核酸分子。向导RNA包含RNA结合域特异性识别的序列。向导RNA还与内源RNA中的靶标序列特异性杂交并且在待编辑的核苷酸处包含错配(mismatch)。在某些实施方式中,RNA编辑酶是作用于RNA的腺苷脱氨酶(Adenosine Deaminase Acting on RNA,ADAR),如ADRAR1或ADAR2。在某些实施方式中,RNA结合域是λN肽,并且RNA结合域特异性识别的序列是BoxB序列。在某些实施方式中,内源RNA是甲基CpG结合蛋白2(MECP2)RNA。在某些实施方式中,核定位信号是SV40大T抗原核定位信号。这些方法的核酸分子可以包含在单一载体内,如病毒载体(例如,腺相关病毒(AAV)载体)。
根据本发明的另一个方面,提供了用于编辑细胞中、特别是细胞核中的内源RNA序列的其它方法。在某些实施方式中,该方法包括向细胞递送编码一种或多种向导RNA的核酸分子,其中向导RNA包含内源脱氨酶、如人作用于RNA的腺苷脱氨酶(ADAR)特异性识别的序列和/或结构。向导RNA还与内源RNA中的靶标序列特异性杂交并且在待编辑的核苷酸处包含错配。在某些实施方式中,ADAR是ADRA1或ADAR2。在某些实施方式中,内源RNA是甲基CpG结合蛋白2(MECP2)RNA。在某些实施方式中,核酸分子包含在病毒载体(例如,AAV载体)内。
根据本发明的另一个方面,提供了用于编辑细胞中、特别是细胞核中的内源RNA序列的其它方法。在某些实施方式中,该方法包括向细胞递送编码向导RNA(例如,AAV内的向导RNA)的核酸分子,其中向导RNA包含内源人作用于RNA的腺苷脱氨酶(ADAR)特异性识别的序列和/或结构。因此,在多个方面,本发明的用于编辑的方法可以在不存在重组RNA编辑酶的情况下(例如,在不存在重组ADAR的情况下)进行。因此,在实施方式中,本发明的方法利用内源ADAR活性来进行本文的编辑。
根据本发明的另一个方面,提供了治疗、抑制和/或预防受试者中的Rett综合征的方法。在某些实施方式中,该方法包括使用本发明的RNA编辑方法。例如,该方法可以包括向受试者施用编码包含连接至RNA结合域的RNA编辑酶的融合蛋白的核酸分子和编码向导RNA的核酸分子,其中该融合蛋白包含核定位信号。在某些实施方式中,该方法包括向受试者施用编码向导RNA的核酸分子,其中向导RNA包含内源人脱氨酶、如作用于RNA的腺苷脱氨酶(ADAR)特异性识别的序列和/或结构,并且其中向导RNA与甲基CpG结合蛋白2(MECP2)RNA特异性杂交并且在内源MECP2 RNA的突变核苷酸处包含错配。
附图说明
图1A-1D显示编辑效率是序列依赖性的。图1A:显示三种G>A突变相对于MeCP2中的甲基DNA结合域(MBD)、转录阻遏子域(TRD)和NCoR相互作用域(NID)的位置的示意图。图1B:定点RNA编辑的核心组件的示意图。杂交Editase含有来自噬菌体λ的RNA结合域(λN)和人作用于RNA的腺苷脱氨酶2(hADAR2)的催化域(脱氨酶域)。还包括3个拷贝的核定位信号(NLS)和2个拷贝的人流感血球凝集素(HA)-表位标签,但是未显示。向导RNA与Mecp2 mRNA互补,并且含有λN RNA结合域所识别的发夹(茎环)。与靶标A相反,已将C引入向导以提高编辑效率。图1C:在具有(顶部)或不具有(底部)向导的Editase向N2A成神经细胞瘤细胞转染后,Mecp2W104X cDNA的测序色谱图。图1D:使用Mecp2 cDNA直接测序定量并且包括图1C中的数据的A-向-I编辑的百分比(平均值±SD;n=3)。浅灰色柱,仅用Editase转染的细胞;深灰色柱,用Editase和向导转染的细胞。通过单因素ANOVA和Bonferroni事后检验,***P<0.001,****P<0.0001。ns:不显著。
图2A-2F显示使用对Mecp2 mRNA具有位点特异性A-G错配的向导,可以减少通过更有效的Editase的脱靶编辑。图2A:向导RNA和EditaseWT或EditaseE488Q向N2A细胞转染后,R106Q(平均值±SD,n=3)位点处A-向-I编辑的百分比(平均值±SD;n=3,包括图2B中的数据)。图2B:用EditaseWT(顶部)或EditaseE488Q(底部)编辑的Mecp2R106Q cDNA的代表性色谱图。图2C:相对于两种不同的向导RNA的MeCP2 mRNA。标准向导(顶部)在靶标A(加粗突出显示)含有A-C错配(R106Q)以提高编辑。修饰的向导(底部)在通过星号标记的脱靶A含有A-G错配以抑制该位点处的编辑。所提供的靶标序列为SEQ ID NO:52。图2D:在用EditaseE488Q和在靶标位点仅含有错配的向导(顶部)或者在脱靶位点含有中靶A-C错配和A-G错配两者的修饰的向导(底部)转染N2A细胞之后的MeCP2 cDNA的色谱图。图2E:通过含有A-G错配的向导严重减少了脱靶编辑(平均值±SD;n=3,包括图2D中的数据)。图2F:脱靶A-G错配的存在不影响R106Q位点处的编辑(平均值±SD;n=3,包括图2D中的数据)。浅灰色柱,仅用Editase转染的细胞;深灰色柱,用Editase和向导转染的细胞;黑色柱,用Editase和含有A-G错配的向导转染的细胞。通过单因素ANOVA和Bonferroni事后检验,**P<0.01,***P<0.001,****P<0.0001。ns:不显著。
图3A-3B显示了原代神经元的AAV1/2转导后,内源MeCP2 mRNA的序列分析。图3A:在用AAV1/2病毒转导后7天,通过分离自Mecp2R106Q/y海马神经元(DIV14)的cDNA的序列分析的编辑定量(平均值±SD,n=3)。+向导是指含有受神经元突触素I启动子控制的Editase和分别受U6启动子控制表达的6个拷贝的向导的AAV1/2。向导在靶标A对于R106Q含有C错配,并且在脱靶A T105T含有G错配。对照病毒编码受突触素I启动子控制的Editase,但缺少任何向导序列(-向导)。通过非配对双尾t检验,****P<0.0001。图3B:相对于向导RNA区的Mecp2 mRNA(SEQ ID NO:52)和原代氨基酸序列(SEQ ID NO:53)。对靶标A加粗,并且星号表示脱靶编辑的A残基。向导中的发夹表示λN肽识别的BoxB序列的位置。图提供了对Mecp2mRNA内的脱靶位点处的编辑的定量(平均值±SD;n=3)。残基N126S在向导区外部。
图4显示定点RNA编辑提高了MeCP2蛋白水平,借此表明了在编辑之后,内源导致疾病的蛋白的功能恢复。提供了7天前,用表达单独的Editase或者Editase和向导的AAV1/2转导的Mecp2R106Q/y或野生型(WT,Mecp2+/y)姊妹株(sibling)海马神经元(DIV14)的全细胞裂解液的代表性免疫印迹。向导在R106Q位点含有C错配,并且在脱靶A,T105T含有G错配。图提供了免疫印迹的定量(平均值±SD,n=3),每个条件均对β-肌动蛋白进行归一化。浅灰色柱,仅用Editase转导的细胞;深灰色柱,用Editase和向导转导的细胞。通过非配对双尾t检验,***P<0.001。
图5A-5G显示定点RNA编辑恢复了MeCP2结合至异染色质的能力,从而表明在编辑后,内原蛋白功能的恢复。显示了对Editase(HA)和MeCP2免疫标记的海马神经元(DIV14)的代表性共聚焦图像。DAPI染色指出了核并显示了异染色质焦点。插图划定了在邻近的图中以更高放大倍数和更高增益成像的细胞。图5A:野生型(Mecp2+/y)神经元培养物。图5B:用仅表达Editase(无向导)的AAV1/2病毒转导的Mecp2R106Q/y神经元培养物。这些神经元从未显示出MeCP2在异染色质中的富集。图5C和5D:用表达Editase和在靶标A含有C错配的向导的AAV1/2病毒转导的Mecp2R106Q/y神经元培养物。在图5D中,+和-分别表示在异染色质中存在和不存在MeCP2富集的核。比例尺,10μm。图5E-5G:各柱状图代表了来自3个载玻片中的每一个的三个视野的细胞定量(仅Editase,n=134;Editase和向导,n=137)(平均值±SD)。图5E:在对来自未感染的细胞信号设定阈值后,通过HA核染色识别的Editase+细胞的百分比。百分比相对于DAPI+细胞的总数。图5F:在异染色质(焦点)中具有MeCP2富集的Editase+细胞的百分比。图5G:在异染色质(焦点)中具有MeCP2富集的所有细胞的百分比。ns:不显著。
图6提供了来自野生型小鼠或者用编码仅Editase或Editase和向导RNA的AAV载体处理的Mecp2317G>A(Mecp2R106Q)小鼠的脑中的齿状神经元异染色质中的MeCP2强度图。
图7提供了多种向导RNA的示意图以及不处理或用具有2个BoxB茎环的向导RNA、包含来自GluA2的R/G结合位点的向导RNA或者具有内环的向导RNA处理的HEK细胞中的Mecp2317G>A(Mecp2R106Q)的编辑百分比的图。还用受CMV启动子控制的全长天然ADAR2 cDNA转染HEK细胞。
具体实施方式
本发明部分基于以下出乎意料的发现:可以使用定点RNA编辑,从而在RNA水平(例如,mRNA)修复导致疾病的点突变,例如,Rett综合征潜在的甲基CpG结合蛋白2(MECP2)DNA结合域基因中的鸟苷向腺苷(G>A)的突变。重要地,这种定点RNA编辑(尤其是)对于修复内源RNA和恢复蛋白功能是有用的。因此,在实施方式中,本发明涉及用于定点RNA编辑的组合物和方法。
具有在人中引起Rett综合征的Mecp2中的突变的工程化小鼠(种系(生殖细胞系,germ line)或限制于神经细胞中的任一种)显示出生长异常、焦虑和运动缺陷,这类似于Rett综合征患者(Guy et al.(2001)Nat.Genet.,27:322-326;Lioy et al.(2011)Nature475:497-500;Chen et al.(2001)Nat.Genet.,27:327-331)。小鼠中的研究表明最稳健的Rett综合征表型是神经学表型,其影响神经元和神经胶质两者(Lioy et al.(2011)Nature475:497-500;Luikenhuis et al.(2004)Proc.Natl.Acad.Sci.,101:6033-6038),尽管多种其它组织也可能受影响(Ross et al.(2016)Hum.Mol.Genet.,25:4389-4404)。如人中一样,雄性Rett小鼠所患疾病比雌性小鼠更严重。例如,雌性Rett小鼠具有正常寿命期,而雄性小鼠在3至4个月大时死亡(Guy et al.(2001)Nat.Genet.,27:322-326;Chen et al.(2001)Nat.Genet.,27:327-331)。在细胞水平,Rett雄性和雌性小鼠中的神经细胞具有较小的胞体、核并且过程复杂性降低(Belichenko et al.(2009)Neurobiol.Dis.,34:71-77;Belichenko et al.(2009)J.Comp.Neurol.,514:240-258;Fukuda et al.(2005)J.Neuropathol.Exp.Neurol.,64:537-544;Kishi et al.(2004)Mol.Cell.Neurosci.,27:306-321;Robinson et al.(2012)Brain 135:2699-2710;Tropea et al.(2009)Proc.Natl.Acad.Sci.,106:2029-2034;Stuss et al.(2012)PLoS One 7:e31896),这使人想起受影响的人细胞(Armstrong et al.(1995)J.Neuropathol.Exp.Neurol.,54:195-201;Li et al.(2013)Cell Stem Cell 13:446-458;Belichenko et al.(1994)Neuroreport.,5:1509-1513;Bauman et al.(1995)Neurology 45:1581-1586)。重要地,通过条件性Cre重组酶(Guy et al.(2007)Science 315:1143-1147)或基因疗法方法(Sinnett et al.(2017)Mol.Ther.Methods Clin.Dev.,5:106-115;Gadalla et al.(2017)Mol.Ther.Methods Clin.Dev.,5:180-190;Garg et al.(2013)J.Neurosci.,33:13612-13620;Gadalla et al.(2013)Mol.Ther.,21:18-30),Mecp2-缺陷小鼠(Mecp2-nullmice)中MeCP2的恢复逆转了多种Rett-样症状和细胞缺陷,甚至是在疾病晚期。表型逆转表明在人中,可以用基因替换策略来治疗Rett综合征(Robinson et al.(2012)Brain 135:2699-2710;Sinnett et al.(2017)Mol.Ther.Methods Clin.Dev.,5:106-115;Gadalla etal.(2017)Mol.Ther.Methods Clin.Dev.,5:180-190;Garg et al.(2013)J.Neurosci.,33:13612-13620;Gadalla et al.(2013)Mol.Ther.,21:18-30)。然而,在人中MeCP2基因的重复导致MeCP2过表达和严重的神经障碍(Van Esch et al.(2005)Am.J.Hum.Genet.,77:442-453)。此外,在不同的神经细胞类型中,小鼠中MeCP2的表达水平不同,并且小鼠中MeCP2功能的丧失导致了基因表达中细胞特异性的变化(Skene et al.(2010)Mol.Cell.,37:457-468;Ballas et al.(2009)Nat.Neurosci.,12:311-317;Shahbazian et al.(2002)Hum.Mol.Genet.,11:115-124;Sugino et al.(2014)J.Neurosci.,34:12877-12883;Linhoff et al.(2015)Cell 163:246-255)。这些发现着重说明必需精细调节MeCP2基因替换,从而在神经***中的多种细胞类型之间恢复正常MeCP2水平和细胞生理学的困难。
在本文中,已表明由于在正常转录本的背景中修复RNA,因此在RNA水平修复MECP2突变克服了MECP2过表达和细胞类型特异性调控两个问题。靶向了Rett综合征潜在的鸟苷向腺苷(G>A)的突变(Fyfe et al.(2003)J.Child.Neurol.,18:709-713)。天然存在的酶家族—作用于RNA的腺苷脱氨酶(ADAR)在内源mRNA中通过水解使A脱氨基为肌苷(I)(Bass etal.(1988)Cell 55:1089-1098;Bass et al.(1987)Cell 48:607-613;Melcher et al.(1996)Nature 379:460-464;O’Connell et al.(1998)Methods 15:51-62;Kim et al.(1994)Proc.Natl.Acad.Sci.,91:11457-11461)。肌苷与胞嘧啶(C)碱基配对并通过核糖体翻译为G(Basilio et al.(1962)Proc.Natl.Acad.Sci.,48:613–616)。一种ADAR家族成员ADAR2在脑中高水平表达,在脑中它通过初级转录本的脱氨基,在转录后改变蛋白功能,如离子通道渗透性(Bhalla et al.(2004)Nat.Struct.Mol.Biol.,11:950-956;Sommer etal.(1991)Cell 67:11-19;Burns et al.(1997)Nature 387:303-308)。除其催化活性之外,通过ADAR2的天然编辑需要通过前体mRNA中的内含子介导的双链RNA结构的识别,其将靶标A正确布置在外显子中用于编辑(Bhalla et al.(2004)Nat.Struct.Mol.Biol.,11:950-956;Dawson et al.(2004)J.Biol.Chem.,279:4941-4951;Higuchi et al.(1993)Cell 75:1361-1370;Maas et al.(1996)J.Biol.Chem.,271:12221-12226;Lomeli et al.(1994)Science266:1709-1713;Yang et al.(1997)Proc.Natl.Acad.Sci.,94:4354-4359)。已利用处于多种构型的人ADAR2(hADAR2)中的克隆催化域来靶向异源表达的mRNA中的G>A修复,其通常在终止密码子处(Hanswillemenke et al.(2015)J.Am.Chem.Soc.,137:15875-15881;Vogel et al.(2014)ChemMedChem 9:2021-2025;Vogel et al.(2014)AngewChem.Int.Ed.Engl.,53:6267-6271;Schneider et al.(2014)Nucleic Acids Res.,42:e87;Montiel-González et al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalezet al.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)。在一种方法中,用来自噬菌体λ的以纳摩尔亲和力结合至特异性短RNA发卡(Austin et al.(2002)J.Am.Chem.Soc.,124:10966-10967)的RNA结合肽(λN;Montiel-Gonzalez et al.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)替换ADAR2中的天然RNA结合域。然后,通过杂交ADAR2蛋白与含有λN识别的茎环和与靶标mRNA互补的区域的RNA向导一起表达,实现了异源mRNA的靶向编辑(Montiel-González et al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalez etal.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)。
