CN113121654A - 新型腺相关病毒衣壳蛋白及包含其的新型腺相关病毒载体 - Google Patents
新型腺相关病毒衣壳蛋白及包含其的新型腺相关病毒载体 Download PDFInfo
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- CN113121654A CN113121654A CN202110420886.5A CN202110420886A CN113121654A CN 113121654 A CN113121654 A CN 113121654A CN 202110420886 A CN202110420886 A CN 202110420886A CN 113121654 A CN113121654 A CN 113121654A
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Abstract
本发明涉及新型AAV衣壳蛋白、编码该衣壳蛋白的核酸分子、包含该衣壳蛋白的载体以及包含该载体的药物。本发明的AAV载体具有高实心率,可作为治疗性基因的送递载体用于治疗各种疾病。
Description
技术领域
本公开属于基因治疗技术领域。具体地,本公开涉及新型腺相关病毒(AAV)衣壳蛋白、编码该新型AAV衣壳蛋白的核酸分子。本公开还涉及高实心率的新型AAV载体以及包含该新型AAV载体的药物,该新型AAV载体包含该新型AAV衣壳蛋白。
背景技术
近年来,基因治疗蓬勃发展。作为在治疗性基因送递方面非常有前景的载体,腺相关病毒(AAV,adeno-associated virus)在各种器官组织中具有高转导效率、长期治疗效果和低致病性,这些特性使AAV载体在基因治疗领域具有明显的优势(参考文献1)。
AAV载体由蛋白质衣壳和携带目的基因的转基因表达盒组成。AAV衣壳由60个衣壳蛋白组装而成,具有确定的形状和结构。组成AAV衣壳构建模块的三种蛋白(VP1、VP2和VP3)在细胞内的比例可能会因各种因素的影响而波动较大,而且特定的衣壳蛋白的翻译后修饰可能会有所差异。这些复杂的变化会导致形成空壳AAV载体的概率增加。空壳AAV载体不携带目的基因,仅由特定血清型的AAV蛋白质衣壳组成。已知治疗效率与AAV载体的遗传物质含量密切相关,因此,空壳AAV载体的存在会导致用于医学应用的AAV病毒的所需剂量增加,并且可能会引起针对载体衣壳的免疫反应,导致不必要的副作用。
因此,为了实现更好的治疗效果,提高AAV载体的转导能力和效价,期望对AAV衣壳蛋白进行合适的改造,获得高实心率的新型腺相关病毒载体。
参考文献:
1.Li et al.,Nat Rev Genet(2020)21:255-272
发明内容
经过大量研究,发明人发现,通过用合成寡肽“GIVADNLQQQ”替换AAV(例如AAV5)衣壳蛋白的可变区(例如VRVIII)的1-10个氨基酸(例如aa574-579)并引入T711S的点突变,可以获得新型AAV(例如AAV5)衣壳蛋白。由该新型AAV衣壳蛋白包装的新型AAV载体具有高实心率,因此具有更好的转导能力,可应用于各种疾病的预防、诊断和治疗。
因此,在第一方面,本公开提供一种新型腺相关病毒(AAV)衣壳蛋白,所述新型AAV衣壳蛋白通过用寡肽GIVADNLQQQ替换AAV衣壳蛋白的可变区的1-10个氨基酸并引入T711S的点突变构建而成。
上述腺相关病毒(AAV)可以选自任何AAV血清型。AAV血清型的实例包括天然的AAV(例如,天然的AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11,AAV12、AAV-DJ、AAV-DJ8、AAV-DJ9、AAVrh8、AAVrh8R、AAVrh10、禽AAV、牛AAV、犬AAV、马AAV和绵羊AAV)和其他人工改造的AAV(例如,人工改造的AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11,AAV12、AAV-DJ、AAV-DJ8、AAV-DJ9、AAVrh8、AAVrh8R、AAVrh10、禽AAV、牛AAV、犬AAV、马AAV和绵羊AAV),优选AAV5。
在一个实施方式中,上述可变区选自VRII、VRIII、VRIV、VRV、VRVI、VRVII和VRVIII,优选VRVIII。在一个优选实施方式中,上述新型AAV衣壳蛋白通过用寡肽GIVADNLQQQ替换AAV5衣壳蛋白的可变区VRVIII的aa574-579并引入T711S的点突变构建而成。
在一个优选实施方式中,上述新型AAV衣壳蛋白的氨基酸序列与SEQ ID NO:1所示的氨基酸序列具有至少95%的同一性,优选上述新型AAV衣壳蛋白的氨基酸序列与SEQ IDNO:1所示的氨基酸序列具有至少96%、97%、98%、99%或100%的同一性。在一个更优选实施方式中,上述新型AAV衣壳蛋白包含SEQ ID NO:1所示的氨基酸序列。在一个更优选实施方式中,上述新型AAV衣壳蛋白的氨基酸序列如SEQ ID NO:1所示。
