CN113717248B - 腺相关病毒突变体及其应用 - Google Patents
腺相关病毒突变体及其应用 Download PDFInfo
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- CN113717248B CN113717248B CN202111029031.6A CN202111029031A CN113717248B CN 113717248 B CN113717248 B CN 113717248B CN 202111029031 A CN202111029031 A CN 202111029031A CN 113717248 B CN113717248 B CN 113717248B
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Abstract
本发明涉及生物领域中的病毒体及其应用，具体公开了一种具有心脏靶向性的腺相关病毒突变体及其应用，其中异源肽为：(a)由SEQ ID No:15所示的氨基酸序列组成的蛋白质；或者，(b)在(a)中的氨基酸序列经过取代、缺失或添加一个或几个氨基酸且具有异源肽活性的由(a)衍生出的蛋白质。并且利用本发明AAV衣壳蛋白突变体构建得到的重组腺相关病毒病毒体特异性高，安全性好，免疫原性低，应用范围广泛，并且对心脏的感染性好，靶向性佳，在小鼠体内表达外源基因时间长。
Description
本申请是CN112194706A(申请日为2020年09月30日、申请号为202011070091.8、发明创造名称为腺相关病毒突变体及其应用)的分案申请。
技术领域
本发明涉及生物领域中的病毒体及其应用，尤其是涉及一种具有心脏靶向性的腺相关病毒突变体及其应用。
背景技术
腺相关病毒(adeno-associated virus，AAV)，也称腺伴随病毒，属于微小病毒科依赖病毒属，是目前发现的一类结构最简单的单链DNA缺陷型病毒，需要辅助病毒(通常为腺病毒)参与复制。AAV基因组为4.7kb左右的单链DNA片段，包含于直径20nm的正二十面体非包膜病毒衣壳中，可分成三个功能区域：两个开放阅读框(Rep基因、Cap基因)和末端反向重复序列(ITR)。Rep基因的开放阅读框编码4个多功能非结构蛋白家族(Rep)蛋白，即Rep40、Rep52、Rep68与Rep78，主要功能涉及病毒/载体基因组的复制、转录的调控、整合以及AAV基因组的组装。Cap基因的开放阅读框编码三个衣壳蛋白VP1、VP2和VP3，分子量为别为87、73、61kDa，是装配成完整病毒所需的衣壳蛋白，它们在病毒整合、复制和装配中起重要作用。衣壳蛋白序列之间的差异导致不同血清型的AAV与不同的细胞表面受体结合，这使得不同AAV血清型具有不同的组织嗜性。末端反向重复序列(ITR)在AAV基因组的5’和3’末端形成两个T字形结构，作为复制起点并在病毒基因组整合入宿主基因组，在随后的从整合状态中拯救病毒DNA的过程中均发挥了非常关键的作用。
重组腺相关病毒载体(rAAV)源于非致病的野生型腺相关病毒，由于其具有宿主范围广、非致病性、低免疫原性、长期稳定表达外源基因、良好的扩散性能和物理性质稳定等优点，已被广泛地应用于基础研究和临床试验中，被视为最有前途的基因转移载体之一，在世界范围内的基因治疗和疫苗研究中得到广泛应用。经过10余年的研究，重组腺相关病毒的生物学特性己被深入了解，尤其是其在各种细胞、组织和体内实验中的应用效果方面已经积累了许多资料。在医学研究中，rAAV被用于多种疾病的基因治疗的研究(包括体内、体外实验)；同时作为一种有特点的基因转移载体，还广泛用于基因功能研究、构建疾病模型、制备基因敲除鼠等方面。
在20世纪80年代开始开发AAV2作用于基因治疗的载体以来，已经开发了涉及允许靶向患者的特定组织和细胞亚型的过程的新的平台，这些方法的核心技术是基于现有的AAV变体(血清型)和试错评估和随机引入的AAV衣壳突变体的体内选择。