先前,尚无通过定点RNA编辑修复的内源RNA或mRNA,特别是对于获得功能蛋白的修复。然而,在本文中首次证实了这种用于内源Mecp2中G>A突变的方法。Mecp2中的突变位于编码确定功能的域中。另外,可以通过序列分析、Western印迹并且在单细胞水平、通过免疫化学监测修复的保真度。在本文中,将重组hADAR2-λN蛋白(在本文中也称为Editase)用于内源Mecp2转录本内G>A突变的有效修复。在确定转染的小鼠成神经细胞瘤(N2A)细胞中的Mecp2编辑参数之后,将腺相关病毒(AAV)用于转导来自在DNA结合域中含有严重的人G>A突变(MeCP2317G>A;MeCP2R106Q)的Rett综合征小鼠模型的原代神经元培养物。这种突变导致MeCP2蛋白水平降低并且导致与异染色质的结合大大降低。首先,在神经元中定量突变RNA的编辑效率,然后测试编辑是否能够挽救MeCP2蛋白水平并致使在异染色质焦点中的结合的富集,这是MeCP2在细胞,包括神经元、神经胶质和非神经元细胞类型中的重要性质。本文所提供的结果显示定点RNA编辑可以治疗性地修复Rett综合征以及受基因疗法作用的其它神经学疾病潜在的导致疾病的MeCP2突变。
根据本发明,提供了编辑细胞中核酸分子的方法。在具体的实施方式中,待编辑的核酸分子是RNA分子,具体地核内的RNA分子(例如,初级转录本、前体mRNA或mRNA(例如,从核中转运出之前的mRNA))。在具体的实施方式中,待编辑的核酸分子是内源的和/或是核转录本。通过基因编辑如通过CRISPR技术,基因组中的脱靶突变是永久性的。相反,细胞中的RNA转换表示RNA内的脱靶突变将是暂时的。另外,不同于CRISPR基因组编辑,RNA编辑可以被降解。因此,脱靶突变不必需编辑成100%。
在实施方式中,本发明提供了RNA编辑核酸分子的方法,其提供了蛋白表达和/或功能的精细调节。例如,本发明的方法使得能够相对于未编辑的状态,使蛋白的表达和/或功能恢复至正常水平。在本文所述的处理背景中,本发明的方法使得能够相对于未处理的状态,使蛋白的表达和/或功能恢复至正常水平或至少接近正常水平。
在实施方式中,本发明提供了RNA编辑核酸分子的方法,其(例如)在所述的疗法的背景中提供了(例如,通过剂量施用)可调的瞬时编辑。例如,本发明使得能够对靶标RNA进行可逆编辑。
在具体的实施方式中,待编辑的细胞是非***细胞。在具体的实施方式中,待编辑的细胞是神经元和/或胶质细胞。在具体的实施方式中,待编辑的细胞是非神经元细胞。在具体的实施方式中,待编辑的细胞是神经元。细胞(例如,神经元)可以位于中枢神经***(例如,脑、脊髓)和/或周围神经***中。细胞可以处于要治疗(例如,体内处理方法)的受试者中或者可以体外处理细胞,然后向受试者施用细胞(例如,离体处理方法)。
在本发明的某些实施方式中,该方法包括向细胞递送1)编码连接或融合至RNA结合域的RNA编辑酶的核酸分子和2)向导RNA或编码向导RNA的核酸分子。在具体的实施方式中,RNA结合域连接至RNA编辑酶的N末端。在实施方式中,包含RNA编辑酶和RNA结合域的融合蛋白不包含至少一个核定位信号(NLS)。在实施方式中,包含RNA编辑酶和RNA结合域的融合蛋白还包含至少一个核定位信号(NLS)。例如,包含RNA编辑酶和RNA结合域的融合蛋白还包含1、2、3、4、5或更多个NLS。当使用多个NLS时,每个NLS可以直接彼此连接或者通过1至约5个氨基酸的氨基酸接头间隔。在具体的实施方式中,NLS位于融合蛋白的N末端。在Kosugi等人(J.Biol.Chem.(2009)284:478-485;并入本文作为参考)中提供了NLS的实例。在具体的实施方式中,NLS包含共有序列K(K/R)X(K/R)(SEQ ID NO:58)(例如,单分型NLS)。在具体的实施方式中,NLS包含共有序列(K/R)(K/R)X10-12(K/R)3/5(SEQ ID NO:59),其中(K/R)3/5表示5个氨基酸中的至少3个是赖氨酸或精氨酸。在具体的实施方式中,NLS包括c-myc NLS。在具体的实施方式中,c-myc NLS包含序列PAAKRVKLD(SEQ ID NO:54)。在具体的实施方式中,NLS是核质蛋白NLS。在具体的实施方式中,核质蛋白NLS包含序列KRPAATKKAGQAKKKK(SEQID NO:60)。在具体的实施方式中,NLS包括SV40大T抗原NLS。在具体的实施方式中,SV40大T抗原NLS包含序列PKKKRKV(SEQ ID NO:47)。在具体的实施方式中,融合蛋白包含3个SV40大T抗原NLS(例如,序列DPKKKRKVDPKKKRKVDPKKKRKV(SEQ ID NO:67))。在多个实施方式中,NLS可以在上述序列(例如,SEQ ID NO:58、59、60、47、54或67)中包含突变/变化,从而使它们含有1个或多个替换、添加或缺失(例如,约1,或约2,或约3,或约4,或约5,或约10,或约15,包括约1至5,或约1至10,或约1至15个替换、添加或缺失)。在具体的实施方式中,NLS内的赖氨酸氨基酸可以被精氨酸氨基酸替换,和/或NLS内的精氨酸氨基酸可以被赖氨酸氨基酸替换。融合蛋白还可以任选地在融合蛋白的N末端包含纯化标签(例如,HA标签)。
本发明的核酸分子可以包含在单个载体内或者包含在不同的载体内。例如,编码连接或融合至RNA结合域的RNA编辑酶的核酸分子和编码向导RNA的核酸分子包含在单个载体内。可以将核酸分子连续(之前或之后)和/或在相同时间(同时)递送至细胞。可以在同一组合物或在不同组合物(例如,当包含在不同的载体中时)中递送核酸分子。在具体的实施方式中,在单个载体,具体地病毒载体,如AAV载体中递送核酸分子。
在具体的实施方式中,RNA编辑酶是人的。在具体的实施方式中,RNA编辑酶是脱氨酶。脱氨酶的实例无限制地包括作用于RNA的腺苷脱氨酶(ADAR)、脱脂蛋白B mRNA编辑酶、催化多肽样蛋白(APOBEC(例如,APOBEC1、APOBEC3A、APOBEC3G))和激活诱导的胞苷脱氨酶(AICDA或AID;将C:G转化为T:A)。在具体的实施方式中,RNA编辑酶是ADAR,如ADAR1、ADAR2或ADAR3。在具体的实施方式中,RNA编辑酶是ADAR1(参见,例如,Gene ID:103和GenBank登录号NM_001111.5和NP_001102.3及其同工型)。在具体的实施方式中,RNA编辑酶是ADAR2。RNA编辑酶可以小于全长。在具体的实施方式中,RNA编辑酶缺少其天然RNA结合域。例如,RNA编辑酶可以包含酶的催化域或由其组成。
人ADAR1的氨基酸序列的实例为:
在具体的实施方式中,ADAR1的脱氨酶域包括SEQ ID NO:72的氨基酸839-1222。在具体的实施方式中,RNA编辑酶包括与其脱氨酶域的SEQ ID NO:72具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列。
在具体的实施方式中,RNA编辑酶包括人ADAR2的脱氨酶域。在具体的实施方式中,人ADAR2的脱氨酶域包括GenBank登录号U82120的氨基酸299-701。在具体的实施方式中,ADAR2或其脱氨酶域包括E488Q突变(Montiel-González et al.(2016)Nucleic AcidsRes.,44:e157)。在具体的实施方式中,人ADAR2的脱氨酶域包括:
在具体的实施方式中,人ADAR2的脱氨酶域包括:
在具体的实施方式中,RNA编辑酶包括与SEQ ID NO:55或71具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列。
如上所述,RNA编辑酶连接至RNA结合域。RNA编辑酶可以直接(即,无接头序列)连接至RNA结合域或者可以通过多肽接头连接。例如,多肽接头可以包含1至约50个氨基酸,1至约25个氨基酸,1至约20个氨基酸,1至约15个氨基酸,1至约10个氨基酸或者1至约5个氨基酸。在具体的实施方式中,接头包括序列(GGGGS)n(SEQ ID NO:44),其中n为1至约10,具体地1至约5。例如,接头序列可以是:GGGGSGGGGSGGGGS(SEQ ID NO:45)。在多个实施方式中,接头可以在上述序列(例如,SEQ ID NO:44或45)中包含突变/变化,从而使它们含有1个或多个替换、添加或缺失(例如,约1,或约2,或约3,或约4,或约5,或约10,或约15,包括约1至5,或约1至10,或约1至15个替换、添加或缺失)。
RNA结合域可以是特异性识别特定RNA序列和/或RNA结构(例如,发夹)的任何多肽。在具体的实施方式中,RNA结合域是人工RNA结合域,具体地,对RNA具有高亲合力的RNA结合域。在具体的实施方式中,RNA结合域是噬菌体RNA结合域(参见,例如,Keryer-Bibenset al.Biol.Cell(2008)100:125-138)。例如,RNA结合域是λN肽(参见,例如,Cilley etal.RNA(1997)3:57-67)或噬菌体MS2外壳蛋白(coat protein)(参见,例如,Johansson etal.Sem.Virol.(1997)8:176-185)。在具体的实施方式中,λN肽包含以下氨基酸序列:MNARTRRRERRAEKQAQWKAAN(SEQ ID NO:46)。在具体的实施方式中,λN肽包括与SEQ ID NO:46具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列。
在实施方式中,融合蛋白包含通过氨基酸接头连接至人ADAR2脱氨酶域(例如,SEQID NO:55或71)的氨基末端的λN肽(SEQ ID NO:46)。在具体的实施方式中,接头包括序列(GGGGS)n(SEQ ID NO:44;其中n为1至约10或者1至约5)或者序列GGGGSGGGGSGGGGS(SEQ IDNO:45)。在具体的实施方式中,融合蛋白包括以下序列:
在具体的实施方式中,融合蛋白还在N末端包含至少一个NLS。在具体的实施方式中,NLS包括SV40大T抗原NLS(例如,SEQ ID NO:47)。在具体的实施方式中,融合蛋白包含3个SV40大T抗原NLS(例如,SEQ ID NO:67)。在具体的实施方式中,融合蛋白包括以下序列:
在具体的实施方式中,融合蛋白包括与SEQ ID NO:68或69具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列。
本发明的向导RNA包括靶向靶标序列(例如,互补序列)或与靶标序列特异性杂交的序列,以及RNA结合域所识别的序列。向导RNA包括与针对待改变或待编辑的核苷酸(例如,腺苷)的靶标序列的错配。如本文所使用的,术语“特异性杂交”不表示核酸分子需要与靶标序列100%互补。而是,序列—不包括待改变/待编辑的错配核苷酸—可以与靶标序列至少80%、85%、90%、95%、97%、99%或100%互补,具体地至少95%、97%、99%或100%互补。然而,如本文所解释的,该序列可以包含附加的错配(例如,G错配)以减少脱靶编辑。在实施方式中,该序列可以含有约1,或约2,或约3,或约4,或约5,或约10,或约15,包括约1至5,或约1至10,或约1至15个错配。在具体的实施方式中,具有互补性的区域(例如,向导RNA和靶标序列之间)为至少约10,至少约12,至少约15,至少约17,至少约20,至少约25,至少约30,至少约35个或更多个核苷酸。在具体的实施方式中,具有互补性的区域(例如,向导RNA和靶标序列之间)为约15至约30个核苷酸,约15至约25个核苷酸,约20至约30个核苷酸,约20至约25个核苷酸,或者约20、21、22、23、24或25个核苷酸。通常,向导RNA和靶标序列之间的错配将朝向向导RNA和靶标序列之间的互补性区域的中间(例如,在向导RNA序列的中间50%内)。在具体的实施方式中,靶标序列包括SEQ ID NO:52。
向导RNA包括对细胞中RNA的修正或所期望的编辑。向导RNA可以用于修正任何突变,具体地点突变,包括错义突变和无义突变。例如,对于Rett综合征,存在常见的G>A突变。这些突变导致以下氨基酸变化:R106Q(CAA)、W104X(UAG)和R306H(CAC)。就无义突变来说,这些可以是C向T的突变,且A处于3'位以形成终止密码子或者处于中间位置(例如,UAG至UGG)。可以编辑无义突变以除去终止密码子。在具体的实施方式中,向导RNA包括C以匹配这些突变体的A,从而可以将A脱氨基为I(例如,通过ADAR)。
本发明的向导RNA包括RNA结合域所识别的一个或多个序列。在具体的实施方式中,向导RNA包括RNA结合域所识别的两个序列。在具体的实施方式中,RNA结合域所识别的两个序列可以位于错配或与靶标序列特异性杂交的序列的两侧。例如,RNA结合域所识别的一个序列(例如,BoxB)位于靶标突变5'端的约15-20或者约16-18个核苷酸,并且RNA结合域所识别的第二序列(例如,BoxB)位于靶标突变3'端的约8-12或约10个核苷酸。在具体的实施方式中,RNA结合域所识别的序列不位于向导RNA的末端(即,向导RNA末端的序列可以与靶标序列互补)。当存在RNA结合域所识别的两个或更多个序列时,序列可以是相同或不同的—尽管优选地通过相同的RNA结合域识别它们。在具体的实施方式中,RNA结合域所识别的序列是BoxB序列。在具体的实施方式中,BoxB序列包括GCCCUGAAAAAGGGC(SEQ ID NO:48)或者GGCCCUGAAAAAGGGCC(SEQ ID NO:49)。在具体的实施方式中,BoxB序列与SEQ ID NO:48或49具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性。
在具体的实施方式中,向导RNA靶向表1中所列的序列或者包括表1中所列的序列(包括DNA分子的RNA形式)。在具体的实施方式中,向导RNA靶向与表1中所列的序列具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列或者包括该序列。在具体的实施方式中,向导RNA包括SEQ ID NO:15-22中的一个,具体地SEQ ID NO:15、17、19或21,或者包括与SEQ ID NO:15-22中的一个,具体地SEQ ID NO:15、17、19或者21具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列。
包含编码向导RNA的核酸序列的核酸分子可以包含编码向导RNA的核酸序列的多个拷贝。例如,核酸分子可以包含分别受启动子控制的1、2、3、4、5、6、7、8、9、10或更多个编码向导RNA的核酸序列的拷贝。
在具体的实施方式中,通过载体(例如,质粒)、具体地病毒载体递送(例如,通过感染、转染、电穿孔等)并在细胞中表达本发明的核酸分子。本发明的表达载体可以使用强启动子、组成型启动子、组织或细胞特异性启动子、泛在启动子和/或调控启动子。在具体的实施方式中,编码连接或融合至RNA结合域的RNA编辑酶的核酸分子的启动子是组织或细胞特异性启动子。在具体的实施方式中,启动子是神经元特异性启动子或泛在启动子。启动子的实例在本领域中是熟知的并且包括(但不限于)突触素启动子,具体地突触素I启动子、CAG启动子和MECP2启动子。对于向导RNA,RNA启动子的实例在本领域中是熟知的并且包括(但不限于)RNA聚合酶III启动子(例如,U6和H1;参见,例如,Myslinski et al.(2001)Nucl.Acids Res.,29:2502-09)或已知表达短RNA的其它启动子。在具体的实施方式中,启动子是人U6启动子。表达本发明的分子的表达载体的实例无限制地包括质粒和病毒载体(例如,腺相关病毒(AAV)、腺病毒、反转录病毒和慢病毒)。在具体的实施方式中,载体是AAV(例如,AAV-1至AAV-12及其它血清型以及杂交AAV载体;例如,AAV1,或者AAV2,或者AAV3,或者AAV4,或者AAV5,或者AAV6,或者AAV7,或者AAV8,或者AAV9,或者AAV10,或者AAV11,或者AAV12)。在具体的实施方式中,载体能够感染神经元和/或神经胶质。