在第二方面,本公开提供一种核酸分子,所述核酸分子编码上述新型AAV衣壳蛋白。
在一个优选实施方式中,上述核酸分子的核苷酸序列与SEQ ID NO:2所示的核苷酸序列具有至少95%的同一性,优选上述核酸分子的核苷酸序列与SEQ ID NO:2所示的氨基酸序列具有至少96%、97%、98%、99%或100%的同一性。
在一个优选实施方式中,上述核酸分子包含SEQ ID NO:2所示的核苷酸序列。在一个更优选实施方式中,上述核酸分子的核苷酸序列如SEQ ID NO:2所示。
在第三方面,本公开提供一种新型AAV载体,所述新型AAV载体包含上述新型AAV衣壳蛋白。
在一个优选实施方式中,上述新型AAV载体还包含异源多核苷酸,所述异源多核苷酸包含编码治疗性蛋白质的核苷酸序列。在一个优选实施方式中,上述新型AAV载体还包含病毒基因组,所述病毒基因组可以是天然的AAV基因组或包含异源核酸的重组病毒基因组,所述病毒基因组可编码报告蛋白、天然蛋白、重组蛋白、抗原、抗体和/或用于核苷酸干扰(RNAi)治疗的多聚寡聚核苷酸元件(shRNA、miRNA)等。
在一个优选实施方式中,异源核酸编码一种或多种哺乳动物蛋白,或者是RNAi组分的序列(例如shRNA、siRNA、反义寡核苷酸)。在另一个优选实施方式中,异源核酸编码某些抗体、抗原、合成蛋白或多肽的蛋白质序列。
在第四方面,本公开提供上述新型AAV载体在制备用于治疗疾病的药物中的应用。
在第五方面,本公开提供一种药物,其包含上述新型AAV载体和可使病毒载体成药的试剂。
在一个实施方式中,可使病毒载体成药的试剂包括盐、有机物和表面活性剂。
在一个实施方式中,上述药物通过全身途径或局部途径施用,例如通过静脉内施用、肌内施用、皮下施用、经口施用、局部接触、腹膜内施用和病灶内施用。
在第六方面,本公开提供一种疾病的方法,包括向有需要的受试者施用治疗有效量的上述药物。
附图说明
图1示出了候选AAV衣壳蛋白的筛选方法。
图2为AAVz82的示意图。通过用寡肽GIVADNLQQQ替换AAV5衣壳蛋白的可变区VRVIII的aa574-579并引入T711S的点突变,得到AAVz82,其氨基酸序列如图2所示。
图3显示通过qPCR和银染定量的5×107个细胞(培养基+裂解物)生产的AAV(野生型AAV5、AAV8和AAV9;AAVz82)颗粒的滴度,以及AAV病毒颗粒的实心率。数据显示为平均值±SD,n=3。
图4显示AAVz82衣壳蛋白的氨基酸序列(SEQ ID NO:1)。
图5显示编码AAVz82衣壳蛋白的核酸序列(SEQ ID NO:2)。
具体实施方式
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员的通常理解相同的含义。
在本文中,术语“包含”、“包括”和“含有”应被解释为开放式术语(即意味着“包括但不限于”)。
在本文中,术语“患者”和“受试者”可互换使用并且以其常规意义使用,指患有或容易患有可通过施用本公开的药物进行预防或治疗的病症的生物体,并且包括人和非人动物。
在一个实施方式中,受试者是非人动物(例如,黑猩猩和其他猿和猴物种;农场动物,如牛、绵羊、猪、山羊和马;家养哺乳动物,例如狗和猫;实验动物包括啮齿类动物,如小鼠、大鼠和豚鼠;禽类,包括家禽、野禽和猎禽,如鸡、火鸡和其他鸡类、鸭、鹅等)。在一个实施方式中,受试者是哺乳动物。在一个实施方式中,受试者是人。
在本文中,术语“治疗”包括:(1)抑制病状、疾病或者病症,即,阻止、减少或者延迟疾病的发展或其复发或者其至少一种临床或者亚临床症状的发展;或者(2)缓解疾病,即,引起病状、疾病或者病症或者其临床或者亚临床症状中的至少一种消退。
在本文中,术语“治疗有效量”指产生施用它要达到的治疗效果的剂量。
在本文中,术语“改善”指与疾病有关的症状的改善,并且可以指至少一种衡量或定量该症状的参数的改善。
在本文中,术语“预防”病状、疾病或者病症包括:预防、延迟或者减少受试者中发展的病状、疾病或者病症的至少一种临床或者亚临床症状出现的发生率和/或可能性,该受试者可能患有或易患该病状、疾病或者病症但尚未经历或者表现出该病状、疾病或者病症的临床或亚临床症状。
在本文中,术语“局部施用”或“局部途径”是指具有局部作用的给药。
在本文中,术语“载体”是指包裹多核苷酸的一个或一系列大分子,其促进多核苷酸在体外或体内递送到靶细胞中。载体的分类包括但不限于质粒、病毒载体、脂质体和其他基因递送载体。待递送的多核苷酸有时被称为“转基因(transgene)”,包含但不限于可以增强、抑制、削弱、保护、触发或预防某些生物学功能和生理机能的某些蛋白质或合成多肽的编码序列、疫苗开发中感兴趣的编码序列(例如表达适于在哺乳动物中引发免疫应答的蛋白、多肽或肽的多核苷酸)、RNAi组分的编码序列(例如,shRNA、siRNA、反义寡核苷酸),或可选的标记。