有中国专利文献CN106062200B公开了一种重组腺相关病毒载体，包括变体AAV2衣壳蛋白，所述变体AAV2衣壳蛋白相对于野生型AAV2衣壳蛋白包含至少4个氨基酸取代，将其重组腺相关病毒载体在制备用于将基因产物递送至受试者的神经元、视网膜或肝脏组织的药物中的用途；目前重组腺相关病毒对心脏方面的相关研究尚少，仍然需要改善重组腺相关病毒在体内转基因表达和组织特异性方面的特性。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种具有心脏靶向性的异源肽、腺相关病毒衣壳蛋白突变体及其应用，与rAAV9相比，利用本发明腺相关病毒突变体构建的重组腺相关病毒病毒体对心脏具有更好的感染性，安全性好，免疫原性低宿主范围广可高效感染分裂和非分裂细胞等；并且从动物体内筛选得到的AAV衣壳蛋白突变体性质稳定。
为实现上述目的，本发明采取的技术方案为：
一种异源肽，所述异源肽为：
(a)由SEQ ID No:15所示的氨基酸序列组成的蛋白质；或者，
(b)在(a)中的氨基酸序列经过取代、缺失或添加一个或几个氨基酸且具有异源肽活性的由(a)衍生出的蛋白质。
一种AAV衣壳蛋白突变体，所述AAV衣壳蛋白突变体包含上述的异源肽。
在本发明的技术方案中，通过分子生物学技术在AAV9衣壳蛋白(其核酸序列来源于专利EP1463805B1的SEQ ID NO:2)中插入SEQ ID No:15中任一种的异源肽获得AAV衣壳蛋白突变体，然后利用AAV衣壳蛋白突变体构建重组腺相关病毒病毒体，通过小鼠尾静脉注射，将携带增强型绿色荧光蛋白的构建好的重组腺相关病毒病毒体转染于小鼠，经过荧光显微镜观察得到重组腺相关病毒病毒体可以提高对心脏的感染性，在心脏处表达性较高。
作为本发明所述AAV衣壳蛋白突变体优选实施方式，所述AAV衣壳蛋白突变体是将异源肽插入或置换AAV衣壳蛋白的5个氨基酸至20个氨基酸形成的连续段得到的。
作为本发明所述AAV衣壳蛋白突变体优选实施方式，所述异源肽的插入位点位于AAV衣壳蛋白氨基酸位置411-650之间。
经不同的实验研究发现，AAV衣壳蛋白的氨基酸位置411-650之间是AAV组织靶向的主要区域，将特定肽段插入该区域，可改变其组织的靶向性。
作为本发明所述AAV衣壳蛋白突变体优选实施方式，所述异源肽的插入位点位于AAV衣壳蛋白氨基酸588和589之间。
通过在AAV衣壳蛋白-VP1蛋白的氨基酸588和589之间插入异源肽，使得构建得到的重组腺相关病毒病毒体对心脏的感染性佳，通过免疫荧光检测可得当序列为SEQ ID No:15的异源肽插入AAV9衣壳蛋白中氨基酸588和589之间或其他血清型病毒体衣壳蛋白的相应位置处，对心脏细胞的感染性较佳，靶向性好。
本发明还提供了一种重组腺相关病毒病毒体，包括：
a.上述AAV衣壳蛋白突变体；和
b.编码异源基因产物的异源多核苷酸。
作为本发明所述重组腺相关病毒病毒体的优选实施方式，所述基因产物是多肽，多肽可以为肿瘤靶向多肽、生物活性多肽、心脏肽和保护心脏的多肽。
作为本发明所述重组腺相关病毒病毒体的优选实施方式，所述基因产物是干扰RNA、适配体、内切核酸酶、指导RNA中的一种。
另外，本发明的另一目的在于提供一种如上所述的的重组腺相关病毒病毒体在制备用于将基因产物递送至受试者组织的药物中的用途。
作为本发明所述用途的优选实施方式，所述组织选自心脏组织。
另外，本发明的另一目的在于提供上述重组腺相关病毒病毒体在制备预防或治疗心脏疾病药物中的用途。
作为本发明所述用途的优选实施方式，所述心脏疾病选自心肌梗死、心肌缺血损伤、冠心病、心肌肥厚和心肌纤维化。
与现有技术相比，本发明重组腺相关病毒病毒体特异性高，安全性好，免疫原性低，应用范围广泛，可应用于心脏等组织，并且对心脏的感染性好，靶向性佳，在小鼠体内表达外源基因时间长。
附图说明