根据另一个方面,本发明的方法,包括RNA编辑和治疗方法,包括将向导RNA或编码向导RNA的核酸分子递送至细胞,如上文中所述,而不递送编码连接或融合至RNA结合域的RNA编辑酶的核酸分子。在神经***中,高水平表达ADAR(例如,ADAR 1-3)。因此,本发明的向导RNA可以将内源脱氨酶如ADAR酶,具体地ADAR1或ADAR2吸引至内源MECP2 RNA。因此,在实施方式中,本发明允许内源ADAR酶的参与,并且不需要重组ADAR酶。通过仅使用向导RNA,避免了对非哺乳动物RNA结合域的任何潜在的免疫应答。此外,该方法允许在AAV载体上包含高度迭代的向导序列并且减少了脱靶编辑。在本发明的这一方面的具体实施方式中,向导包含靶向靶标序列(例如,互补序列)或与靶标序列特异性杂交的序列,以及脱氨酶、具体地ADAR(例如,ADAR1或ADAR2)所识别的序列。向导RNA可以无限制地包括RNA发夹(例如,基于ADAR的天然靶标)、产生ADAR所识别的双链“凸出”的错配和/或内源ADAR中靶编辑(ontarget editing)通常所需的任何其它序列。在具体的实施方式中,向导RNA包含1、2或更多个BoxB序列。在具体的实施方式中,向导RNA包含来自GluR2的R/G结合位点(Wettengel etal.(2017)Nucleic Acids Res.,45(5):2797-2808;Fukuda et al.(2017)Sci.Rep.,7:41478;例如,包含GUGGAAUAGUAUAACAA-UAUGCUAAAUGUUGUUAUAGUAUCCCAC(SEQ ID NO:70)或者具有至少80%、85%、90%、95%、97%、99%或100%的同源性或同一性,具体地至少95%、97%、99%或100%的同源性或同一性的序列)。在具体的实施方式中,向导RNA包含具有内生环(Lehmann et al.(1999)J.Mol.Biol.,291(1):1-13;例如,包含4、6、8、10或更多个核苷酸的环)。在具体的实施方式中,向导RNA包含与MECP2 RNA互补的区域,用于编辑的错配(例如,A:C),和任选地用于脱靶编辑的A:G错配。在具体的实施方式中,编码向导RNA的核酸分子包含在如本文所述的载体中。在具体的实施方式中,从U6启动子或者表达小RNA的其它启动子表达向导RNA。
根据本发明,提供了治疗、抑制和/或预防中枢神经***遗传疾病的方法。根据本发明,提供了治疗、抑制和/或预防进行性神经发育疾病的方法。例如,在实施方式中,本发明提供了对以受试者RNA突变为特征的遗传中枢神经***疾病的治疗、抑制和/或预防。在实施方式中,本发明提供了由于(例如)通过编辑RNA以读作具有G而使异常G突变恢复,从而将RNA的翻译直接或间接恢复为正常蛋白的治疗、抑制和/或预防进行性神经发育疾病的方法。
根据本发明,治疗、抑制和/或预防中枢神经***遗传疾病,包括进行性神经发育疾病,包括Rett综合征的方法是体内或离体有效的。例如,对于体内方法,向受试者施用本发明的核酸分子(例如,编码所述融合蛋白,例如,编码所述向导RNA的核酸分子)。对于离体方法,将细胞(同基因或同种异体细胞)与本发明的核酸分子(例如,编码所述融合蛋白,例如,编码所述向导RNA的核酸分子)接触并引入受试者。与治疗有关的实施方式等同地适用于体内方法和离体方法。
根据本发明,提供了治疗、抑制和/或预防与MECP2基因有关的遗传疾病的方法。在实施方式中,本发明提供了(例如)RNA水平的基因编辑,以将功能性MECP2蛋白的水平恢复至未患病或健康受试者的水平。Mecp2可以是人或小鼠的,具体地人的。在实施方式中,本发明提供了(例如)RNA水平的基因编辑,以相对于患病状态提高功能性MECP2蛋白的水平。在实施方式中,与MECP2基因有关的遗传疾病是新生儿脑病、小头畸形、X染色体连锁智力障碍、PPM-X综合征(躁郁症、锥体束征、帕金森症和大睾丸)、双相障碍、帕金森病、肌张力升高、反射亢进和大睾丸或其组合。在实施方式中,与MECP2基因有关的遗传疾病影响男性或女性受试者。
根据本发明,提供了治疗、抑制和/或预防Rett综合征的方法。在具体的实施方式中,Rett综合征的特征在于MeCP2中的G>A突变。例如,Rett综合征的特征可以为MECP2中的R106Q、W104X或R306H突变。以GenBank Gene ID 4204和GenBank登录号NM_004992.3和NP_004983.1提供了人MECP2的示例性氨基酸和核苷酸序列(还参见GenBank登录号NM_001110792.1、NP_001104262.1、NM_001316337.1和NP_001303266.1的同工型)。在具体的实施方式中,Rett综合征包含MeCP2中的R106Q突变。在具体的实施方式中,该方法包括施用编码连接或融合至RNA结合域的RNA编辑酶的核酸分子和向导RNA或编码向导RNA的核酸分子。在具体的实施方式中,该方法包括施用向导RNA或编码向导RNA的核酸分子。可以将核酸分子直接施用于受试者或者可以将其递送至细胞,然后施用于受试者。
在具体的实施方式中,MECP2的氨基酸序列为:
在上文中,通过下划线指出了R106、W104和R306。在具体的实施方式中,编码MECP2的核酸为:
在实施方式中,本发明提供了治疗、抑制和/或预防Rett综合征,包括经典Rett综合征和变体Rett综合征(也称为非经典Rett综合征)的方法。在实施方式中,Rett综合征为Zappella变体、Hanefeld变体、Rolando变体和/或‘顿挫型’变体。
在实施方式中,本发明提供了Rett综合征的一种或多种症状的减轻、改善和/或消除,其无限制地包括共济失调、手动不受控制(例如,手部扭绞或挤压、拍打、搓手、洗手或手向口移动)、获得性小头畸形、自闭症类似行为、呼吸紊乱、进食或吞咽困难、生长停滞、张力减退、惊恐发作、锉牙(夜间磨牙)、震颤、失用症、心律不齐(例如,QT间隔和/或T-波异常)和癫痫发作。
在实施方式中,可以在本发明的(例如)Rett综合征的治疗、抑制和/或预防方法中与任何下列各项组合使用本发明的组合物:十三酸、芬戈莫德(例如GILENYA)、***、EPI-743(vatiquinone)、沙立佐坦(EMD-128,130)、抑制素(例如洛伐他汀)、三环类抗抑郁剂(TCA,例如,地昔帕明)、醋酸格拉替雷(例如,COPAXONE)、右美沙芬和/或口服胆固醇24-羟化酶(CH24H)抑制剂(例如,TAK-935/OV935)。
如上所述,本发明提供了用于Rett综合征的抑制、治疗和/或预防的核酸分子、载体以及组合物和方法。本发明还涵盖了包含本文所述的至少一种核酸的组合物。在具体的实施方式中,组合物包含至少一种向导RNA或者编码向导RNA的核酸分子(例如,表达载体)和至少一种药用载体。组合物还可以包含编码连接或融合至RNA结合域的RNA编辑酶的核酸分子。在具体的实施方式中,在单一表达载体(例如,病毒载体(例如,AAV))内编码全部核酸分子。作为另外一种选择,核酸分子可以与至少一种药用载体一起包含在不同的组合物中。本发明还涵盖了包含第一组合物和第二组合物的试剂盒,该第一组合物包含至少一种向导RNA或者编码向导RNA的核酸分子(例如,表达载体),该第二组合物包含至少一种编码连接或融合至RNA结合域的RNA编辑酶的核酸分子。第一和第二组合物还可以包含至少一种药用载体。在具体的实施方式中,本发明的试剂盒包含第一组合物,该第一组合物包含至少一种向导RNA或者编码向导RNA的核酸分子(例如,表达载体)和/或编码连接或融合至RNA结合域的RNA编辑酶的核酸分子。第一和第二组合物还可以包含至少一种药用载体。
如上文所解释的,本发明的组合物对于治疗Rett综合征是有用的。可以向对其有需要的受试者施用治疗有效量的组合物。考虑到本文所提供的教导内容,施用剂量、方法和时间是本领域技术人员可容易确定的。
如本文所述的组分通常将作为药物制剂施用于患者。如本文所使用的术语“患者”或“受试者”是指人或动物受试者。可以在医师的指导下治疗性地使用本发明的组分以用于治疗所指明的疾病或病症。
可以方便地配制包含本发明的组分的药物制剂以用于与可用的介质(例如,药用载体)如水、缓冲盐水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、二甲基亚砜(DMSO)、油类、去污剂、助悬剂或其适合的混合物一起施用。所选的介质中的试剂的浓度可以是不同的并且可以基于药物制剂所期望的施用途径来选择介质。除了任何常规介质或试剂与要施用的试剂不相容以外,考虑了其在药物制剂中的使用。
适合的药物制剂的选择基于所选择的施用方法。例如,可以通过直接注射到任何所期望的组织(例如,脑)或者周围区域来施用本发明的组分。在这种情况下,药物制剂包含分散在与血液或靶组织相容的介质中的组分。
可以(例如)肠胃外,通过注射至血流(例如,静脉内),或者通过皮下、肌内或腹膜内注射施用治疗剂(therapy)。在具体的实施方式中,通过直接注射(例如,直接注射至待治疗的组织中)来施用治疗剂。用于注射的药物制剂在本领域中是已知的。如果将注射选择作为施用治疗剂的方法,则必须采取步骤以确保足够量的分子达到它们的靶细胞以发挥生物学作用。
可以根据常规药物混合技术制备含有与药物载体密切混合的作为活性成分的本发明的化合物的药物组合物。基于施用如静脉内、口服或肠胃外施用所期望的制剂形式,载体可以采取多种形式。在口服剂量形式的制备中,可以使用任何常规药物介质,例如就口服液体制剂(例如混悬剂、酏剂和溶液剂)来说,水、二醇、油类、乙醇、调味剂、防腐剂、着色剂等;或者就口服固体制剂(例如粉末剂、胶囊剂和片剂)来说,载体如淀粉、糖、稀释剂、成粒剂、润滑剂、粘结剂、崩解剂等。可以制备可注射混悬剂,在这种情况下,可以使用适当的液体载体、助悬剂等。
可以以剂量单位形式配制本发明的药物制剂以便于剂量的施用和均一性。如本文所使用的剂量单位形式是指适合于进行治疗的患者的药物制剂的物理分离的单元。每个剂量应含有计算以产生所期望的效果的活性成分的量以及所选择的药物载体。用于确定适当的剂量单位的程序对于本领域技术人员来说是熟知的。基于患者体重,剂量单位可以成比例地升高或降低。如本领域中已知的,可以通过剂量浓度曲线计算确定用于减轻特定病理条件的适当浓度。
本发明的方法还可以包括在本发明的组合物的施用之后,监测受试者中的疾病或病症以监测方法的效力。例如,可以监测受试者的Rett综合征的特征。
定义
提供了以下定义以有利于理解本发明:
除非上下文明确规定,否则单数形式的“一种”、“一”和“该”包括复数提及物。
“药用”是指联邦或州政府管理机构批准的,或者美国药典或其它公认的药典中所列的在动物,并且更具体地在人中使用的。
“载体”是指本发明的活性剂与之一起施用的例如稀释剂、佐剂、防腐剂(例如,Thimersol、苯甲醇)、抗氧化剂(例如,抗坏血酸、焦亚硫酸钠)、增溶剂(例如,80、聚山梨酯80)、乳化剂、缓冲液(例如,Tris HCl、乙酸盐、磷酸盐)、抗微生物剂、膨胀物质(例如,乳糖、甘露糖醇)、赋形剂、助剂或媒介剂(运载体,vehicle)。药用载体可以是无菌液体,如水和油,包括石油、动物、植物或合成来源的那些。水或水性盐溶液以及葡萄糖和甘油水溶液也优选地用作载体,具体地用于可注射溶液。适合的药物载体描述于Remington:TheScience and Practice of Pharmacy,(Lippincott,Williams and Wilkins);Libermanet al.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.;和Rowe etal.,Eds.,Handbook of Pharmaceutical Excipients,Pharmaceutical Pr.。
如本文所使用的术语“治疗”是指向患有疾病的患者提供益处,包括患者的病况(例如,一种或多种症状)的改善、病况发展的延缓等的任何类型的治疗。
如本文所使用的,术语“预防”是指对具有发展病况的风险的受试者进行预防性治疗,致使受试者将发展病况的概率降低。
化合物或药物组合物的“治疗有效量”是指对于预防、抑制或治疗特定病症或疾病和/或其症状有效的量。
如本文所使用的,术语“受试者”是指动物,具体地哺乳动物,具体地人。
术语“分离的”是指化合物与其生产期间所存在的其它组分的分隔。“分离的”不表示排除与其它化合物或材料的人工或合成混合物,或者不表示排除不显著防碍基本活性以及例如由于不完全纯化或稳定剂的添加而可能存在的杂质的存在。
术语“接头”、“接头域”和“连接”表示包含共价连接至少两种化合物、例如RNA编辑酶和RNA结合域的共价键或原子链的化学部分。接头可以是氨基酸序列(例如,1-50个氨基酸、1-25个氨基酸、1-20个氨基酸、1-15个氨基酸、1-10个氨基酸或者1-5个氨基酸)。
如本文所使用的术语“寡核苷酸”包括由两个或更多个、优选地大于三个核糖核苷酸和/或脱氧核糖核苷酸组成的核酸分子。寡核苷酸的确切大小将取决于多种因素并且取决于寡核苷酸的具体应用和使用。
如本文所使用的“核酸”或“核酸分子”是指任何单链或双链DNA或RNA分子,并且如果是单链的,则其互补序列的分子处于线性或环状形式。在讨论核酸分子时,可以根据以5'至3'的方向提供序列的正常惯例,在本文中描述特定核酸分子的序列或结构。提及本发明的核酸时,有时使用术语“分离的核酸”。当应用于DNA时,该术语是指与其所来源的生物的天然存在的基因组中它所紧邻的序列相分离的DNA分子。例如,“分离的核酸”可以包括***载体如质粒或病毒载体的DNA分子,或者整合到宿主生物的原核或真核细胞的基因组DNA中的DNA分子。
“载体(vector)”是对其可以连接另一种基因序列或元件(DNA或RNA)的基因元件,如质粒、粘粒、杆粒、噬菌体或病毒。载体可以是复制子以使得所连接的序列或元件复制。载体可以是RNA或DNA,并且可以是单链或双链的。载体可以包括表达操纵子或元件,其无限制地如转录和翻译控制序列,如启动子、增强子、翻译起始信号、多腺苷酸化信号、终止子等,并且其有利于多核苷酸或多肽编码序列在宿主细胞或生物中的表达。
“表达操纵子”是指可以具有转录和翻译控制序列如启动子、增强子、翻译起始信号(例如,ATG或AUG密码子)、多腺苷酸化信号、终止子等,并且有利于核酸或多肽编码序列在宿主细胞或生物中的表达的核酸区段。“表达载体”是有利于核酸或多肽编码序列在宿主细胞或生物中的表达的载体。
如本文所使用的,“核定位信号”(NLS)是指有利于所连接的多肽向细胞核移动的分子或多肽。在具体的实施方式中,核定位信号是将蛋白导向核的肽。通常,NLS包含几乎碱性的、带正电荷的氨基酸(具体地赖氨酸和精氨酸)。NLS可以是单分型、双分型或多分型的。NLS通常为短肽(例如,小于约20个氨基酸,小于约15个氨基酸或小于约10个氨基酸)。在Kosugi et al.(J.Biol.Chem.(2009)284:478-485;并入本文作为参考)中提供了NLS的实例。在具体的实施方式中,NLS包含共有序列K(K/R)X(K/R)(SEQ ID NO:58)(例如,单分型NLS)。在具体的实施方式中,NLS包含共有序列(K/R)(K/R)X10-12(K/R)3/5(SEQ ID NO:59),其中(K/R)3/5表示5个氨基酸中的至少3个是赖氨酸或精氨酸。在具体的实施方式中,NLS为SV40大T抗原NLS(例如,PKKKRKV(SEQ ID NO:47))。在具体的实施方式中,c-myc NLS包含序列PAAKRVKLD(SEQ ID NO:54)。在具体的实施方式中,NLS为核质蛋白NLSKRPAATKKAGQAKKKK(SEQ ID NO:60)。对于所提供的序列,赖氨酸和精氨酸氨基酸是可互换的。
在多个实施方式中,包含NLS降低或消除了脱靶编辑,例如,相对于不存在NLS的情况下的编辑。例如,在多个实施方式中,本发明的包括NLS的基因编辑方法使脱靶编辑降低了约10%、或约20%、或约30%、或约40%、或约50%、或约60%、或约70%、或约80%、或约90%、或约100%。在多个实施方式中,本发明的涉及NLS的基因编辑方法使脱靶编辑降低了约2倍、或约3倍、或约5倍、或约10倍、或约30倍。
提供以下实施例以说明本发明的多种实施方式。以下实施例是说明性的并且不意欲以任何方式限制本发明。
实施例1
材料和方法
质粒构建
获得了编码融合至野生型ADAR2催化域的λN肽的pcDNA 3.1+质粒(Thermo FisherScientific)(Montiel-Gonzalez et al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalez et al.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)。通过野生型Editase的重叠PCR产生了EditaseE488Q cDNA并将其克隆至pcDNA3.1+中。通过在杂交的Editase的框中和N末端***2个拷贝的HA表位和3个拷贝的SV40 NLS,在pcDNA3.1+中改变两种形式的Editase(pGM1090,野生型;pGM1091,E488Q)。对于Mecp2-BoxB向导,将代表3种不同的Mecp2G>A突变的合成寡核苷酸和它们的反义序列与Bsa1悬突退火并克隆至pENTR/U6多接头(pENTR/U6 polylinker)[pGM1099(W104X)、pGM1181(306H)、pGM1085(R106Q)](ThermoFisher Scientific)中。含有脱靶A-G错配的Mecp2-BoxB向导(pGM11089)也存在于pENTR/U6中。对于Mecp2编辑底物,将小鼠Mecp2 E1同工型cDNA的EcoRI-KpnI片段(GenBank登录号NP_001075448.1)克隆至pEGFP-N3(Clontech)的多克隆位点。使用相同限制性位点悬突,通过重叠PCR产生Mecp2的各个G>A突变,并作为与eGFP的融合蛋白在pEGFP-N3(ThermoFisher Scientific)中框内克隆。通过序列分析验证所有亚克隆。表1中列出了在质粒构建和PCR扩增中使用的引物序列。