在本文中,术语“免疫应答”是指宿主组织和细胞遭遇免疫原如AAV衣壳蛋白和转基因后参与的过程。它涉及淋巴网状组织、血液、脾脏或其他相关组织中免疫活性细胞(例如T淋巴细胞、B细胞、单核细胞、巨噬细胞)的增殖、迁移和分化,从而导致抗体的产生或细胞介导的反应性的发展。换言之,宿主通过感染或疫苗接种而暴露于免疫原后诱导主动免疫应答。主动免疫是通过从免疫或非免疫宿主中“转移预先形成的物质(例如抗体、转移因子、胸腺移植物、白介素-2)”而获得的,而被动免疫则不是。
在本文中,术语“镶嵌(mosaic)”AAV衣壳核酸编码序列或衣壳蛋白指通过DNA混编、易错PCR和定点突变的方法人工设计和改造的AAV衣壳序列。
在本文中,术语“转导”、“转染”和“转化”是指异源多核苷酸被递送至宿主细胞发生转录和翻译产生多肽产物的过程,包括利用重组病毒将异源多核苷酸引入宿主细胞。
在本文中,术语“基因送递”指的是将异源多核苷酸引入细胞来进行基因传递,包括靶向、结合、摄取、转运、复制子整合和表达。
在本文中,术语“基因表达”或“表达”是指基因转录、翻译和翻译后修饰产生基因的RNA或蛋白产物的过程。
在本文中,术语“感染”是指包含多核苷酸组分的病毒或病毒颗粒将多核苷酸递送至细胞中并产生其RNA和蛋白质产物的过程,也可指病毒在宿主细胞中的复制过程。
在本文中,术语“多肽”是指至少20个通过肽键连接的氨基酸的聚合物。术语“多肽”和“蛋白质”在本文中同义地是指由多于20个氨基酸组成的聚合物。该术语还包括合成氨基酸聚合物。
在本文中,术语“多核苷酸”或“核酸”是指任意长度的核苷酸的聚合形式,包括脱氧核苷酸、核糖核苷酸、其杂合序列和类似物。多核苷酸可包括修饰的核苷酸,比如甲基化或加帽的核苷酸或核苷酸类似物。
在本文中,与多核苷酸相关的术语“重组”意味着该多核苷酸是通过多步克隆步骤得到的不同于天然多核苷酸的合成产物。重组病毒是包含重组多核苷酸的病毒颗粒。
在本文中,核酸序列为单链形式,从左到右为5’-3’的方向。本文中涉及的核酸序列和氨基酸序列参考IUPACIUB生化命名委员会推荐的形式。氨基酸序列采用单字母符号或三字母符号。
在一个实施方式中,本公开提供一种新型AAV5衣壳蛋白,其通过用寡肽GIVADNLQQQ替换AAV5衣壳蛋白的可变区VRVIII的aa574-579并引入T711S的点突变构建而成。作为新型AAV5衣壳蛋白的一个示例,AAVz82衣壳蛋白的氨基酸序列如SEQ ID NO:1所示,编码AAVz82的核酸分子的核苷酸序列如SEQ ID NO:2所示。
本领域技术人员已知,AAV衣壳蛋白含有VP1、VP2和VP3蛋白,VP2和VP3蛋白在VP1蛋白内部的起始密码子处经历转录和翻译过程,即,VP1序列包含VP2和VP3序列。本公开提供了AAVz82衣壳的VP1蛋白的氨基酸序列(SEQ ID NO:1)。
在一个实施方式中,本公开提供另一种新型AAV衣壳蛋白,其通过用与“GIVADNLQQQ”具有至少95%(例如,至少95%、96%、97%、98%、99%或100%)同一性的寡肽替换AAV衣壳的可变区VRVIII的1-10个氨基酸并引入T711S的点突变构建而成。在一个实施方式中,AAV衣壳蛋白可以为任何AAV血清型衣壳蛋白,包括天然AAV衣壳蛋白(例如,天然的1-11型AAV、禽AAV、牛AAV、犬AAV、马AAV和绵羊AAV的衣壳蛋白)和其他人工改造的AAV衣壳蛋白(例如,人工改造的1-11型AAV、禽AAV、牛AAV、犬AAV、马AAV和绵羊AAV的衣壳蛋白)。不同AAV血清型的基因组序列、ITR序列、Rep和Cap蛋白在本领域内是已知的。这些序列可以在文献或在公共数据库查找,例如GenBank数据库。
氨基酸的保守性替换是本领域已知的。在一个实施方式中,本公开的AAV衣壳蛋白在以下同一组中的氨基酸可进行保守性替换:a)甘氨酸和丙氨酸;b)缬氨酸、异亮氨酸、亮氨酸和脯氨酸;c)天冬氨酸和谷氨酸;d)天冬酰胺和谷氨酰胺;e)丝氨酸、苏氨酸赖氨酸、精氨酸和组氨酸;f)苯丙氨酸、色氨酸和酪氨酸;g)蛋氨酸和半胱氨酸。在一些实施方式中,上述不同组的氨基酸之间的非保守性替换也是允许的。
在一个实施方式中,本公开的AAV载体可以装载异源多核苷酸用于将基因递送到靶细胞中。因此,本公开的AAV载体可用于在体外或体内将核酸递送至细胞。
在一个实施方式中,由AAV载体递送的异源多核苷酸编码充当报告子的多肽(即报告蛋白)。报告蛋白用于指示被AAV成功感染的细胞。这些报告蛋白包括但不限于绿色荧光蛋白、β-半乳糖苷酶、碱性磷酸酶、荧光素酶和氯霉素乙酰转移酶。
在一个实施方式中,由AAV载体递送到靶细胞的异源多核苷酸编码用于治疗用途的天然蛋白质,所述天然蛋白质经密码子优化或未经密码子优化。
在一个实施方式中,由AAV载体递送到靶细胞的异源多核苷酸编码合成多肽,包括但不限于,Aflibercept、各种重组白介素(例如白介素-1和白介素-18)、TNF-α拮抗可溶性受体、激活素II型可溶性受体、抗VEGF抗体、抗硬化蛋白抗体、抗RANKL抗体、抗C5抗体、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、抗CGRP抗体、抗HER2抗体、抗EGFR抗体、针对促炎细胞因子的抗体及其受体。