图1为本发明构建的随机7肽载体库的结构示意图；
图2为本发明构建的突变Rep-CAP质粒的结构示意图；
图3为rAAV9病毒作为对照组对小鼠心脏的影响的镜检示意图；
图4A为AAV衣壳蛋白突变体1对小鼠心脏的影响的镜检示意图；
图4B为AAV衣壳蛋白突变体2对小鼠心脏的影响的镜检示意图；
图4C为AAV衣壳蛋白突变体3对小鼠心脏的影响的镜检示意图；
图4D为AAV衣壳蛋白突变体4对小鼠心脏的影响的镜检示意图；
图5为rAAV9病毒与AAV衣壳蛋白突变体1-4的免疫荧光对比统计图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。
在以下实施例中，AAV9核酸序列来源于专利EP1463805B1的SEQ ID NO:2，AAV5核酸序列来源于http://www.ncbi.nlm.nih.gov/nuccore/NC006152，AAV2核酸序列来源于http://www.ncbi.nlm.nih.gov/nuccore/NC001401。
实施例1、构建AAV9衣壳蛋白突变体库骨架载体和突变Rep-CAP载体
1.构建AAV9衣壳蛋白突变体库骨架质粒：
骨架载体包含AAV5 p41启动子片段，AAV2 rep剪接信号序列，以及突变移码的AAV9的CAP序列(其中AAV9的CAP序列将原氨基酸位点449的K突变为R，核酸序列由tcaaag突变为tctaga，引入XbaI酶切位点；将原氨基酸位点594的氨基酸G的核酸序列由ggc突变为ggt，引入BshTI酶切位点；同时在原氨基酸位点588与位点589位之间插入一段包含终止密码的34bp序列，以造成序列的移码，避免骨架载体酶切不干净造成的污染)，并在CAP序列之后加入SV40 polyA序列。将上述序列通过基因合成法合成，并插入到rAAV载体的ITR序列之间，形成AAV9衣壳蛋白突变体库骨架质粒。
2.构建突变Rep-CAP质粒：
在AAV9中CAP序列的VP1、VP2、VP3蛋白的起始密码子后的50bp内插入终止密码子的方式，使Rep-CAP载体只能表达Rep蛋白，而不能表达CAP序列的VP1、VP2、VP3蛋白，从而避免原AAV9中CAP序列的污染，同样将设计好的上述序列，通过基因合成法合成，并插入替换Rep-CAP载体的CAP序列(参见图2)。
3.构建随机7肽载体库：
采用oligo6设计2条引物，包括引物1(5'->3')：
ACTCATCGACCAATACTTGTACTATCTCTCTAGAAC
引物2(5'->3')：
GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCCTGTGCMNNMNNMNNMNNMNNMNNMNNTTGGGCACTCTGGTGGTTTGTG
其中一条含有随机7肽的21bp核酸序列，并以AAV9衣壳蛋白突变体库骨架载体为模板，进行PCR扩增获得包含随机序列的片段(参见图1)。将片段进行凝胶电泳和胶回收目的大小片段，得到纯化的随机7肽库的核酸片段。将该片段通过Gibson同源重组连接的方式连接入AAV9衣壳蛋白突变体库骨架载体(经过XbaI与BshTI双酶切和胶回收纯化)。连接后的载体通过PCR产物纯化试剂盒进行纯化后，用Plasmid-Safe DNase酶消化，以去除没有连接上的片段。最后再通过PCR产物纯化试剂盒进行纯化后，即为构建好的AAV9随机7肽载体库。
4.构建随机7肽病毒突变体库：
通过3质粒转染的方式，将突变的Rep-Cap质粒，AAV9随机7肽载体库质粒，pHelper质粒以合适的量共转于HEK-293T细胞中，采用碘克沙醇梯度超高速离心纯化AAV病毒，测量病毒滴度在1012GC/mL-1013GC/mL为合适滴度，放置-80℃备用。
5.筛选AAV衣壳蛋白突变体：
将上述构建的随机7肽病毒突变体库按1011GC的剂量，通过尾静脉注射的方式注入C57小鼠体内，在SPF级环境中饲养1周后，解剖小鼠进行心脏取材，取材后的组织置于-80℃中保存。