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表1:向导、PCR和测序引物。所提供序列的SEQ ID NO在括号中提供。
质粒构建体
已描述了含有λN肽和野生型ADAR2催化域融合cDNA(Editase)的初始构建体(Montiel-Gonzalez et al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalez etal.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)。将其改变以在杂交的Editase(pGM1090)的框中和N末端包含2个拷贝的HA表位标签,以及之后的3个拷贝的SV40 NLS。要进行这种改变,将编码2个拷贝的HA表位标签的两个单链寡核苷酸和Kozak序列与EcoRI和BspeI悬突退火并5'连接至λN域序列。通过PCR从pECFP-Nuc(Clontech)扩增3个拷贝的SV40NLS并使用BspEI悬突添加至HA表位标签和λN域之间。使用相同的步骤产生在ADAR2催化域中含有E488Q突变的质粒pGM1091。
用于AAV转导实验的质粒pGM1258含有受突触素I启动子控制的Editase cDNA和分别受人U6启动子控制的6个拷贝的具有脱靶A-G错配的Mecp2R106Q向导DNA。为了引入U6-Mecp2R106Q向导区,通过限制性消化(NdeI/ApaI)从质粒pX552(60958;Addgene;Swiech etal.(2015)Nat.Biotechnol.,33:102-106)除去人U6启动子和CRISPR sgRNA序列,并以两步,在这些位点之间***6个U6-Mecp2R106Q向导序列。在第1步中,使用以下限制性位点:NdeI/MfeI、MfeI/SpeI和SpeI/NheI+ApaI(pGM1257),通过PCR扩增子(pGM1108模板)的四向连接(four-way ligation),将U6-Mecp2R106Q向导区的3个拷贝克隆至pX552中。在第2步中,使用添加以下限制性位点:NheI/SacI、SacI/AfIII和AfIII/ApaI的引物,通过从pGM1108PCR扩增产生U6-Mecp2R106Q向导区的另外3个拷贝。通过用NheI/ApaI消化的pGM1257的限制和与三个U6-Mecp2R106Q PCR扩增子的四向连接产生了最终的质粒pGM1258。为了将EditasecDNA引入到pGM1258中,从质粒pGM1091扩增了对应于Editase的ORF的序列并使用NcoI和EcoRI悬突,将其添加至pGM1257中突触素I启动子的下游。
AAV载体和病毒制备
含有人突触素I启动子的AAV1/2主链载体pX552得自Addgene(质粒60958;Swiechet al.(2015)Nat.Biotechnol.,33:102-106)。通过用不具有和具有6个拷贝的向导cDNA(pGM1186,仅Editase;pGM1258,Editase和R106Q向导)的HA-标签化NLS Editase cDNA替换eGFP-KASH编码序列来改变pX552。在病毒产生之前,通过序列分析验证Editase和向导序列。
通过无腺病毒的质粒转染法,以每个载体3个225cm2***规模,在人胚肾293(HEK293)细胞中产生了每个AAV1/2嵌合载体(Matsushita et al.(1998)Gene Ther.,5:938-945;Earley et al.(2017)J.Virol.,91:e01980-16)。在每个烧瓶中,用总计45μg的下列4种与聚乙烯亚胺(PEI)混合的质粒DNA(DNA:PEI的重量比为1:2)转染约2×107个HEK293细胞。质粒DNA混合物含有15μg的pHelper(Agilent)、分别为7.5μg的pHLP19-1和pHLP19-2以及含有具有两个末端反向重复(ITR)的AAV载体基因组序列的AAV载体Editase重组质粒中的一种(15μg)。pHLP19-1是提供AAV2 Rep蛋白和AAV1 VP蛋白的AAV1辅助质粒,而pHLP19-2是提供AAV2 Rep蛋白和AAV2 VP蛋白的AAV2辅助质粒(Grimm et al.(2003)Blood102:2412-2419)。转染后3天,收获细胞。然后,通过细胞胞溶从细胞中回收AAV载体颗粒,并使用HiTrapTM肝素柱(GE Healthcare;Desterro et al.(2003)J.Cell Sci.,116:1805-1818)纯化。使用对Editase编码序列所产生的探针,通过定量斑点印迹测定确定各病毒的滴度。
细胞培养
将Neuro2A细胞(ATCC CCL-131)在37℃,5%CO2的加湿培育箱中维持在DMEM(Thermo Fisher Technologies)中和10%FBS(批号AAC20-0955;HyClone)中。原代神经元来源于通过靶向同源重组(Janelia Farms)产生并通过基因分型鉴定的Mecp2R106Q小鼠系。所有动物研究经Oregon Health and Science University Institutional Animal Careand Use Committee的批准。通过断头杀死幼犬(P0)并将脑在冰冷的具有25mM Hepes的Hank基础盐溶液(HBSS,pH 7.4)中解剖。切下不具有脑膜的单个海马体(hippocampi),并通过基因型汇合。用1%胰蛋白酶和0.01%DNase I在HBSS中在37℃处理组织10分钟。在室温下,在HBSS中清洗组织块3次,并在含有25mM葡萄糖、1%pen/strep、1%马血清(批号B02307-7021;HyClone)和1%FBS的最低必需培养基(Gibco)中解离。通过0.4-μm过滤器过滤使神经元解离,并将其在聚L-赖氨酸涂覆的皿中以5×105个细胞每孔的密度在12-孔皿中或者以5×104个细胞每孔的密度在96-孔玻璃室中,在由Neurobasal-A(Thermo FisherScientific)、1×Glutamax(Thermo Fisher Scientific)、2%B27(Thermo FisherScientific)和青霉素/链霉素组成的神经元生长培养基中铺板。24小时后,对神经元进行完全培养基更换以除去细胞碎片。每2-3天更换一半培养基。细胞维持在37℃,5%CO2中。
Mecp2R106Q小鼠的产生和基因分型
产生Mecp2R106Q小鼠的靶标载体由以下组成:Mecp2外显子3,随后是位于内含子3中的翻转酶识别靶标(frt)侧接的新霉素盒,Mecp2外显子4的第一1.2kb和从磷酸甘油酸激酶启动子(PGK)表达的新霉素抗性基因。将线性化构建体电穿孔至小鼠胚胎干细胞(mESCs)并通过G418敏感性和测序识别出正确靶向的克隆。通过标准程序从mESC产生表达敲入Mecp2R106Q等位基因的小鼠。通过Mecp2R106Q小鼠和从Rosa 26基因座表达翻转酶重组酶的小鼠(库存号009086;Jackson Labs)杂交,除去新霉素抗性盒。通过测序确认盒的除去。
使用扩增Mecp2基因第三内含子区的以下引物:Mecp2-R106Q Fwd(5'ggacctatgtatgatgaccc 3'(SEQ ID NO:50))和Mecp2-R106Q Rev(5'ggtcattgggctagactgaa3'(SEQ ID NO:51))进行Mecp2R106Q小鼠的基因分型。来自Mecp2R106Q敲入动物的扩增子含有用于除去新霉素盒的残余frt位点,其导致PCR产物比野生型多93个碱基对(392bpvs.299bp)。
RNA编辑
对于N2A细胞的分析,将细胞以1.3×103个细胞每孔的密度接种至12-孔板。24小时后,使用比例为2:1的LipofectamineTM2000(Thermo Fisher Scientific)与DNA,在Opti-MEMTM减血清培养基(Thermo Fisher Scientific)中,用含有野生型或E488Q Editase(pGM1090和1091)、1个拷贝的向导(pGM1099、pGM1181或pGM1108)和Mecp2-egfp cDNA(pGM1174、pGM1172或pGM1173)的质粒转染细胞。每孔所添加的质粒DNA的量为125ng靶标、250ng Editase和2.5μg向导。72小时后,收获细胞并根据生产商的说明,使用RNA Mini试剂盒(Ambion)分离总RNA。使用TURBO DNA-freeTM试剂盒(Ambion)除去残余的质粒DNA。使用/>III第一链合成***(Life Technologies)反转录总RNA,并使用低聚dT引物介导(primed)。在pEGFP-N3中的CMV启动子中使用5'引物并且在egfp基因中使用反向引物,通过PCR将转染的Mecp2-egfp cDNA扩增以用于序列分析。对于原代神经元的编辑分析,在DIV7,以每个细胞3-6×104个病毒基因组的感染复数,用AAV1/2转导5×105个海马原代神经元。病毒体积不超过培养基总体积的5%。转导后1周收获细胞,并如对于转染的N2A细胞的,分析编辑效率。
通过反转录PCR(RT-PCR)和PCR产物的直接测序确定了A至I的编辑效率。使用Bioedit软件包(mbio.ncsu.edu/BioEdit/bioedit.html;文件>原始序列迹线数据的批量导出(Batch Export of Raw Sequence Trace Data)),通过处理4-染料-迹线序列确定了来自反义链的测序峰高的定量。然后,使用给定位点处T(未编辑)和C(编辑)的最大峰高并计算编辑的cDNA的百分比{100%×[C峰高/(T峰高+C峰高)]}来确定每个位点的编辑的量。通过测量含有降低比例的R106Q突变体与野生型Mecp2质粒的混合物中G-A的峰高来确定5%编辑的检测限。定量反义链的C/T峰高,因为它比使用有义链的A/G峰高更准确(Eggington et al.(2011)Nat.Commun.,2:319)。然而,为清楚起见,以反向互补显示所有色谱图。
Western印迹
将用AAV1/2转导的原代海马神经元在100μL全细胞裂解缓冲液(25mM Tris,pH7.6、150mM NaCl、1%Igepal CA-630;Sigma)、1%脱氧胆酸盐、0.1%SDS、蛋白酶抑制剂(完全无EDTA;Roche)、1mM β-巯基乙醇和250单位/mL核酸酶(Sigma-Aldrich)中裂解。将裂解液以9,300×g,在4℃离心10分钟,并分离可溶性部分。使用BCA蛋白质测定试剂盒(PierceBiotechnology)测量蛋白浓度。将等量的蛋白裂解液在4-12%Bis-Tris凝胶(Thermo Fisher Scientific)上在Mops-SDS运行缓冲液(Thermo Fisher Scientific)中分离,并将蛋白在硝化纤维素膜(GE Healthcare Life Sciences)上印迹。用3%BSA在1×TBST(具有0.05%/>20的TBS)中的溶液封闭膜1小时,然后与兔抗-mMeCP2(Covance)或者兔抗-β-肌动蛋白(8227;Abcam)在4℃培育过夜。用1×TBST清洗3次后,将印迹与抗兔IgG/>680(1:10,000稀释;Thermo Scientific)一起培育1小时。使用成像***(Li-COR Biosciences)定量印迹。
免疫染色
将海马原代神经元在4%多聚甲醛的PBS溶液中,在室温下固定20分钟。在室温下,用1×PBSG(0.1M甘氨酸在1×PBS中的溶液)清洗固定细胞2次,10分钟。然后,将细胞在4℃封闭并渗透[0.5%Igepal CA-630,Sigma;3%BSA(源)在1×PBS中的溶液]1小时,并在加湿的室内,在4℃与抗MeCP2(兔mAb D4F3;Cell Signaling)和HA(大鼠mAb 3F10;Roche)的原代抗体一起培育过夜。将细胞在含有0.5%Igepal的1×PBS中清洗3次,并与第二抗体Alexa488和Alexa 568(Thermo Fisher Scientific)培育1小时。在用含有0.5%Igepal的1×PBS再一次清洗后,将细胞与300nM DAPI培育5分钟,然后再次用1×PBS清洗。使用Gold antifade试剂(Thermo Fisher Scientific),将细胞封固过夜。使用40×水浸物镜,在Zeiss 710共聚焦显微镜上作为0.5μm光学切片的z-向堆叠采集所有图像。在所有样品中,使用相同背景采集HA和MeCP2荧光图像。通过ImageJ细胞计数器插件(NationalInstitutes of Health,imagej.nih.gov/ij,1.60_65版(32位))确定总细胞数和抗体阳性细胞数。
统计分析
使用6.0版GraphPad软件(Prism)进行所有统计。使用单因素ANOVA,然后通过Bonferroni事后检验分析N2A细胞中A向I编辑的百分比。使用非配对t检验,分别分析了Mecp2R106Q/y转导的神经元中A向I编辑的水平,比较MeCP2蛋白水平的Western印迹和显示MeCP2在异染色质焦点处富集的神经元数目。所有实验结果表示为平均值±SD。
结果
将Editase靶向异源表达的Mecp2 mRNA可以修复Mecp2 G>A突变
在人MECP2中存在至少三个G>A突变导致典型Rett综合征。两个突变存在于甲基DNA结合域(MBD)内(MeCP2R106Q和MeCP2W104X),而一个(MeCP2R306H)存在于NCoR相互作用域(NID)中(Fyfe et al.(2003)J.Child.Neurol.,18:709-713;Lyst et al.(2013)Nat.Neurosci.,16:898-902)(图1A)。为了确定Editase是否可以修复这些突变,在Editase、向导RNA和Mecp2 cDNA向N2A细胞中瞬时转染后测试了编辑。为了将异源表达的MeCP2蛋白与内源蛋白相区分,用C末端eGFP对异源表达的MeCP2加标签。从巨细胞病毒(CMV)即早基因启动子-增强子表达了Editase和Mecp2-gfp cDNA,并从人U6小核RNA基因启动子表达了向导。除λN肽之外,将3个拷贝的猿猴病毒40大T抗原核定位信号(NLS)添加至Editase,这是因为ADAR2作为初级转录本编辑核中的内源mRNA(Desterro et al.(2003)J.Cell.Sci.,116:1805-1818)。每个向导RNA含有两个茎环(BoxB),其代表了λN肽所识别的序列。一个BoxB茎环位于靶标A 5'端的16-18个碱基处,而第二个BoxB茎环位于靶标A 3'端的10个碱基处(图1B)。茎环相对于靶标A的数目和位置基于以下研究(Montiel-Gonzálezet al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalez et al.(2013)Proc.Natl.Acad.Sci.,110:18285-18290)并且是在转染分析中对于Mecp2通过经验确定的。在互补向导中的位点处具有C错配的编辑是最优的(Schneider et al.(2014)NucleicAcids Res.,42:e87;Wong et al.(2001)RNA 7:846-858;et al.(2003)NucleicAcids Res.,31:4874-4881),并且所有Mecp2向导mRNA含有这种错配。
用编码Editase、MeCP2-GFP的不同质粒和含有或缺少向导序列的第三质粒共转染N2A细胞。3天后,将Sanger测序用于分析从Mecp2-gfp mRNA的靶标区合成的cDNA(图1C和1D)。通过确定靶标A位置处的相对峰高来测量编辑效率。与需要双链RNA的ADAR2介导的编辑一致,以向导依赖性方式编辑所有3种Mecp2突变(图1C和1D)。与ADAR2催化域的序列偏好性类似,靶标A的编辑百分比随5'核苷酸的情况而改变(Eggington et al.(2011)Nat.Commun.,2:319;Lehmann et al.(2000)Biochemistry 39:12875-12884)。具体地,基于体外筛选,对于通过ADAR2催化域的A脱氨基,最优的5'核苷酸层级为U>A>C>G,并且最优的3'核苷酸是C~G~A>U。最有效地编辑W104X(UAG)(76±10%),随后是R306H(CAC,34±3%)和R106Q(CAA,25±2%),这对于Mecp2无统计学差异(图1D)。为了进一步优化Editase***对于Mecp2 G>A突变的修复,主要针对R106Q,这是因为在人患者中,它比W104X突变更常见,并且导致了比R306H更严重的Rett综合征形式(Fyfe et al.(2003)J.Child.Neurol.,18:709-713;Cuddapah et al.(2014)J.Med.Genet.,51:152-158)。
脱氨酶域中的突变E488Q提高了杂交Editase的编辑效率