在一个实施方式中,由AAV载体递送的异源多核苷酸可由RNAi组分(例如,siRNA、shRNA、snRNA、microRNA、核酶、反义寡核苷酸和反义多核苷酸)组成,它们可以敲低以异常方式激活的任何内源基因或侵入宿主细胞的异源基因,例如,本领域已知的病毒或细菌的多核苷酸。RNAi组分通常与其靶基因在序列上具有60-100%的同一性,并导致相应的蛋白质产物减少至少30%(例如30%、40%、50%、60%、70%、80%、90%、100%)。
在一个实施方式中,由AAV载体递送的异源多核苷酸包含调节序列,例如转录/翻译控制信号、复制起点、聚腺苷酸化信号、内部核糖体进入位点(IRES)或2A信号(例如,P2A、T2A、F2A)、启动子和增强子(例如CMV启动子或具有脊椎动物β-肌动蛋白、β-球蛋白或β-球蛋白调节元件的其他杂CMV启动子、EF1启动子、泛素启动子、T7启动子、SV40启动子、VP16或VP64启动子)。启动子和增强子的使用取决于它们的组织特异性表达谱。启动子/增强子也可以被化学药品或激素(如强力霉素或他莫昔芬)诱导,具体取决于在所需时间点触发基因表达的需要。此外,启动子/增强子可以是天然序列或合成序列,即原核或真核序列。
在一个实施方式中,用于基因表达的诱导型调控元件可以是组织特异性或组织嗜性启动子/增强子元件。
在一个实施方式中,本公开的AAV载体包含AAV衣壳蛋白和病毒基因组,病毒基因组可以是天然的AAV基因组或者是用于治疗目的的异源多核苷酸的重组载体。在一个实施方式中,异源多核苷酸编码哺乳动物蛋白或RNAi组分(例如,shRNA、siRNA、反义寡核苷酸)。在一个实施方式中,异源多核苷酸编码某些抗体、抗原、合成蛋白质或多肽的氨基酸序列。
在一个实施方式中,病毒基因组的翻译产物会增强、抑制、削弱、保护、触发或预防哺乳动物中参与代谢调节和健康维持的一种或多种内源信号通路。
在一个实施方式中,可以将本公开的AAV病毒颗粒在体外施用给宿主细胞,然后将细胞植入受试者中。由此,包装在病毒中的异源核酸通过细胞被引入受试者体内进行转录和/或翻译,产生从细胞分泌到受试者体内或调节宿主细胞生物活性的蛋白质或RNA产物,从而起到治疗作用。
在一个实施方式中,本公开的AAV载体被制成药物制剂(例如,注射剂、片剂、胶囊剂、散剂)施用于人或其他哺乳动物。该药物制剂还包含其他成分,例如药物辅料、水溶性或有机溶剂(例如水、甘油、乙醇、甲醇、异丙醇、氯仿、苯酚或聚乙二醇)、盐(例如氯化钠、氯化钾、磷酸盐、乙酸盐、碳酸氢盐、Tris-HCl和Tris-乙酸盐)、延缓溶解试剂(例如石蜡)、表面活性剂、抗微生物剂、脂质体、脂质复合物、免疫抑制剂(例如可的松、泼尼松、环孢霉素)、非甾体抗炎药(NSAID,例如阿司匹林、布洛芬、对乙酰氨基酚)微球、硬质基质、半固体载体、纳米球或纳米颗粒。药物制剂中AAV颗粒的滴度可以为105-1014vg/mL。此外,可以通过吸入、全身或局部(例如,静脉内、皮下、肠胃外、肌内、脑室内、口服、腹膜内和鞘内)给药方式以单剂量或多剂量递送AAV。
在一个实施方式中,本公开提供了一种药物,其包含本公开的AAV载体和可使AAV载体成药的试剂(例如,盐、有机物和表面活性剂)。药物可用于体外转导细胞或体内转导哺乳动物(例如啮齿动物、灵长类动物和人类),从而治疗各种疾病。
在一个实施方式中,本公开涉及由细胞生产AAV载体的方法。所述细胞支持高效转染编码AAV Rep/Cap蛋白的质粒、辅助基因和编码天然病毒基因组或异源蛋白的重组载体。可以采用本领域技术人员熟知的三质粒转染法,由HEK293细胞生产本公开的AAV载体。例如,通过将编码GFP等重组蛋白的顺向质粒、AAV Rep/Cap质粒、pHelper质粒共转染至HEK293细胞中,来生产本公开的AAV载体。
可以采用本领域技术人员熟知的标准方法来生产多肽、抗体或抗原结合片段;改变核酸序列;生产转化细胞;构建重组AAV载体;改造衣壳蛋白;包装表达AAV Rep和Cap序列的载体;瞬时转染和稳定转染包装细胞。
下面结合附图和实施例对本公开作进一步详细的说明。以下实施例仅用于说明本公开而不用于限制本公开的范围。实施例中未注明具体条件的实验方法,系按照本领域已知的常规条件,或按照制造厂商所建议的条件进行操作。
实施例
实施例1:改造和筛选AAV
如图1所示:首先,将改造的AAV库和辅助质粒转染至HEK293细胞中。接着,将包含AAV的HEK293细胞裂解物和Ad5(腺病毒5型)一起加入到培养的C2C12成肌细胞中。富集细胞裂解物并重复感染C2C12细胞4-5次。通过对C2C12细胞裂解物进行PCR来富集候选AAV衣壳的病毒基因组带并进行测序。通过筛选,挑选出富集度高的血清型序列,得到血清型突变体AAVz82(图2)。