通过组织DNA提取试剂盒提取随机7肽病毒突变体库中的AAV基因组，并设计相应引物进行PCR扩增，扩增后的PCR产物进行凝胶电泳确认条带大小，并将目的条带片段切下来，使用胶回收试剂盒进行产物的回收。将回收后的PCR产物片段与酶切骨架(XbaI与BshTI双酶切并胶回收骨架片段)进行重组连接，连接后的产物转化stbl3感受态细胞，并涂Amp抗性平板，培养过夜，次日挑单克隆菌落进行测序。同时将扩增后的PCR片段产物用于下一轮随机库的构建，并重复动物体内筛选的过程。经过2-4轮筛选过程，并通过比对测序结果，直至发现高度重复的富集序列。将高度重复的序列作为候选AAV衣壳蛋白突变体，AAV衣壳蛋白突变体具有SEQ ID No:1～SEQ ID No:12核酸序列中任意一种的异源肽，异源肽的氨基酸序列如SEQ ID No:13～SEQ ID No:24所示，将候选AAV衣壳蛋白突变体分别标记为AAV衣壳蛋白突变体1～4(依次具有SEQ ID No:1～SEQ ID No:4核酸序列的异源肽)，其核酸序列如SEQ ID No:25、SEQ ID No:27、SEQ ID No:29、SEQ ID No:31所示；其氨基酸序列如SEQID No:26、SEQ ID No:28、SEQ ID No:30、SEQ ID No:32所示，然后进行进一步的动物实验验证。
实施例2、构建AAV衣壳蛋白突变体
1.构建突变型血清型载体：
1)酶切骨架：将AAV9的Rep-CAP质粒用BsiWI和AfeI双酶切，凝胶电泳并切下目的片段大小的条带进行凝胶回收；
2)目的片段：将筛选获得的目的质粒AAV衣壳蛋白突变体用BsiWI和AfeI双酶切，凝胶电泳并切下目的片段大小的条带进行凝胶回收；
3)连接：取1个干净的200uL PCR管做好标记并放在冰盒上，将上述酶切骨架和目的片段按摩尔比1:3配制反应液，PCR仪中16℃反应30min进行连接；
4)转化：取50μL感受态细胞在冰上解冻；10μL的连接产物与stbl3感受态细胞混合，冰上放置20-30分钟；42℃热激45秒；快速置于冰上冰浴2分钟，加入400μL SOC培养基(不含抗生素)，37℃，200rpm培养1h；均匀涂于Amp+抗性平板，37℃培养14-16个小时。
5)摇菌：挑选单克隆菌，在4ml液体LB培养基(Amp+抗性)中扩大培养，37℃培养14-16小时。
2.质粒提取：
将上述获得的菌液经过12000rpm离心1分钟，倒掉上清培养基；加入250μL的buffer P1/RNaseA混合液，高速涡旋重悬细菌；加入250μL的buffer P2，上下颠倒8-10次；加入350μL的buffer P3，立即颠倒混匀8-10次让溶液彻底中和；13000rpm离心10分钟，取上清过柱；12000离心1分钟，倒掉废液，加入500μL的PW1，12000离心1分钟，倒掉废液；加入600μL的PW2，12000离心1分钟，倒掉上清；加入600μL的PW2，12000离心1分钟，倒掉上清；12000rpm空转2分钟；加入55℃预热洗脱液30-50μL，静置2分钟，12000rpm离心1分钟。获得质粒经过浓度检测，经过酶切鉴定的阳性质粒取10μL送测序，阳性质粒保存在-20℃。测序结果表明，获得质粒能够编码变异型衣壳蛋白VP1。
3.包装和纯化突变型血清型病毒体
将得到的含突变型血清型的Rep-Cap质粒，表达一个绿色荧光蛋白eGFP的质粒pAAV-CAG-eGFP，pHelper质粒以合适的量共转于HEK-293T细胞中，采用碘克沙醇梯度超高速离心纯化AAV病毒，测量病毒滴度在1013GC/mL为合适滴度，放置-80℃备用。
实施例3、AAV衣壳蛋白突变体对小鼠心脏的影响
实验步骤为：
1)尾静脉注射小鼠
选取6-8周，18-20g雄性SPF级C57小鼠，用rAAV9病毒作为对照组，以本文所述AAV衣壳蛋白突变体作为实验组，每组至少5只小鼠，每只小鼠尾静脉注射1012GC病毒量，1周后进行小鼠心脏取材。