含有E488Q突变的hADAR2催化域通过提高催化速率(Montiel-González et al.(2016)Nucleic Acids Res.,44:e157;Kuttan et al.(2012)Proc.Natl.Acad.Sci.,109:E3295-E3304)和催化域对底物RNA的亲合力(Lehmann et al.(2000)Biochemistry 39:12875-12884)两者提高了A>I的编辑效率。这种特性使得E488Q突变能够实现不利的5'和3'背景的更高编辑水平(Montiel-González et al.(2016)Nucleic Acids Res.,44:e157;Kuttan et al.(2012)Proc.Natl.Acad.Sci.,109:E3295-E3304)。为了测试EditaseE488Q是否将提高具有次优5'C的Mecp2R106Q中的靶标A的编辑效率,用Mecp2R106Q-egfp和EditaseE488QcDNA共转染N2A细胞。序列分析表明编辑需要向导表达,并且与野生型Editase相比,通过EditaseE488Q,Mecp2 mRNA的编辑百分比提高了2倍(51±11%vs.22±5%,n=3,P<0.01)(图2A)。
在杂交Editase中使用野生型hADAR2或hADAR2E488Q催化域,在转染的Mecp2R106Q-egfp cDNA的向导区内检测到了1个脱靶编辑位点(图2B)。该位点的编辑导致产生了沉默密码子改变,T105T(ACA>ACG)。脱靶位点的G错配可以降低转染底物中的脱靶编辑(Vogel etal.(2014)Angew Chem.Int.Ed.Engl.,53:6267-6271)。为了确定G错配是否还将降低Mecp2mRNA中的脱靶编辑,在用编码Mecp2R106Q-egfp cDNA、EditaseE488Q和在脱靶A附近具有G错配的向导的质粒转染的N2A细胞中分析了编辑效率(图2C)。当用含有A-G错配的向导靶向Editase时,脱靶编辑的量显著减少(错配时为4.9±0%,无错配时为33±5%,n=3,P<0.0001;图2D和2E),对靶标A处的编辑无显著影响(图2D和2F)。所有编辑事件需要向导RNA的存在(图2E和2F)。
定点RNA编辑修复内源导致Rett的突变,恢复蛋白水平和MeCP2功能
然后,测试了EditaseE488Q是否可以(i)修复内源Mecp2 mRNA中的R106Q错义突变,(ii)恢复蛋白水平和(iii)恢复MeCP2结合异染色质的能力,这是小鼠中逆转Rett样症状所需的标志性功能特征(Garg et al.(2013)J.Neurosci.,33:13612-13620)。对于这些测试,从小鼠分离神经元并进行工程化以在内源Mecp2基因中包含R106Q突变。用两种AAV(AAV1/2)中的任一个转导所培养的神经元。两种病毒表达受人突触素I启动子控制的EditaseE488Q(Swiech et al.(2015)Nat.Biotechnol.,33:102-106)并且一种病毒另外含有分别受人U6启动子控制的向导的6个拷贝(脱靶错配向导;图2C)。另一种病毒用作对照并且缺少所有向导序列。从P0 Mecp2R106Q/y小鼠产生海马神经元并在体外第7天(DIV 7)用含有向导的载体或携带AAV1/2杂交衣壳的对照AAV载体转导。在使病毒表达另外7天后,从实验和对照培养制备Mecp2 cDNA并通过Sanger测序分析。发现在表达Editase和向导两者的培养中72±5%的Mecp2 mRNA被修复(图3A),而在用缺少向导的对照病毒转导的神经元中无可检测的编辑。除R106Q处的编辑之外,序列分析还在Mecp2 cDNA内鉴别了几个脱靶编辑位点(图3B)。脱靶位点主要发生在与向导RNA互补的区域内,尽管有一个事件发生在向导外部(N126S)。
通过用Western印迹测量AAV1/2转导的培养中MeCP2蛋白的量,测试了RNA编辑的功能结果。与MBD中的其它突变类似(Goffin et al.(2011)Nat.Neurosci.,15:274-283;Brown et al.(2016)Hum.Mol.Genet.,25:558-570),与野生型水平相比,Mecp2R106Q蛋白水平降低(图4)。突变MeCP2蛋白水平的降低可能是由于不稳定所造成的(Goffin et al.(2011)Nat.Neurosci.,15:274-283)。与仅Editase的表达相比,突变原代神经元中Editase和向导的表达将MeCP2蛋白水平提高了约3倍(图4;具有向导的为35.3±2%,相比于无向导的为12.9±1%,n=3,P<0.001)。这首次证明了在编辑之后,内源导致疾病的蛋白功能恢复。
MeCP2以高亲合力体外和体内结合至甲基-CpG(Skene et al.(2010)Mol.Cell.,37:457-468;Lagger et al.(2017)PLoS Genet.,13:e1006793),这是对正常功能来说至关重要的性质。在小鼠细胞中,MeCP2的MBD中的突变降低了与含有富含mCG的扩增的卫星序列的异染色质的结合(Brown et al.(2016)Hum.Mol.Genet.,25:558-570;Heckman et al.(2014)eLife 3:e02676)。MBD突变MeCP2R106Q也显示出与甲基-CpG的体外结合降低(Yang etal.(2016)ACS Chem.Biol.,11:2706-2715)。为了确定MeCP2R106Q在细胞中是否具有类似的降低并且G>A突变Mecp2 RNA的编辑是否恢复了异染色质中的富集,在具有或作为对照不具有向导的情况下,用编码HA-标签化Editase的AAV1/2转导的Mecp2R106Q/y神经元培养中对核进行免疫标记(图5)。将强烈结合DNA中富含A-T的区域的荧光指示剂DAPI(4',6-二脒基-2-苯基吲哚)用于识别核和异染色质。在来自野生型神经元(Mecp2+/y)的培养物中,核在DAPI染色的异染色质(焦点)中显示出典型的MeCP2富集,从而反映了功能性MBD(图5A)。相反,在从用缺少向导序列的Editase病毒转导的Mecp2R106Q/y姊妹株(siblings)制备的培养物中,如所期望的,对于防止与DNA结合的MBD中的突变,MeCP2免疫荧光在整个核中弥散分布(Goffin et al.(2011)Nat.Neurosci.,15:274-283;Heckman et al.(2014)eLife 3:e02676)(图5B)。染色强度也小于野生型核中的强度,推测这反应了MeCP2蛋白的不稳定性。相反,表达Editase和向导RNA两者的Mecp2R106Q神经元显示MeCP2免疫荧光明显提高至与野生型核类似的水平,并且MeCP2蛋白在异染色质焦点富集,从而表明MBD功能恢复(图5C和5D)。为了定量免疫荧光结果,不管是否存在向导,首先在相同的细胞百分比中表达Editase的3个实验中进行确定(仅Editase为67±7%,Editase和向导为67±10%;分别地,n=134和137个细胞;图5E)。然后,在用Editase和向导转导的培养物中确定,74±11%的细胞表达Editase(图5F),并且总细胞的49±8%显示出MeCP2在异染色质焦点处富集(图5G)。在用缺少向导的病毒转导的Mecp2R106Q核中,从未检测到MeCP2在异染色质焦点内的富集,这与显示编辑依赖于向导的存在的测序结果一致。
ADAR已用于修复非洲蟾蜍(Xenopus)***中的外源mRNA中的G>A突变(Woolfet al.(1995)Proc.Natl.Acad.Sci.,92:8298-8302)。本文所提供的数据表明使用工程化hADAR2催化域的定点RNA编辑可以修复内源突变mRNA并逆转由突变所造成的细胞缺陷。
三种基因编码小鼠和人中的ADAR蛋白,但仅ADAR1和ADAR2显示出A-至-I的催化活性(Nishikura,K.(2010)Annu.Rev.Biochem.,79:321-349)。天然ADAR介导的编辑对于在脑中在转录后调节蛋白的功能是至关重要的,这首先显示用于调节离子通道和受体(Bhallaet al.(2004)Nat.Struct.Mol.Biol.,11:950-956;Sommer et al.(1991)Cell 67:11-19;Burns et al.(1997)Nature 387:303-308),但现已知扩展至多种其它蛋白和非编码RNA(Chen et al.(2012)Curr.Top.Microbiol.Immunol.,353:111-121;Nishikura,K.(2016)Nat.Rev.Mol.Cell Biol.,17:83-96)。ADAR2催化域因其编辑异源mRNA的能力(Vogel etal.(2014)Angew Chem.Int.Ed.Engl.,53:6267-6271;Schneider et al.(2014)NucleicAcids Res.,42:e87;Montiel-González et al.(2016)Nucleic Acids Res.,44:e157;Montiel-Gonzalez et al.(2013)Proc.Natl.Acad.Sci.,110:18285-18290;Wong et al.(2001)RNA7:846-858)并且因其良好鉴别的编辑机制(Kuttan et al.(2012)Proc.Natl.Acad.Sci.,109:E3295-E3304;Matthews et al.(2016)Nat.Struct.Mol.Biol.,23:426-433)而受到关注。的确,发现当Editase在催化域内含有E488Q突变时,Mecp2 mRNA的编辑效率提高(Montiel-González et al.(2016)NucleicAcids Res.,44:e157;Kuttan et al.(2012)Proc.Natl.Acad.Sci.,109:E3295-E3304;Phelps et al.(2015)Nucleic Acids Res.,43:1123-1132)。与双链RNA复合的hADAR2催化域结构的阐明(Matthews et al.(2016)Nat.Struct.Mol.Biol.,23:426-433)提供了用于产生其它突变以进一步优化编辑效率和对MeCP2的特异性以及产生其它突变的有价值的资源(Wang et al.(2016)Nucleic Acids Res.,44:9872-9880)。与先前工作不同,本文中的所有构建体包含NLS,其提高了编辑效率,具体地内源mRNA的编辑效率,因为ADAR通常编辑核内的初级转录本(Wong et al.(2001)RNA7:846-858)。
在转染的细胞中,EditaseE488Q在靶标A处更高的编辑效率也导致了向导区内一个位点处更高的脱靶编辑。通过使用G-A错配减少了单个脱靶编辑位点(Schneider et al.(2014)Nucleic Acids Res.,42:e87)。值得注意地,除靶标mRNA之外,代表高度表达的mRNA的5个cDNA的测序未显示脱靶编辑(Montiel-González et al.(2016)Nucleic AcidsRes.,44:e157)。然而并且出乎意料地,在本发明使用神经元的研究中,脱靶编辑位点在转染和内源Mecp2 mRNA之间是不同的。具体地,在内源修复的Mecp2 mRNA中,发现向导区内的几个其它脱靶编辑位点以及向导区外的一个位点在cDNA表达的Mecp2 mRNA中不存在(图3B)。转染和内源Mecp2 mRNA之间脱靶编辑位点的差异可能反映了可以影响RNA折叠以及其它后续加工事件的序列差异。重要地,内源Mecp2 mRNA中的脱靶位点均未报道会导致Rett综合征(Fyfe et al.(2003)J.Child Neurol.,18:709-713)。Rett综合征小鼠模型可以进一步用于显示通过有症状的小鼠中野生型MeCP2的恢复,逆转了细胞和行为症状(Guy etal.(2007)Science 315:1143-1147;Sinnett et al.(2017)Mol.Ther.MethodsClin.Dev.,5:106-115;Gadalla et al.(2017)Mol.Ther.Methods Clin.Dev.,5:180-190;Garg et al.(2013)J.Neurosci.,33:13612-13620;Gadalla et al.(2013)Mol.Ther.,21:18-30)。
实施例2
将具有Mecp2突变Mecp2317G>A的小鼠用于体内研究本发明的方法。Mecp2317G>A突变产生了具有R106Q氨基酸改变的MeCP2。简要地,用具有或不具有6个拷贝的向导RNA的编码具有本发明的E488Q突变的Editase的AAV载体处理具有Mecp2突变Mecp2317G>A的小鼠。由于其亲神经性,使用具有PHP.B衣壳的AAV载体(AAV9变体)(Hordeaux et al.(2018)Mol.Ther.,26(3):664-668)。将1.1×1010病毒基因组当量(vge)的AAV立体定向地注入小鼠的海马体中。在直接病毒注射后3-4周,将小鼠处死并检测脑中的MeCP2功能。如表2所示,在脑中观察到了有效的体内靶向的RNA编辑和MeCP2功能的恢复。此外,基于RNA序列分析,齿状颗粒神经元中的A至I的编辑效率确定为39%,而CA1神经元中的A至I的编辑效率确定为64%。如图6所示,与用无向导RNA的AAV注射的小鼠相比,在用具有向导RNA的AAV注射的小鼠中,齿状异染色质中的MeCP2强度更强。这些结果表明了MeCP2 DNA结合性能的挽救。
表2:表达Editase酶并且显示MeCP2体内功能的细胞的数目定量。将编码Editase和向导RNA的AAV PHP.B注入Mecp2317G>A小鼠的海马体。注射后3周,将小鼠处理用于免疫组织化学。在对来自未感染的细胞信号设定阈值后,通过注射小鼠的脑切片的HA免疫染色识别了Editase+细胞。百分比相对于通过DAPI所鉴别的细胞总数。显示异染色质(焦点)内的MeCP2富集的Editase+细胞的百分比指示了MeCP2蛋白功能的恢复。n=864个细胞。
实施例3
质粒构建
将编码含有氨基末端Flag标签的全长人ADAR2的序列从酵母表达载体亚克隆至pcDNA 3.1+(Thermo Fisher Scientific)。为了表达设计为召集全长ADAR2的Mecp2向导,将合成寡核苷酸与Bsa1悬突退火并克隆至pENTR/U6多接头[pGM1099(2xBoxB向导W104X)、pGM1192(内环向导W104X)、pGM1310(GluA2茎环W104X)](Thermo Fisher Scientific)。在实施例1中描述了含有Mecp2311G>A(W104X)突变的Mecp2编辑底物。通过序列分析验证了所有亚克隆。表3中列出了在质粒构建和PCR扩增中使用的引物序列。
细胞培养
将HEK293T细胞(ATCC CRL-3216)在37℃,5%CO2的加湿培育箱中维持在DMEM(Thermo Fisher Technologies)中和10%FBS中。
RNA编辑
对于使用全长ADAR2的编辑分析,将HEK293T细胞以1.3×103个细胞每孔的密度接种至12-孔板。24小时后,使用比例为2:1的LipofectamineTM2000(Thermo FisherScientific)与DNA,在Opti-MEMTM减血清培养基(Thermo Fisher Scientific)中,用编码全长人ADAR2(pGM1155)、1个拷贝的向导序列(pGM1099、pGM1192或pGM1310)和Mecp2311G>A-egfp cDNA的质粒转染细胞。每孔所添加的质粒DNA的量为125ng靶标、250ng人ADAR2和2.5μg向导。72小时后,收获细胞并根据生产商的说明,使用RNA Mini试剂盒(Ambion)分离总RNA。使用TURBO DNA-freeTM试剂盒(Ambion)除去残余的质粒DNA。使用III第一链合成***(Life Technologies)反转录总RNA,并使用低聚dT引物介导(primed)。在pEGFP-N3中的CMV启动子中使用5'引物并且在egfp基因中使用反向引物,通过PCR将转染的Mecp2311G>A-egfp cDNA扩增以用于序列分析。/>
表3:向导、PCR和测序引物。SEQ ID NO提供在括号中。
结果
用受巨细胞病毒(CMV)启动子控制的全长人ADAR2和Mecp2317G>A转染人胚肾(HEK)细胞。人ADAR2是模拟内源ADAR2的全长天然ADAR2分子。Mecp2317G>A突变导致R106Q氨基酸改变(Mecp2R106Q)。然后,将细胞用1)如上所述,具有2个BoxB茎环的向导RNA(参见,例如,实施例1),2)包含来自GluA2的R/G结合位点的向导RNA(Wettengel et al.(2017)NucleicAcids Res.,45(5):2797-2808;Fukuda et al.(2017)Sci.Rep.,7:41478),或3)具有内环的向导RNA(Lehmann et al.(1999)J.Mol.Biol.,291(1):1-13)处理。如图7所示,包括包含2个BoxB茎环的向导RNA在内的向导RNA能够召集全长ADAR2以编辑转染的HEK细胞中的Mecp2 RNA。这些结果证明了全长ADAR向除靶标RNA序列之外,可以包括通常不包含在靶标RNA内的序列的存在的靶标RNA的召集。
尽管以上已描述并具体举例说明了本发明的某些优选实施方式,但是不意欲将本发明限制于这些实施方式。在不背离如所附权利要求所示的本发明的范围和精神的情况下,可以对其作出多种改变。
序列表
<110> 盖尔·曼德尔(Mandel, Gail)
约翰·P·阿德尔曼(Adelman, John P.)