AAVz82颗粒通过AAVX(Thermo Scientific)亲和层析加碘克沙醇超速离心的方法进行纯化,并浓缩至200-500μl,用于下一步实验以确定载体的实心率。
实施例2:AAVz82的产量和实心率
用亲和层析加碘克沙醇超速离心的方法纯化5×107个细胞中生产的AAV(AAVz82、AAV5、AAV8和AAV9)病毒颗粒。然后,将病毒颗粒稀释10000倍,用DNase I在37℃消化1小时,在100℃放置10分钟灭活DNase I。通过qPCR和银染实验对病毒产量进行定量。接着,用已知滴度的AAV8病毒标准品以10倍梯度稀释的6个滴度梯度(1x1010、1x109、1x108、1x107、1x106、1x105 vg/ml)作为标准品,计算qPCR定量结果与银染定量结果的比值,得到AAV的实心率。如图3所示,qPCR定量的由HEK293细胞产生的实心AAVz82病毒基因组数目与野生型AAV5、8、9相当,这表明合成寡肽的替换对病毒的生产没有负面影响。此外,图3显示,AAVz82病毒颗粒的实心率显著高于野生型AAV5、8、9。由此可见,AAVz82具有较高的实心率。
以上实验结果表明,与野生型AAV5、AAV8和AAV9相比,用寡肽GIVADNLQQQ替换AAV5衣壳蛋白的可变区VRVIII的aa574-579并引入T711S的点突变所得到的AAVz82载体的实心率显著升高。因此,与野生型AAV5、8、9相比,当本公开的AAVz82在临床上用作治疗载体时,潜在不良反应的发生率降低,可以取得更好的治疗效果。
虽然通过参照本公开的某些优选实施方式,已经对本公开进行了图示和描述,但本领域的普通技术人员应该明白,以上内容是结合具体的实施方式对本公开所作的进一步详细说明,不能认定本公开的具体实施只局限于这些说明。本领域技术人员可以在形式上和细节上对其作各种改变,包括做出若干简单推演或替换,而不偏离本公开的精神和范围。
序列表
<110> 信念医药科技(上海)有限公司
上海信致医药科技有限公司
<120> 新型腺相关病毒衣壳蛋白及包含其的新型腺相关病毒载体
<160> 2
<170> SIPOSequenceListing 1.0
<210> 2
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> AAVz82衣壳蛋白的氨基酸序列
<400> 2
Met Ser Phe Val Asp His Pro Pro Asp Trp Leu Glu Glu Val Gly Glu
1 5 10 15
Gly Leu Arg Glu Phe Leu Gly Leu Glu Ala Gly Pro Pro Lys Pro Lys
20 25 30
Pro Asn Gln Gln His Gln Asp Gln Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Asn Tyr Leu Gly Pro Gly Asn Gly Leu Asp Arg Gly Glu Pro Val
50 55 60
Asn Arg Ala Asp Glu Val Ala Arg Glu His Asp Ile Ser Tyr Asn Glu
65 70 75 80
Gln Leu Glu Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Glu Lys Leu Ala Asp Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Lys Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Phe
115 120 125
Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Thr Gly Lys Arg Ile
130 135 140
Asp Asp His Phe Pro Lys Arg Lys Lys Ala Arg Thr Glu Glu Asp Ser
145 150 155 160
Lys Pro Ser Thr Ser Ser Asp Ala Glu Ala Gly Pro Ser Gly Ser Gln
165 170 175
Gln Leu Gln Ile Pro Ala Gln Pro Ala Ser Ser Leu Gly Ala Asp Thr
180 185 190
Met Ser Ala Gly Gly Gly Gly Pro Leu Gly Asp Asn Asn Gln Gly Ala
195 200 205
Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr Trp
210 215 220
Met Gly Asp Arg Val Val Thr Lys Ser Thr Arg Thr Trp Val Leu Pro
225 230 235 240
Ser Tyr Asn Asn His Gln Tyr Arg Glu Ile Lys Ser Gly Ser Val Asp
245 250 255
Gly Ser Asn Ala Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Ser His Trp Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Tyr Trp Gly Phe Arg Pro Arg Ser Leu Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Val Gln Asp Ser Thr
305 310 315 320
Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp
325 330 335
Asp Asp Tyr Gln Leu Pro Tyr Val Val Gly Asn Gly Thr Glu Gly Cys
340 345 350
Leu Pro Ala Phe Pro Pro Gln Val Phe Thr Leu Pro Gln Tyr Gly Tyr
355 360 365
Ala Thr Leu Asn Arg Asp Asn Thr Glu Asn Pro Thr Glu Arg Ser Ser
370 375 380
Phe Phe Cys Leu Glu Tyr Phe Pro Ser Lys Met Leu Arg Thr Gly Asn
385 390 395 400
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
405 410 415
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
420 425 430
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
435 440 445
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
450 455 460
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
465 470 475 480
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
485 490 495
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
500 505 510
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
515 520 525
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
530 535 540
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
545 550 555 560
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gly Ile Val
565 570 575
Ala Asp Asn Leu Gln Gln Gln Pro Ala Thr Gly Thr Tyr Asn Leu Gln
580 585 590
Glu Ile Val Pro Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu Gln
595 600 605
Gly Pro Ile Trp Ala Lys Ile Pro Glu Thr Gly Ala His Phe His Pro
610 615 620
Ser Pro Ala Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met Met
625 630 635 640
Leu Ile Lys Asn Thr Pro Val Pro Gly Asn Ile Thr Ser Phe Ser Asp
645 650 655
Val Pro Val Ser Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Thr
660 665 670
Val Glu Met Glu Trp Glu Leu Lys Lys Glu Asn Ser Lys Arg Trp Asn
675 680 685
Pro Glu Ile Gln Tyr Thr Asn Asn Tyr Asn Asp Pro Gln Phe Val Asp
690 695 700
Phe Ala Pro Asp Ser Thr Gly Glu Tyr Arg Ser Thr Arg Pro Ile Gly