约翰·辛纳蒙(Sinnamon, John)
<120> 用于编辑RNA的组合物和方法
<130> 3422-P06619WO00
<150> 62/569,376
<151> 2017-10-06
<160> 72
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 E1 Fwd EcoRI引物
<400> 1
gcgcgaattc caccatggcc gccgctgccg ccac 34
<210> 2
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 E1 Rev KpnI无终止密码子引物
<400> 2
gcgcgggtac cgctaactct ctcggtcacg ggc 33
<210> 3
<211> 35
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X mut引物 Fwd引物
<400> 3
caccttgcct gaaggttaga cacgaaagct taaac 35
<210> 4
<211> 35
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X mut引物 Rev引物
<400> 4
gtttaagctt tcgtgtctaa ccttcaggca aggtg 35
<210> 5
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q mut引物 Fwd引物
<400> 5
cctgaaggtt ggacacaaaa gcttaaacaa agg 33
<210> 6
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q mut引物 Rev引物
<400> 6
cctttgttta agcttttgtg tccaaccttc agg 33
<210> 7
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R306H mut引物 Fwd引物
<400> 7
cccatcaaga agcacaagac ccgggag 27
<210> 8
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R306H mut引物 Rev引物
<400> 8
ctcccgggtc ttgtgcttct tgatggg 27
<210> 9
<211> 79
<212> DNA
<213> 人工序列
<220>
<223> Editase EcoRI Kozak HA Fwd引物
<400> 9
gaattcgcca ccatggtgta cccctatgac gtgcctgact acgccagcgg ctatccatac 60
gatgtccccg attatgctt 79
<210> 10
<211> 76
<212> DNA
<213> 人工序列
<220>
<223> Editase HA BspEI Rev引物
<400> 10
ccggaagcat aatcggggac atcgtatgga tagccgcagg cgtagtcagg cacgtcatag 60
gggtaccatg gtggcg 76
<210> 11
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> EGFP F2引物
<400> 11
caccatcttc ttcaaggacg ac 22
<210> 12
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> SV40 3xNLS Rev引物
<400> 12
gacaatccgg aggtggatcc tacctttctc tt 32
<210> 13
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> hDD E488Q Fwd引物
<400> 13
aatagagtct ggtcagggga cgattcc 27
<210> 14
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> hDD E488Q Rev引物
<400> 14
ggaatcgtcc cctgaccaga ctctatt 27
<210> 15
<211> 86
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X 2xBoxB向导Fwd
<400> 15
caccgtcctt tgtttggccc tgaaaaaggg ccctttcgtg tccaaccttc aggcaagggg 60
ccctgaaaaa gggccggtca tcatac 86
<210> 16
<211> 86
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X 2xBoxB向导Rev
<400> 16
aaaagtatga tgaccggccc tttttcaggg ccccttgcct gaaggttgga cacgaaaggg 60
ccctttttca gggccaaaca aaggac 86
<210> 17
<211> 88
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q 2xBoxB向导Fwd
<400> 17
caccgcagac ttcctggccc tgaaaaaggg cctttaagct ttcgtgtcca accttcaggc 60
aggccctgaa aaagggcctg gggtcatc 88
<210> 18
<211> 88
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q 2xBoxB向导Rev
<400> 18
aaaagatgac cccaggccct ttttcagggc ctgcctgaag gttggacacg aaagcttaaa 60
ggcccttttt cagggccagg aagtctgc 88
<210> 19
<211> 89
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R306H 2xBoxB向导Fwd
<400> 19
caccgatgct gaccgtggcc ctgaaaaagg gccccgggtc ttgcgcttct tgatgggagc 60
aggccctgaa aaagggcctc tcatgcaca 89
<210> 20
<211> 90
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R306H 2xBoxB向导Rev
<400> 20
aaaatgtgca tgagaggccc tttttcaggg cctgctcccc atcaagaagc gcaagacccg 60
gggccctttt tcagggccac ggtcagcatc 90
<210> 21
<211> 89
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q脱靶错配2xBoxB向导Fwd
<400> 21
caccgcagac ttcctggccc tgaaaaaggg cctttaagct ttccgggtcc aaccttcagg 60
caggccctga aaaagggcct ggggtcatc 89
<210> 22
<211> 88
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 R106Q脱靶错配2xBoxB向导Rev
<400> 22
aaaagatgac cccaggccct ttttcagggc ctgcctgaag gttggacccg aaagcttaaa 60
ggcccttttt cagggccagg aagtctgc 88
<210> 23
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> CMV-mMecp2 ATG Fwd引物
<400> 23
tcaagcttcg aattccacca tggcc 25
<210> 24
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> GFP-N3接头Rev引物
<400> 24
ccttgctcac catggtggcg a 21
<210> 25
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 -14 mMecp2 ATG Fwd引物
<400> 25
aacccgtccg gaaaatggcc 20
<210> 26
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> mMecp2-3'UTR+92 Rev引物
<400> 26
ggaagctttg tcagagccct acccataag 29
<210> 27
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 554 Rev引物
<400> 27
ctcctggagg ggctccctct c 21
<210> 28
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 914 Rev引物
<400> 28
gaccgtatgg aagactcctt ca 22
<210> 29
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 1122 Rev引物
<400> 29
actgctgctg cgcccctt 18
<210> 30
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> hU6 AflII Fwd引物
<400> 30
gtgtcttaag gagggcctat ttcccatgat t 31
<210> 31
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> hU6 MfeI Fwd引物
<400> 31
gtgtcaattg gagggcctat ttcccatgat t 31
<210> 32
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> hU6 NheI Fwd引物
<400> 32
gtgtgctagc gagggcctat ttcccatgat t 31
<210> 33
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> hU6 SacI Fwd引物
<400> 33
gtgtgagctc gagggcctat ttcccatgat t 31
<210> 34
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> hU6 SpeI Fwd引物
<400> 34
gtgtactagt gagggcctat ttcccatg 28
<210> 35
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> hU6 (m) NdeI Fwd引物
<400> 35
gtgtcatatg cttaccgtaa cttgaaag 28
<210> 36
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 AflII Rev引物
<400> 36
atatcttaag aaaaaagatg accccaggcc ct 32
<210> 37
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 ApaI Rev引物
<400> 37
cacagggccc aaaaaagatg accccaggcc ct 32
<210> 38
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 MfeI Rev引物
<400> 38
atatcaattg aaaaaagatg accccaggcc ct 32
<210> 39
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 SacI Rev引物
<400> 39
atatgagctc aaaaaagatg accccaggcc ct 32
<210> 40
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 SpeI Rev引物
<400> 40
atatactagt aaaaaagatg accccaggcc ct 32
<210> 41
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> R106QgV2 (+2)ApaI Rev引物
<400> 41
gcgcgggccc ttcgaagcta gcaaaaaaga tgaccccagg ccct 44
<210> 42
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> 2xHA Editase Fwd NcoI Kozak引物
<400> 42
attcgccacc atggtgtacc cctatgacgt g 31
<210> 43
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> Editase EcoRI Rev引物
<400> 43
gcgcgaattc tcaatggtga tggtgatggt 30
<210> 44
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 接头
<220>
<221> 变体
<222> (6)...(10)
<223> 氨基酸6-10是GGGGS或不存在
<220>
<221> 变体
<222> (11)...(15)
<223> 氨基酸11-15是GGGGS或不存在
<220>
<221> 变体
<222> (16)...(20)
<223> 氨基酸16-20是GGGGS或不存在
<220>
<221> 变体
<222> (21)...(25)
<223> 氨基酸21-25是GGGGS或不存在
<220>
<221> 变体
<222> (26)...(30)
<223> 氨基酸26-30是GGGGS或不存在
<220>
<221> 变体
<222> (31)...(35)
<223> 氨基酸31-35是GGGGS或不存在
<220>
<221> 变体
<222> (36)...(40)
<223> 氨基酸36-40是GGGGS或不存在
<220>
<221> 变体
<222> (41)...(45)
<223> 氨基酸41-45是GGGGS或不存在
<220>
<221> 变体
<222> (46)...(50)
<223> 氨基酸46-50是GGGGS或不存在
<400> 44
Gly Gly Gly Gly Ser Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
20 25 30
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40 45
Xaa Xaa
50
<210> 45
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 46
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> λN肽
<400> 46
Met Asn Ala Arg Thr Arg Arg Arg Glu Arg Arg Ala Glu Lys Gln Ala
1 5 10 15
Gln Trp Lys Ala Ala Asn
20
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> SV40大T-抗原NLS
<400> 47
Pro Lys Lys Lys Arg Lys Val
1 5
<210> 48
<211> 15
<212> RNA
<213> 人工序列
<220>
<223> BoxB序列
<400> 48
gcccugaaaa agggc 15
<210> 49
<211> 17
<212> RNA
<213> 人工序列
<220>
<223> BoxB序列
<400> 49
ggcccugaaa aagggcc 17
<210> 50
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> Mecp2-R106Q Fwd引物
<400> 50
ggacctatgt atgatgaccc 20
<210> 51
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> Mecp2-R106Q Rev引物
<400> 51
ggtcattggg ctagactgaa 20
<210> 52
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 靶标序列
<400> 52
ttgcctgaag gttggacaca aaagcttaaa 30
<210> 53
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 靶标序列
<400> 53
Leu Pro Glu Gly Trp Thr Gln Lys Leu Lys
1 5 10
<210> 54
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> c-myc NLS
<400> 54
Pro Ala Ala Lys Arg Val Lys Leu Asp
1 5
<210> 55
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> 人ADAR2的脱氨酶域
<400> 55
Leu His Leu Asp Gln Thr Pro Ser Arg Gln Pro Ile Pro Ser Glu Gly
1 5 10 15
Leu Gln Leu His Leu Pro Gln Val Leu Ala Asp Ala Val Ser Arg Leu
20 25 30
Val Leu Gly Lys Phe Gly Asp Leu Thr Asp Asn Phe Ser Ser Pro His
35 40 45
Ala Arg Arg Lys Val Leu Ala Gly Val Val Met Thr Thr Gly Thr Asp
50 55 60
Val Lys Asp Ala Lys Val Ile Ser Val Ser Thr Gly Thr Lys Cys Ile
65 70 75 80
Asn Gly Glu Tyr Met Ser Asp Arg Gly Leu Ala Leu Asn Asp Cys His
85 90 95
Ala Glu Ile Ile Ser Arg Arg Ser Leu Leu Arg Phe Leu Tyr Thr Gln
100 105 110
Leu Glu Leu Tyr Leu Asn Asn Lys Asp Asp Gln Lys Arg Ser Ile Phe
115 120 125
Gln Lys Ser Glu Arg Gly Gly Phe Arg Leu Lys Glu Asn Val Gln Phe
130 135 140
His Leu Tyr Ile Ser Thr Ser Pro Cys Gly Asp Ala Arg Ile Phe Ser
145 150 155 160
Pro His Glu Pro Ile Leu Glu Glu Pro Ala Asp Arg His Pro Asn Arg
165 170 175
Lys Ala Arg Gly Gln Leu Arg Thr Lys Ile Glu Ser Gly Glu Gly Thr
180 185 190
Ile Pro Val Arg Ser Asn Ala Ser Ile Gln Thr Trp Asp Gly Val Leu
195 200 205
Gln Gly Glu Arg Leu Leu Thr Met Ser Cys Ser Asp Lys Ile Ala Arg
210 215 220
Trp Asn Val Val Gly Ile Gln Gly Ser Leu Leu Ser Ile Phe Val Glu
225 230 235 240
Pro Ile Tyr Phe Ser Ser Ile Ile Leu Gly Ser Leu Tyr His Gly Asp
245 250 255
His Leu Ser Arg Ala Met Tyr Gln Arg Ile Ser Asn Ile Glu Asp Leu
260 265 270
Pro Pro Leu Tyr Thr Leu Asn Lys Pro Leu Leu Ser Gly Ile Ser Asn
275 280 285
Ala Glu Ala Arg Gln Pro Gly Lys Ala Pro Asn Phe Ser Val Asn Trp
290 295 300
Thr Val Gly Asp Ser Ala Ile Glu Val Ile Asn Ala Thr Thr Gly Lys
305 310 315 320
Asp Glu Leu Gly Arg Ala Ser Arg Leu Cys Lys His Ala Leu Tyr Cys
325 330 335
Arg Trp Met Arg Val His Gly Lys Val Pro Ser His Leu Leu Arg Ser
340 345 350
Lys Ile Thr Lys Pro Asn Val Tyr His Glu Ser Lys Leu Ala Ala Lys
355 360 365
Glu Tyr Gln Ala Ala Lys Ala Arg Leu Phe Thr Ala Phe Ile Lys Ala
370 375 380
Gly Leu Gly Ala Trp Val Glu Lys Pro Thr Glu Gln Asp Gln Phe Ser
385 390 395 400
Leu Thr Pro
<210> 56
<211> 486
<212> PRT
<213> 智人
<400> 56
Met Val Ala Gly Met Leu Gly Leu Arg Glu Glu Lys Ser Glu Asp Gln
1 5 10 15
Asp Leu Gln Gly Leu Lys Asp Lys Pro Leu Lys Phe Lys Lys Val Lys
20 25 30
Lys Asp Lys Lys Glu Glu Lys Glu Gly Lys His Glu Pro Val Gln Pro
35 40 45
Ser Ala His His Ser Ala Glu Pro Ala Glu Ala Gly Lys Ala Glu Thr
50 55 60
Ser Glu Gly Ser Gly Ser Ala Pro Ala Val Pro Glu Ala Ser Ala Ser
65 70 75 80
Pro Lys Gln Arg Arg Ser Ile Ile Arg Asp Arg Gly Pro Met Tyr Asp
85 90 95
Asp Pro Thr Leu Pro Glu Gly Trp Thr Arg Lys Leu Lys Gln Arg Lys
100 105 110
Ser Gly Arg Ser Ala Gly Lys Tyr Asp Val Tyr Leu Ile Asn Pro Gln
115 120 125
Gly Lys Ala Phe Arg Ser Lys Val Glu Leu Ile Ala Tyr Phe Glu Lys
130 135 140
Val Gly Asp Thr Ser Leu Asp Pro Asn Asp Phe Asp Phe Thr Val Thr
145 150 155 160
Gly Arg Gly Ser Pro Ser Arg Arg Glu Gln Lys Pro Pro Lys Lys Pro
165 170 175
Lys Ser Pro Lys Ala Pro Gly Thr Gly Arg Gly Arg Gly Arg Pro Lys
180 185 190
Gly Ser Gly Thr Thr Arg Pro Lys Ala Ala Thr Ser Glu Gly Val Gln
195 200 205
Val Lys Arg Val Leu Glu Lys Ser Pro Gly Lys Leu Leu Val Lys Met
210 215 220
Pro Phe Gln Thr Ser Pro Gly Gly Lys Ala Glu Gly Gly Gly Ala Thr
225 230 235 240
Thr Ser Thr Gln Val Met Val Ile Lys Arg Pro Gly Arg Lys Arg Lys
245 250 255
Ala Glu Ala Asp Pro Gln Ala Ile Pro Lys Lys Arg Gly Arg Lys Pro
260 265 270
Gly Ser Val Val Ala Ala Ala Ala Ala Glu Ala Lys Lys Lys Ala Val
275 280 285
Lys Glu Ser Ser Ile Arg Ser Val Gln Glu Thr Val Leu Pro Ile Lys
290 295 300
Lys Arg Lys Thr Arg Glu Thr Val Ser Ile Glu Val Lys Glu Val Val
305 310 315 320
Lys Pro Leu Leu Val Ser Thr Leu Gly Glu Lys Ser Gly Lys Gly Leu
325 330 335
Lys Thr Cys Lys Ser Pro Gly Arg Lys Ser Lys Glu Ser Ser Pro Lys
340 345 350
Gly Arg Ser Ser Ser Ala Ser Ser Pro Pro Lys Lys Glu His His His
355 360 365
His His His His Ser Glu Ser Pro Lys Ala Pro Val Pro Leu Leu Pro
370 375 380
Pro Leu Pro Pro Pro Pro Pro Glu Pro Glu Ser Ser Glu Asp Pro Thr
385 390 395 400