705 710 715 720
Thr Arg Tyr Leu Thr Arg Pro Leu
725
<210> 2
<211> 2187
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码AAVz82衣壳蛋白的核酸序列
<400> 2
atgtcttttg ttgatcaccc tccagattgg ttggaagaag ttggtgaagg tcttcgcgag 60
tttttgggcc ttgaagcggg cccaccgaaa ccaaaaccca atcagcagca tcaagatcaa 120
gcccgtggtc ttgtgctgcc tggttataac tatctcggac ccggaaacgg tctcgatcga 180
ggagagcctg tcaacagggc agacgaggtc gcgcgagagc acgacatctc gtacaacgag 240
cagcttgagg cgggagacaa cccctacctc aagtacaacc acgcggacgc cgagtttcag 300
gagaagctcg ccgacgacac atccttcggg ggaaacctcg gaaaggcagt ctttcaggcc 360
aagaaaaggg ttctcgaacc ttttggcctg gttgaagagg gtgctaagac ggcccctacc 420
ggaaagcgga tagacgacca ctttccaaaa agaaagaagg ctcggaccga agaggactcc 480
aagccttcca cctcgtcaga cgccgaagct ggacccagcg gatcccagca gctgcaaatc 540
ccagcccaac cagcctcaag tttgggagct gatacaatgt ctgcgggagg tggcggccca 600
ttgggcgaca ataaccaagg tgccgatgga gtgggcaatg cctcgggaga ttggcattgc 660
gattccacgt ggatggggga cagagtcgtc accaagtcca cccgaacctg ggtgctgccc 720
agctacaaca accaccagta ccgagagatc aaaagcggct ccgtcgacgg aagcaacgcc 780
aacgcctact ttggatacag caccccctgg gggtactttg actttaaccg cttccacagc 840
cactggagcc cccgagactg gcaaagactc atcaacaact actggggctt cagaccccgg 900
tccctcagag tcaaaatctt caacattcaa gtcaaagagg tcacggtgca ggactccacc 960
accaccatcg ccaacaacct cacctccacc gtccaagtgt ttacggacga cgactaccag 1020
ctgccctacg tcgtcggcaa cgggaccgag ggatgcctgc cggccttccc tccgcaggtc 1080
tttacgctgc cgcagtacgg ttacgcgacg ctgaaccgcg acaacacaga aaatcccacc 1140
gagaggagca gcttcttctg cctagagtac tttcccagca agatgctgag aacgggcaac 1200
aactttgagt ttacctacaa ctttgaggag gtgcccttcc actccagctt cgctcccagt 1260
cagaacctct tcaagctggc caacccgctg gtggaccagt acttgtaccg cttcgtgagc 1320
acaaataaca ctggcggagt ccagttcaac aagaacctgg ccgggagata cgccaacacc 1380
tacaaaaact ggttcccggg gcccatgggc cgaacccagg gctggaacct gggctccggg 1440
gtcaaccgcg ccagtgtcag cgccttcgcc acgaccaata ggatggagct cgagggcgcg 1500
agttaccagg tgcccccgca gccgaacggc atgaccaaca acctccaggg cagcaacacc 1560
tatgccctgg agaacactat gatcttcaac agccagccgg cgaacccggg caccaccgcc 1620
acgtacctcg agggcaacat gctcatcacc agcgagagcg agacgcagcc ggtgaaccgc 1680
gtggcgtaca acgtcggcgg gcagatggcc accaacaacg gtatcgtggc agataacttg 1740
cagcagcaac ccgcgaccgg cacgtacaac ctccaggaaa tcgtgcccgg cagcgtgtgg 1800
atggagaggg acgtgtacct ccaaggaccc atctgggcca agatcccaga gacgggggcg 1860
cactttcacc cctctccggc catgggcgga ttcggactca aacacccacc gcccatgatg 1920
ctcatcaaga acacgcctgt gcccggaaat atcaccagct tctcggacgt gcccgtcagc 1980
agcttcatca cccagtacag caccgggcag gtcaccgtgg agatggagtg ggagctcaag 2040
aaggaaaact ccaagaggtg gaacccagag atccagtaca caaacaacta caacgacccc 2100
cagtttgtgg actttgcccc ggacagcacc ggggaataca gaagcaccag acctatcgga 2160
acccgatacc ttacccgacc cctttaa 2187
Claims (16)
1.新型AAV衣壳蛋白,其中,所述新型AAV衣壳蛋白通过用寡肽GIVADNLQQQ替换AAV衣壳蛋白的可变区的1-10个氨基酸并引入T711S的点突变构建而成。
2.根据权利要求1所述的新型AAV衣壳蛋白,其中,所述AAV衣壳蛋白包括天然AAV衣壳蛋白和其他人工改造的AAV衣壳蛋白。
3.根据权利要求2所述的新型AAV衣壳蛋白,其中,所述天然AAV选自天然的AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11,AAV12、AAV-DJ、AAV-DJ8、AAV-DJ9、AAVrh8、AAVrh8R和AAVrh10,优选为天然的AAV5;所述其他人工改造的AAV选自人工改造的AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11,AAV12、AAV-DJ、AAV-DJ8、AAV-DJ9、AAVrh8、AAVrh8R和AAVrh10,优选为人工改造的AAV5。
4.根据权利要求1所述的新型AAV衣壳蛋白,其中,所述可变区选自VRII、VRIII、VRIV、VRV、VRVI、VRVII和VRVIII,优选VRVIII。
5.根据权利要求1所述的新型AAV衣壳蛋白,其中,所述新型AAV衣壳蛋白通过用寡肽GIVADNLQQQ替换AAV5衣壳蛋白的可变区VRVIII的aa574-579并引入T711S的点突变构建而成。
6.根据权利要求1至5中任一项所述的新型AAV衣壳蛋白,其中,所述新型AAV衣壳蛋白的氨基酸序列与SEQ ID NO:1所示的氨基酸序列具有至少95%的同一性,优选所述新型AAV衣壳蛋白的氨基酸序列与SEQ ID NO:1所示的氨基酸序列具有至少96%、97%、98%、99%或100%的同一性。
7.根据权利要求1至5中任一项所述的新型AAV衣壳蛋白,其中,所述新型AAV衣壳蛋白包含SEQ ID NO:1所示的氨基酸序列,优选所述新型AAV衣壳蛋白的氨基酸序列如SEQ IDNO:1所示。
8.核酸分子,其中,所述核酸分子编码权利要求1至7中任一项所述的新型AAV衣壳蛋白。
9.根据权利要求8所述的核酸分子,其中,所述核酸分子的核苷酸序列与SEQ ID NO:2所示的核苷酸序列具有至少95%的同一性,优选所述核酸分子的核苷酸序列与SEQ ID NO:2所示的氨基酸序列具有至少96%、97%、98%、99%或100%的同一性。
10.根据权利要求8或9所述的核酸分子,其中,所述核酸分子包含SEQ ID NO:2所示的核苷酸序列,优选所述核酸分子的核苷酸序列如SEQ ID NO:2所示。
11.新型AAV载体,其中,所述新型AAV载体包含权利要求1至7中任一项所述的新型AAV衣壳蛋白。
12.根据权利要求11所述的新型AAV载体,其中,所述新型AAV载体还包含异源多核苷酸,所述异源多核苷酸包含编码治疗性蛋白质的核苷酸序列。
13.权利要求11或12所述的新型AAV载体在制备用于治疗疾病的药物中的应用。
14.药物,其包含权利要求11或12所述的新型AAV载体和可使病毒载体成药的试剂。
15.根据权利要求14所述的药物,其中,可使病毒载体成药的试剂包括盐、有机物和表面活性剂。
16.根据权利要求14或15所述的药物,其中,所述药物通过全身途径或局部途径施用,例如静脉内施用、肌内施用、皮下施用、经口施用、局部接触、腹膜内施用和病灶内施用。
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