Ser Pro Pro Glu Pro Gln Asp Leu Ser Ser Ser Val Cys Lys Glu Glu
405 410 415
Lys Met Pro Arg Gly Gly Ser Leu Glu Ser Asp Gly Cys Pro Lys Glu
420 425 430
Pro Ala Lys Thr Gln Pro Ala Val Ala Thr Ala Ala Thr Ala Ala Glu
435 440 445
Lys Tyr Lys His Arg Gly Glu Gly Glu Arg Lys Asp Ile Val Ser Ser
450 455 460
Ser Met Pro Arg Pro Asn Arg Glu Glu Pro Val Asp Ser Arg Thr Pro
465 470 475 480
Val Thr Glu Arg Val Ser
485
<210> 57
<211> 1461
<212> DNA
<213> 智人
<400> 57
atggtagctg ggatgttagg gctcagggaa gaaaagtcag aagaccagga cctccagggc 60
ctcaaggaca aacccctcaa gtttaaaaag gtgaagaaag ataagaaaga agagaaagag 120
ggcaagcatg agcccgtgca gccatcagcc caccactctg ctgagcccgc agaggcaggc 180
aaagcagaga catcagaagg gtcaggctcc gccccggctg tgccggaagc ttctgcctcc 240
cccaaacagc ggcgctccat catccgtgac cggggaccca tgtatgatga ccccaccctg 300
cctgaaggct ggacacggaa gcttaagcaa aggaaatctg gccgctctgc tgggaagtat 360
gatgtgtatt tgatcaatcc ccagggaaaa gcctttcgct ctaaagtgga gttgattgcg 420
tacttcgaaa aggtaggcga cacatccctg gaccctaatg attttgactt cacggtaact 480
gggagaggga gcccctcccg gcgagagcag aaaccaccta agaagcccaa atctcccaaa 540
gctccaggaa ctggcagagg ccggggacgc cccaaaggga gcggcaccac gagacccaag 600
gcggccacgt cagagggtgt gcaggtgaaa agggtcctgg agaaaagtcc tgggaagctc 660
cttgtcaaga tgccttttca aacttcgcca gggggcaagg ctgagggggg tggggccacc 720
acatccaccc aggtcatggt gatcaaacgc cccggcagga agcgaaaagc tgaggccgac 780
cctcaggcca ttcccaagaa acggggccga aagccgggga gtgtggtggc agccgctgcc 840
gccgaggcca aaaagaaagc cgtgaaggag tcttctatcc gatctgtgca ggagaccgta 900
ctccccatca agaagcgcaa gacccgggag acggtcagca tcgaggtcaa ggaagtggtg 960
aagcccctgc tggtgtccac cctcggtgag aagagcggga aaggactgaa gacctgtaag 1020
agccctgggc ggaaaagcaa ggagagcagc cccaaggggc gcagcagcag cgcctcctca 1080
ccccccaaga aggagcacca ccaccatcac caccactcag agtccccaaa ggcccccgtg 1140
ccactgctcc cacccctgcc cccacctcca cctgagcccg agagctccga ggaccccacc 1200
agcccccctg agccccagga cttgagcagc agcgtctgca aagaggagaa gatgcccaga 1260
ggaggctcac tggagagcga cggctgcccc aaggagccag ctaagactca gcccgcggtt 1320
gccaccgccg ccacggccgc agaaaagtac aaacaccgag gggagggaga gcgcaaagac 1380
attgtttcat cctccatgcc aaggccaaac agagaggagc ctgtggacag ccggacgccc 1440
gtgaccgaga gagttagctg a 1461
<210> 58
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 共有NLS
<220>
<221> 变体
<222> 2, 4
<223> X是Arg或Lys
<220>
<221> 变体
<222> 3
<223> X是任何氨基酸
<400> 58
Lys Xaa Xaa Xaa
1
<210> 59
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 共有NLS
<220>
<221> 变体
<222> (1)...(2)
<223> X是Arg或Lys
<220>
<221> 变体
<222> (3)...(12)
<223> X是任何氨基酸
<220>
<221> 变体
<222> (13)...(14)
<223> X是任何氨基酸或不存在
<220>
<221> 变体
<222> (15)...(19)
<223> X是任何氨基酸,但是氨基酸中的至少三个必须是Arg或Lys
<400> 59
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa Xaa
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 核质蛋白NLS
<400> 60
Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys
1 5 10 15
<210> 61
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> hADAR2 3xFlag Fwd引物
<400> 61
tggtggaatt cgccaccatg gactacaagg 30
<210> 62
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> hADAR2 Rev引物
<400> 62
tcgagcggcc gctcaatggt gatggtga 28
<210> 63
<211> 60
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X内环向导Fwd
<400> 63
caccgacttc ctttgttatt gctttcgggt ccaaccttca ggcatcctgg ggtcatcata 60
<210> 64
<211> 60
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X内环向导Rev
<400> 64
aaaatatgat gaccccagga tgcctgaagg ttggacccga aagcaataac aaaggaagtc 60
<210> 65
<211> 92
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X GluA2向导Fwd
<400> 65
caccgtggaa tagtataaca atatgctaaa tgttgttata gtatcccact cgtgtccaac 60
cttcatctag agggccctga agagggccct tt 92
<210> 66
<211> 92
<212> DNA
<213> 人工序列
<220>
<223> mMecp2 W104X GluA2向导Rev
<400> 66
aaaaaaaggg ccctcttcag ggccctctag atgaaggttg gacacgagtg ggatactata 60
acaacattta gcatattgtt atactattcc ac 92
<210> 67
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> NLS
<400> 67
Asp Pro Lys Lys Lys Arg Lys Val Asp Pro Lys Lys Lys Arg Lys Val
1 5 10 15
Asp Pro Lys Lys Lys Arg Lys Val
20
<210> 68
<211> 440
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 68
Met Asn Ala Arg Thr Arg Arg Arg Glu Arg Arg Ala Glu Lys Gln Ala
1 5 10 15
Gln Trp Lys Ala Ala Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
Gly Gly Gly Gly Ser Leu His Leu Asp Gln Thr Pro Ser Arg Gln Pro
35 40 45
Ile Pro Ser Glu Gly Leu Gln Leu His Leu Pro Gln Val Leu Ala Asp
50 55 60
Ala Val Ser Arg Leu Val Leu Gly Lys Phe Gly Asp Leu Thr Asp Asn
65 70 75 80
Phe Ser Ser Pro His Ala Arg Arg Lys Val Leu Ala Gly Val Val Met
85 90 95
Thr Thr Gly Thr Asp Val Lys Asp Ala Lys Val Ile Ser Val Ser Thr
100 105 110
Gly Thr Lys Cys Ile Asn Gly Glu Tyr Met Ser Asp Arg Gly Leu Ala
115 120 125
Leu Asn Asp Cys His Ala Glu Ile Ile Ser Arg Arg Ser Leu Leu Arg
130 135 140
Phe Leu Tyr Thr Gln Leu Glu Leu Tyr Leu Asn Asn Lys Asp Asp Gln
145 150 155 160
Lys Arg Ser Ile Phe Gln Lys Ser Glu Arg Gly Gly Phe Arg Leu Lys
165 170 175
Glu Asn Val Gln Phe His Leu Tyr Ile Ser Thr Ser Pro Cys Gly Asp
180 185 190
Ala Arg Ile Phe Ser Pro His Glu Pro Ile Leu Glu Glu Pro Ala Asp
195 200 205
Arg His Pro Asn Arg Lys Ala Arg Gly Gln Leu Arg Thr Lys Ile Glu
210 215 220
Ser Gly Glu Gly Thr Ile Pro Val Arg Ser Asn Ala Ser Ile Gln Thr
225 230 235 240
Trp Asp Gly Val Leu Gln Gly Glu Arg Leu Leu Thr Met Ser Cys Ser
245 250 255
Asp Lys Ile Ala Arg Trp Asn Val Val Gly Ile Gln Gly Ser Leu Leu
260 265 270
Ser Ile Phe Val Glu Pro Ile Tyr Phe Ser Ser Ile Ile Leu Gly Ser
275 280 285
Leu Tyr His Gly Asp His Leu Ser Arg Ala Met Tyr Gln Arg Ile Ser
290 295 300
Asn Ile Glu Asp Leu Pro Pro Leu Tyr Thr Leu Asn Lys Pro Leu Leu
305 310 315 320
Ser Gly Ile Ser Asn Ala Glu Ala Arg Gln Pro Gly Lys Ala Pro Asn
325 330 335
Phe Ser Val Asn Trp Thr Val Gly Asp Ser Ala Ile Glu Val Ile Asn
340 345 350
Ala Thr Thr Gly Lys Asp Glu Leu Gly Arg Ala Ser Arg Leu Cys Lys
355 360 365
His Ala Leu Tyr Cys Arg Trp Met Arg Val His Gly Lys Val Pro Ser
370 375 380
His Leu Leu Arg Ser Lys Ile Thr Lys Pro Asn Val Tyr His Glu Ser
385 390 395 400
Lys Leu Ala Ala Lys Glu Tyr Gln Ala Ala Lys Ala Arg Leu Phe Thr
405 410 415
Ala Phe Ile Lys Ala Gly Leu Gly Ala Trp Val Glu Lys Pro Thr Glu
420 425 430
Gln Asp Gln Phe Ser Leu Thr Pro
435 440
<210> 69
<211> 464
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 69
Asp Pro Lys Lys Lys Arg Lys Val Asp Pro Lys Lys Lys Arg Lys Val
1 5 10 15
Asp Pro Lys Lys Lys Arg Lys Val Met Asn Ala Arg Thr Arg Arg Arg
20 25 30
Glu Arg Arg Ala Glu Lys Gln Ala Gln Trp Lys Ala Ala Asn Gly Gly
35 40 45
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu His Leu
50 55 60
Asp Gln Thr Pro Ser Arg Gln Pro Ile Pro Ser Glu Gly Leu Gln Leu
65 70 75 80
His Leu Pro Gln Val Leu Ala Asp Ala Val Ser Arg Leu Val Leu Gly
85 90 95
Lys Phe Gly Asp Leu Thr Asp Asn Phe Ser Ser Pro His Ala Arg Arg
100 105 110
Lys Val Leu Ala Gly Val Val Met Thr Thr Gly Thr Asp Val Lys Asp
115 120 125
Ala Lys Val Ile Ser Val Ser Thr Gly Thr Lys Cys Ile Asn Gly Glu
130 135 140
Tyr Met Ser Asp Arg Gly Leu Ala Leu Asn Asp Cys His Ala Glu Ile
145 150 155 160
Ile Ser Arg Arg Ser Leu Leu Arg Phe Leu Tyr Thr Gln Leu Glu Leu
165 170 175
Tyr Leu Asn Asn Lys Asp Asp Gln Lys Arg Ser Ile Phe Gln Lys Ser
180 185 190
Glu Arg Gly Gly Phe Arg Leu Lys Glu Asn Val Gln Phe His Leu Tyr
195 200 205
Ile Ser Thr Ser Pro Cys Gly Asp Ala Arg Ile Phe Ser Pro His Glu
210 215 220
Pro Ile Leu Glu Glu Pro Ala Asp Arg His Pro Asn Arg Lys Ala Arg
225 230 235 240
Gly Gln Leu Arg Thr Lys Ile Glu Ser Gly Glu Gly Thr Ile Pro Val
245 250 255
Arg Ser Asn Ala Ser Ile Gln Thr Trp Asp Gly Val Leu Gln Gly Glu
260 265 270
Arg Leu Leu Thr Met Ser Cys Ser Asp Lys Ile Ala Arg Trp Asn Val
275 280 285
Val Gly Ile Gln Gly Ser Leu Leu Ser Ile Phe Val Glu Pro Ile Tyr
290 295 300
Phe Ser Ser Ile Ile Leu Gly Ser Leu Tyr His Gly Asp His Leu Ser
305 310 315 320
Arg Ala Met Tyr Gln Arg Ile Ser Asn Ile Glu Asp Leu Pro Pro Leu
325 330 335
Tyr Thr Leu Asn Lys Pro Leu Leu Ser Gly Ile Ser Asn Ala Glu Ala
340 345 350
Arg Gln Pro Gly Lys Ala Pro Asn Phe Ser Val Asn Trp Thr Val Gly
355 360 365
Asp Ser Ala Ile Glu Val Ile Asn Ala Thr Thr Gly Lys Asp Glu Leu
370 375 380
Gly Arg Ala Ser Arg Leu Cys Lys His Ala Leu Tyr Cys Arg Trp Met
385 390 395 400
Arg Val His Gly Lys Val Pro Ser His Leu Leu Arg Ser Lys Ile Thr
405 410 415
Lys Pro Asn Val Tyr His Glu Ser Lys Leu Ala Ala Lys Glu Tyr Gln
420 425 430
Ala Ala Lys Ala Arg Leu Phe Thr Ala Phe Ile Lys Ala Gly Leu Gly
435 440 445
Ala Trp Val Glu Lys Pro Thr Glu Gln Asp Gln Phe Ser Leu Thr Pro
450 455 460
<210> 70
<211> 45
<212> RNA
<213> 人工序列
<220>
<223> R/G结合位点
<400> 70
guggaauagu auaacaauau gcuaaauguu guuauaguau cccac 45
<210> 71
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> 人ADAR2 E488Q的脱氨酶域
<400> 71
Leu His Leu Asp Gln Thr Pro Ser Arg Gln Pro Ile Pro Ser Glu Gly
1 5 10 15
Leu Gln Leu His Leu Pro Gln Val Leu Ala Asp Ala Val Ser Arg Leu
20 25 30
Val Leu Gly Lys Phe Gly Asp Leu Thr Asp Asn Phe Ser Ser Pro His
35 40 45
Ala Arg Arg Lys Val Leu Ala Gly Val Val Met Thr Thr Gly Thr Asp
50 55 60
Val Lys Asp Ala Lys Val Ile Ser Val Ser Thr Gly Thr Lys Cys Ile
65 70 75 80
Asn Gly Glu Tyr Met Ser Asp Arg Gly Leu Ala Leu Asn Asp Cys His
85 90 95
Ala Glu Ile Ile Ser Arg Arg Ser Leu Leu Arg Phe Leu Tyr Thr Gln
100 105 110
Leu Glu Leu Tyr Leu Asn Asn Lys Asp Asp Gln Lys Arg Ser Ile Phe
115 120 125
Gln Lys Ser Glu Arg Gly Gly Phe Arg Leu Lys Glu Asn Val Gln Phe
130 135 140
His Leu Tyr Ile Ser Thr Ser Pro Cys Gly Asp Ala Arg Ile Phe Ser
145 150 155 160
Pro His Glu Pro Ile Leu Glu Glu Pro Ala Asp Arg His Pro Asn Arg
165 170 175
Lys Ala Arg Gly Gln Leu Arg Thr Lys Ile Glu Ser Gly Gln Gly Thr
180 185 190
Ile Pro Val Arg Ser Asn Ala Ser Ile Gln Thr Trp Asp Gly Val Leu
195 200 205
Gln Gly Glu Arg Leu Leu Thr Met Ser Cys Ser Asp Lys Ile Ala Arg
210 215 220
Trp Asn Val Val Gly Ile Gln Gly Ser Leu Leu Ser Ile Phe Val Glu
225 230 235 240
Pro Ile Tyr Phe Ser Ser Ile Ile Leu Gly Ser Leu Tyr His Gly Asp
245 250 255
His Leu Ser Arg Ala Met Tyr Gln Arg Ile Ser Asn Ile Glu Asp Leu
260 265 270
Pro Pro Leu Tyr Thr Leu Asn Lys Pro Leu Leu Ser Gly Ile Ser Asn
275 280 285
Ala Glu Ala Arg Gln Pro Gly Lys Ala Pro Asn Phe Ser Val Asn Trp
290 295 300
Thr Val Gly Asp Ser Ala Ile Glu Val Ile Asn Ala Thr Thr Gly Lys
305 310 315 320
Asp Glu Leu Gly Arg Ala Ser Arg Leu Cys Lys His Ala Leu Tyr Cys
325 330 335
Arg Trp Met Arg Val His Gly Lys Val Pro Ser His Leu Leu Arg Ser
340 345 350
Lys Ile Thr Lys Pro Asn Val Tyr His Glu Ser Lys Leu Ala Ala Lys
355 360 365
Glu Tyr Gln Ala Ala Lys Ala Arg Leu Phe Thr Ala Phe Ile Lys Ala
370 375 380
Gly Leu Gly Ala Trp Val Glu Lys Pro Thr Glu Gln Asp Gln Phe Ser
385 390 395 400
Leu Thr Pro
<210> 72
<211> 1226
<212> PRT
<213> 智人
<400> 72
Met Asn Pro Arg Gln Gly Tyr Ser Leu Ser Gly Tyr Tyr Thr His Pro
1 5 10 15
Phe Gln Gly Tyr Glu His Arg Gln Leu Arg Tyr Gln Gln Pro Gly Pro
20 25 30
Gly Ser Ser Pro Ser Ser Phe Leu Leu Lys Gln Ile Glu Phe Leu Lys
35 40 45
Gly Gln Leu Pro Glu Ala Pro Val Ile Gly Lys Gln Thr Pro Ser Leu
50 55 60
Pro Pro Ser Leu Pro Gly Leu Arg Pro Arg Phe Pro Val Leu Leu Ala
65 70 75 80
Ser Ser Thr Arg Gly Arg Gln Val Asp Ile Arg Gly Val Pro Arg Gly
85 90 95
Val His Leu Arg Ser Gln Gly Leu Gln Arg Gly Phe Gln His Pro Ser
100 105 110
Pro Arg Gly Arg Ser Leu Pro Gln Arg Gly Val Asp Cys Leu Ser Ser
115 120 125
His Phe Gln Glu Leu Ser Ile Tyr Gln Asp Gln Glu Gln Arg Ile Leu
130 135 140
Lys Phe Leu Glu Glu Leu Gly Glu Gly Lys Ala Thr Thr Ala His Asp
145 150 155 160
Leu Ser Gly Lys Leu Gly Thr Pro Lys Lys Glu Ile Asn Arg Val Leu
165 170 175
Tyr Ser Leu Ala Lys Lys Gly Lys Leu Gln Lys Glu Ala Gly Thr Pro
180 185 190
Pro Leu Trp Lys Ile Ala Val Ser Thr Gln Ala Trp Asn Gln His Ser
195 200 205
Gly Val Val Arg Pro Asp Gly His Ser Gln Gly Ala Pro Asn Ser Asp
210 215 220
Pro Ser Leu Glu Pro Glu Asp Arg Asn Ser Thr Ser Val Ser Glu Asp
225 230 235 240
Leu Leu Glu Pro Phe Ile Ala Val Ser Ala Gln Ala Trp Asn Gln His
245 250 255
Ser Gly Val Val Arg Pro Asp Ser His Ser Gln Gly Ser Pro Asn Ser
260 265 270
Asp Pro Gly Leu Glu Pro Glu Asp Ser Asn Ser Thr Ser Ala Leu Glu
275 280 285
Asp Pro Leu Glu Phe Leu Asp Met Ala Glu Ile Lys Glu Lys Ile Cys
290 295 300
Asp Tyr Leu Phe Asn Val Ser Asp Ser Ser Ala Leu Asn Leu Ala Lys
305 310 315 320
Asn Ile Gly Leu Thr Lys Ala Arg Asp Ile Asn Ala Val Leu Ile Asp
325 330 335
Met Glu Arg Gln Gly Asp Val Tyr Arg Gln Gly Thr Thr Pro Pro Ile
340 345 350
Trp His Leu Thr Asp Lys Lys Arg Glu Arg Met Gln Ile Lys Arg Asn
355 360 365
Thr Asn Ser Val Pro Glu Thr Ala Pro Ala Ala Ile Pro Glu Thr Lys
370 375 380
Arg Asn Ala Glu Phe Leu Thr Cys Asn Ile Pro Thr Ser Asn Ala Ser
385 390 395 400
Asn Asn Met Val Thr Thr Glu Lys Val Glu Asn Gly Gln Glu Pro Val
405 410 415
Ile Lys Leu Glu Asn Arg Gln Glu Ala Arg Pro Glu Pro Ala Arg Leu
420 425 430
Lys Pro Pro Val His Tyr Asn Gly Pro Ser Lys Ala Gly Tyr Val Asp
435 440 445
Phe Glu Asn Gly Gln Trp Ala Thr Asp Asp Ile Pro Asp Asp Leu Asn
450 455 460
Ser Ile Arg Ala Ala Pro Gly Glu Phe Arg Ala Ile Met Glu Met Pro
465 470 475 480
Ser Phe Tyr Ser His Gly Leu Pro Arg Cys Ser Pro Tyr Lys Lys Leu
485 490 495
Thr Glu Cys Gln Leu Lys Asn Pro Ile Ser Gly Leu Leu Glu Tyr Ala
500 505 510
Gln Phe Ala Ser Gln Thr Cys Glu Phe Asn Met Ile Glu Gln Ser Gly
515 520 525
Pro Pro His Glu Pro Arg Phe Lys Phe Gln Val Val Ile Asn Gly Arg
530 535 540
Glu Phe Pro Pro Ala Glu Ala Gly Ser Lys Lys Val Ala Lys Gln Asp
545 550 555 560
Ala Ala Met Lys Ala Met Thr Ile Leu Leu Glu Glu Ala Lys Ala Lys
565 570 575
Asp Ser Gly Lys Ser Glu Glu Ser Ser His Tyr Ser Thr Glu Lys Glu
580 585 590
Ser Glu Lys Thr Ala Glu Ser Gln Thr Pro Thr Pro Ser Ala Thr Ser
595 600 605
Phe Phe Ser Gly Lys Ser Pro Val Thr Thr Leu Leu Glu Cys Met His
610 615 620
Lys Leu Gly Asn Ser Cys Glu Phe Arg Leu Leu Ser Lys Glu Gly Pro
625 630 635 640
Ala His Glu Pro Lys Phe Gln Tyr Cys Val Ala Val Gly Ala Gln Thr
645 650 655
Phe Pro Ser Val Ser Ala Pro Ser Lys Lys Val Ala Lys Gln Met Ala
660 665 670
Ala Glu Glu Ala Met Lys Ala Leu His Gly Glu Ala Thr Asn Ser Met
675 680 685
Ala Ser Asp Asn Gln Pro Glu Gly Met Ile Ser Glu Ser Leu Asp Asn
690 695 700
Leu Glu Ser Met Met Pro Asn Lys Val Arg Lys Ile Gly Glu Leu Val
705 710 715 720
Arg Tyr Leu Asn Thr Asn Pro Val Gly Gly Leu Leu Glu Tyr Ala Arg
725 730 735
Ser His Gly Phe Ala Ala Glu Phe Lys Leu Val Asp Gln Ser Gly Pro
740 745 750
Pro His Glu Pro Lys Phe Val Tyr Gln Ala Lys Val Gly Gly Arg Trp
755 760 765
Phe Pro Ala Val Cys Ala His Ser Lys Lys Gln Gly Lys Gln Glu Ala
770 775 780
Ala Asp Ala Ala Leu Arg Val Leu Ile Gly Glu Asn Glu Lys Ala Glu
785 790 795 800
Arg Met Gly Phe Thr Glu Val Thr Pro Val Thr Gly Ala Ser Leu Arg
805 810 815
Arg Thr Met Leu Leu Leu Ser Arg Ser Pro Glu Ala Gln Pro Lys Thr
820 825 830
Leu Pro Leu Thr Gly Ser Thr Phe His Asp Gln Ile Ala Met Leu Ser
835 840 845
His Arg Cys Phe Asn Thr Leu Thr Asn Ser Phe Gln Pro Ser Leu Leu
850 855 860
Gly Arg Lys Ile Leu Ala Ala Ile Ile Met Lys Lys Asp Ser Glu Asp
865 870 875 880
Met Gly Val Val Val Ser Leu Gly Thr Gly Asn Arg Cys Val Lys Gly
885 890 895
Asp Ser Leu Ser Leu Lys Gly Glu Thr Val Asn Asp Cys His Ala Glu
900 905 910
Ile Ile Ser Arg Arg Gly Phe Ile Arg Phe Leu Tyr Ser Glu Leu Met
915 920 925
Lys Tyr Asn Ser Gln Thr Ala Lys Asp Ser Ile Phe Glu Pro Ala Lys
930 935 940
Gly Gly Glu Lys Leu Gln Ile Lys Lys Thr Val Ser Phe His Leu Tyr
945 950 955 960
Ile Ser Thr Ala Pro Cys Gly Asp Gly Ala Leu Phe Asp Lys Ser Cys
965 970 975
Ser Asp Arg Ala Met Glu Ser Thr Glu Ser Arg His Tyr Pro Val Phe
980 985 990
Glu Asn Pro Lys Gln Gly Lys Leu Arg Thr Lys Val Glu Asn Gly Glu
995 1000 1005
Gly Thr Ile Pro Val Glu Ser Ser Asp Ile Val Pro Thr Trp Asp Gly
1010 1015 1020
Ile Arg Leu Gly Glu Arg Leu Arg Thr Met Ser Cys Ser Asp Lys Ile
1025 1030 1035 1040
Leu Arg Trp Asn Val Leu Gly Leu Gln Gly Ala Leu Leu Thr His Phe
1045 1050 1055
Leu Gln Pro Ile Tyr Leu Lys Ser Val Thr Leu Gly Tyr Leu Phe Ser
1060 1065 1070
Gln Gly His Leu Thr Arg Ala Ile Cys Cys Arg Val Thr Arg Asp Gly
1075 1080 1085
Ser Ala Phe Glu Asp Gly Leu Arg His Pro Phe Ile Val Asn His Pro
1090 1095 1100
Lys Val Gly Arg Val Ser Ile Tyr Asp Ser Lys Arg Gln Ser Gly Lys
1105 1110 1115 1120
Thr Lys Glu Thr Ser Val Asn Trp Cys Leu Ala Asp Gly Tyr Asp Leu
1125 1130 1135
Glu Ile Leu Asp Gly Thr Arg Gly Thr Val Asp Gly Pro Arg Asn Glu
1140 1145 1150
Leu Ser Arg Val Ser Lys Lys Asn Ile Phe Leu Leu Phe Lys Lys Leu
1155 1160 1165
Cys Ser Phe Arg Tyr Arg Arg Asp Leu Leu Arg Leu Ser Tyr Gly Glu
1170 1175 1180
Ala Lys Lys Ala Ala Arg Asp Tyr Glu Thr Ala Lys Asn Tyr Phe Lys
1185 1190 1195 1200
Lys Gly Leu Lys Asp Met Gly Tyr Gly Asn Trp Ile Ser Lys Pro Gln
1205 1210 1215
Glu Glu Lys Asn Phe Tyr Leu Cys Pro Val
1220 1225
Claims (31)
1.一种用于编辑细胞中内源RNA的靶标序列的方法,所述方法包括向所述细胞递送向导RNA或编码向导RNA的核酸分子,
其中所述向导RNA包含内源人作用于RNA的腺苷脱氨酶(ADAR)特异性识别的序列和/或结构,
其中所述向导RNA与所述内源RNA中的所述靶标序列特异性杂交,并且在待编辑的核苷酸处包含错配,以及
其中所述内源RNA是甲基CpG结合蛋白2(MECP2)RNA。
2.根据权利要求1所述的方法,其中所述向导RNA与所述内源RNA中的所述靶标序列至少80%互补。
3.根据权利要求1或2所述的方法,其中所述内源RNA在所述细胞的核内。
4.根据权利要求1或2所述的方法,其中所述ADAR是ADAR1或ADAR2。
5.根据权利要求1或2所述的方法,其中所述待编辑的核苷酸是点突变。
6.根据权利要求5所述的方法,其中所述点突变是在MECP2 RNA中导致疾病的点突变,和/或其中所述点突变是在MECP2 RNA中的鸟苷向腺苷的突变。
7.根据权利要求1-2中任一项所述的方法,其中所述待编辑的核苷酸是无义突变,所述无义突变被编辑以除去终止密码子,或者其中所述向导RNA能够通过处于3'位的A的脱氨基修正C向T的无义突变。
8.根据权利要求1-2中任一项所述的方法,其中所述向导RNA还在所述待编辑的核苷酸的上游或下游包含一个或多个产生双链凸出的错配。
9.根据权利要求1-2中任一项所述的方法,其中所述向导RNA还在所述待编辑的核苷酸的上游或下游包含一个或多个错配。
10.根据权利要求1-2中任一项所述的方法,其中内源ADAR识别所述向导RNA和/或其中内源ADAR对所述内源RNA中的核苷酸碱基进行脱氨基。
11.根据权利要求1-2中任一项所述的方法,其中所述靶标序列的编辑改变由所述靶标序列编码的蛋白的水平和/或功能。
12.根据权利要求1-2中任一项所述的方法,其中所述核酸分子包含在病毒载体内。
13.根据权利要求12所述的方法,其中所述病毒载体是腺相关病毒(AAV)。
14.向导RNA或编码向导RNA的核酸分子在制备用于治疗、抑制和/或预防受试者中的中枢神经***遗传疾病的药物中的用途,其中所述向导RNA包含内源人作用于RNA的腺苷脱氨酶(ADAR)特异性识别的序列和/或结构,其中内源RNA的靶标序列在细胞中被编辑,其中所述向导RNA与甲基CpG结合蛋白2(MECP2)RNA特异性杂交并且在内源MECP2 RNA的突变核苷酸处包含错配。
15.根据权利要求14所述的用途,其中所述向导RNA与所述内源RNA中的所述靶标序列至少80%互补。
16.根据权利要求14或15所述的用途,其中所述向导RNA还在待编辑的核苷酸的上游或下游包含一个或多个产生双链凸出的错配。
17.根据权利要求14或15所述的用途,其中所述中枢神经***遗传疾病是Rett综合征。
18.根据权利要求14或15所述的用途,其中所述内源RNA在核内。
19.根据权利要求14-15中任一项所述的用途,其中所述ADAR是ADAR1或ADAR2。
20.根据权利要求14-15中任一项所述的用途,其中所述突变核苷酸是导致疾病的点突变如无义突变,所述无义突变被编辑以除去终止密码子,或者其中所述向导RNA能够通过处于3'位的A的脱氨基修正C向T的无义突变。
21.根据权利要求14-15中任一项所述的用途,其中内源ADAR识别所述向导RNA和/或其中内源ADAR对内源RNA中的核苷酸碱基进行脱氨基。
22.根据权利要求14-15中任一项所述的用途,其中靶标序列的编辑改变由所述靶标序列编码的蛋白的水平和/或功能。
23.根据权利要求14-15中任一项所述的用途,其中所述核酸分子包含在病毒载体内。
24.根据权利要求23所述的用途,其中所述病毒载体是腺相关病毒(AAV)。
25.一种向导RNA或编码向导RNA的核酸分子,所述向导RNA包括:
a)靶向靶标序列或与靶标序列特异性杂交的序列,其中所述序列包含与MECP2 RNA互补的区域,并且其中所述序列包含针对待改变或待编辑的核苷酸的与所述靶标序列的错配;和
b)由内源脱氨酶识别的序列和/或结构。
26.根据权利要求25所述的向导RNA或编码向导RNA的核酸分子,其中所述向导RNA与所述内源RNA中的所述靶标序列至少80%互补。
27.根据权利要求25或26所述的向导RNA或编码向导RNA的核酸分子,其中所述向导RNA还在所述待编辑的核苷酸的上游或下游包含一个或多个产生双链凸出的错配。
28.根据权利要求25或26所述的向导RNA或编码向导RNA的核酸分子,其中所述错配是A:C错配。
29.根据权利要求25-26中任一项所述的向导RNA或编码向导RNA的核酸分子,其中所述待编辑的核苷酸是点突变。
30.根据权利要求29所述的向导RNA或编码向导RNA的核酸分子,其中所述点突变是在MECP2 RNA中导致疾病的点突变和/或其中所述点突变是在MECP2 RNA中的鸟苷向腺苷的突变。
31.根据权利要求25-26中任一项所述的向导RNA或编码向导RNA的核酸分子,其中所述待编辑的核苷酸是无义突变,所述无义突变被编辑以除去终止密码子,或者其中所述向导RNA能够通过处于3'位的A的脱氨基修正C向T的无义突变。
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PCT/US2018/055029 WO2019071274A1 (en) | 2017-10-06 | 2018-10-09 | COMPOSITIONS AND METHODS FOR EDITING RNA |
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CN (1) | CN111629786B (zh) |
AU (1) | AU2018345919A1 (zh) |
BR (1) | BR112020006786A2 (zh) |
CA (1) | CA3076740A1 (zh) |
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WO2018161032A1 (en) | 2017-03-03 | 2018-09-07 | The Regents Of The University Of California | RNA TARGETING OF MUTATIONS VIA SUPPRESSOR tRNAs AND DEAMINASES |
WO2020043750A1 (en) | 2018-08-28 | 2020-03-05 | Roche Innovation Center Copenhagen A/S | Neoantigen engineering using splice modulating compounds |
AU2020279751A1 (en) * | 2019-05-21 | 2021-12-02 | Beam Therapeutics Inc. | Methods of editing a single nucleotide polymorphism using programmable base editor systems |
JP2023504314A (ja) | 2019-12-02 | 2023-02-02 | シェイプ セラピューティクス インコーポレイテッド | 治療的編集 |
CN114787357A (zh) * | 2019-12-09 | 2022-07-22 | 安斯泰来制药株式会社 | 用于编辑靶标rna的添加了功能性区域的反义型指导rna |
EP4150076A1 (en) * | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of methyl-cpg binding protein 2 (mecp2) |
WO2022078569A1 (en) * | 2020-10-12 | 2022-04-21 | Eberhard Karls Universität Tübingen | Artificial nucleic acids for rna editing |
CN114380918B (zh) * | 2020-10-19 | 2023-03-31 | 上海交通大学 | 一种目标rna单碱基编辑的***和方法 |
US20240150754A1 (en) | 2020-12-25 | 2024-05-09 | Astellas Pharma Inc. | Guide rna for editing polyadenylation signal sequence of target rna |
WO2022256283A2 (en) * | 2021-06-01 | 2022-12-08 | Korro Bio, Inc. | Methods for restoring protein function using adar |
WO2023029532A1 (en) * | 2021-08-30 | 2023-03-09 | Huigene Therapeutics Co., Ltd. | Engineered cas6 protein and uses thereof |
CN113846102B (zh) * | 2021-10-21 | 2024-05-28 | 徐州医科大学 | 一种rna编辑***及其编辑方法与应用 |
CA3236391A1 (en) * | 2021-10-26 | 2023-05-04 | Yiannis SAVVA | Rna-editing compositions and methods of use |
WO2023152371A1 (en) | 2022-02-14 | 2023-08-17 | Proqr Therapeutics Ii B.V. | Guide oligonucleotides for nucleic acid editing in the treatment of hypercholesterolemia |
WO2023173089A1 (en) * | 2022-03-10 | 2023-09-14 | Korro Bio, Inc. | Compositions and methods for nucleic acid editing |
US20230340582A1 (en) * | 2022-04-07 | 2023-10-26 | Trustees Of Boston University | Compositions and methods relating to nucleic acid interaction reporters |
WO2024013361A1 (en) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Oligonucleotides for adar-mediated rna editing and use thereof |
WO2024013360A1 (en) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Chemically modified oligonucleotides for adar-mediated rna editing |
GB202215614D0 (en) | 2022-10-21 | 2022-12-07 | Proqr Therapeutics Ii Bv | Heteroduplex rna editing oligonucleotide complexes |
WO2024099575A1 (en) * | 2022-11-11 | 2024-05-16 | Eberhard Karls Universität Tübingen | Artificial nucleic acids for site-directed editing of a target rna |
WO2024110565A1 (en) | 2022-11-24 | 2024-05-30 | Proqr Therapeutics Ii B.V. | Antisense oligonucleotides for the treatment of hereditary hfe-hemochromatosis |
GB202218090D0 (en) | 2022-12-01 | 2023-01-18 | Proqr Therapeutics Ii Bv | Antisense oligonucleotides for the treatment of aldehyde dehydrogenase 2 deficiency |
WO2024121373A1 (en) | 2022-12-09 | 2024-06-13 | Proqr Therapeutics Ii B.V. | Antisense oligonucleotides for the treatment of cardiovascular disease |
CN117095752B (zh) * | 2023-08-21 | 2024-03-19 | 基诺创物(武汉市)科技有限公司 | 保持密码子偏好性的dna蛋白质编码区域流式数据存储方法 |
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WO2004013160A2 (en) * | 2002-08-05 | 2004-02-12 | University Of Rochester | Protein transducing domain/deaminase chimeric proteins, related compounds, and uses thereof |
US9650627B1 (en) * | 2012-07-19 | 2017-05-16 | University Of Puerto Rico | Site-directed RNA editing |
EP3064585B1 (en) * | 2012-12-12 | 2020-02-05 | The Broad Institute, Inc. | Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation |
US8697359B1 (en) * | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
EP3323890A4 (en) * | 2015-07-14 | 2019-01-30 | Fukuoka University | METHOD FOR INDUCING SITE SPECIFIC RNA MUTATIONS, TARGET EDITION GUIDING RNA-GUIDE USED IN THE METHOD, AND TARGET EDITING GUID-RNA TARGET RNA COMPLEX |
DE102015012522B3 (de) * | 2015-09-26 | 2016-06-02 | Eberhard Karls Universität Tübingen | Verfahren und Substanzen zur gerichteten RNA-Editierung |
AU2017320901B2 (en) * | 2016-09-01 | 2023-11-09 | Proqr Therapeutics Ii B.V. | Chemically modified single-stranded RNA-editing oligonucleotides |
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2018
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2023
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US20200291383A1 (en) | 2020-09-17 |
JP2021502058A (ja) | 2021-01-28 |
CN111629786A (zh) | 2020-09-04 |
IL273817A (en) | 2020-05-31 |
EP3691747A1 (en) | 2020-08-12 |
WO2019071274A1 (en) | 2019-04-11 |
AU2018345919A1 (en) | 2020-05-07 |
EP3691747A4 (en) | 2021-10-06 |
JP2023145597A (ja) | 2023-10-11 |
CA3076740A1 (en) | 2019-04-11 |
BR112020006786A2 (pt) | 2020-10-06 |
EP4389889A2 (en) | 2024-06-26 |
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