2)小鼠心脏组织切片及免疫荧光对比
A.冰冻切片的制备
1.组织固定：新鲜组织固定液固定24h以上，将组织从固定液取出用手术刀将目的部位组织修平整。
2.脱水：将修切好的组织放于15％的蔗糖溶液内4℃冰箱脱水沉底后转入30％的蔗糖溶液内4℃冰箱脱水沉底。
3.OCT包埋：将脱好水的组织取出用滤纸将表面水稍吸干后切面朝上放于包埋台上，组织周围滴上OCT包埋剂，将包埋台放在冰冻切片机的速冻台上速冻包埋，OCT变白变硬后即可进行切片。新鲜组织直接冰冻切片则不需要固定脱水，直接用手术刀将目的部位组织修平整OCT包埋剂包埋切片。
4.切片：将包埋台固定于切片机上，先粗切将组织面修切平整后即可开始切片，切片厚度8-10μm，将干净的载玻片平放于切出的组织片上方即可将组织贴于载玻片上。片子写好标签后-20℃保存备用。
B.免疫荧光及拍片
1.冰冻切片固定：冰冻切片从冰箱拿出来复温，晾干水分,多聚甲醛固定10min，待多聚甲醛完全干后于PBS(PH7.4)中在脱色摇床上晃动洗涤3次，每次5min。
2.抗原修复：组织切片置于盛满EDTA抗原修复缓冲液(PH9.0)的修复盒中于微波炉内进行抗原修复。中火8min,停火8min,中低火7min，此过程中应防止缓冲液过度蒸发，切勿干片。自然冷却后将玻片置于PBS(PH7.4)中在脱色摇床上晃动洗涤3次，每次5min。(修复缓冲液可以根据不同组织确定，均可采用市面上可购买得到的修复缓冲液进行操作)
3.画圈血清封闭：切片稍甩干后用组化笔在组织周围画圈(防止抗体流走)，甩干PBS，滴加BSA，封闭30min。
4.加一抗：在切片上滴加PBS按一定比例配好的一抗，切片平放于湿盒内4℃孵育过夜。(湿盒内加少量水防止抗体蒸发)
5.加二抗：玻片置于PBS(PH7.4)中在脱色摇床上晃动洗涤3次，每次5min。切片稍甩干后在圈内滴加与一抗相应种属的二抗覆盖组织，避光室温孵育50min。
6.DAPI复染细胞核：玻片置于PBS(PH7.4)中在脱色摇床上晃动洗涤3次，每次5min。切片稍甩干后在圈内滴加DAPI染液，避光室温孵育10min。
7.封片：玻片置于PBS(PH7.4)中在脱色摇床上晃动洗涤3次，每次5min。切片稍甩干后用抗荧光淬灭封片剂封片。
8.镜检拍照：切片于荧光显微镜下观察并采集图像(使用一致的曝光时间和条件进行拍片)。(DAPI紫外激发波长330-380nm，发射波长420nm，发蓝光；CY3激发波长510-560，发射波长590nm，发红光)。
9.平均荧光强度统计：使用ImageJ软件处理免疫荧光图片得到荧光强度值并统计分析。
经上述AAV衣壳蛋白突变体对小鼠实验心脏实验结果显示，rAAV9病毒作为对照组的镜检显示(参考图3)，与对照组相比，本发明的AAV衣壳蛋白突变体1-12对小鼠心脏具有更好的感染性，其中AAV衣壳蛋白突变体1-4对小鼠心脏具有更佳的感染性(参考图4A、4B、4C和4D)，以AAV衣壳蛋白突变体对小鼠心脏感染性最佳。
根据图5，AAV衣壳蛋白突变体1-4的平均荧光强度比值要高于rAAV9病毒的平均荧光强度比值，其中以AAV衣壳蛋白突变体体1的平均荧光强度比值最高。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
SEQUENCE LISTING
<110> 广州派真生物技术有限公司
<120> 腺相关病毒突变体及其应用
<130> 2020.09.25
<160> 32
<170> PatentIn version 3.5
<210> 1
<211> 21
<212> DNA
<213> 人工合成
<400> 1
tcgaatgcga cgcgtctggt t 21
<210> 2
<211> 21
<212> DNA
<213> 人工合成
<400> 2
ccgaggagtt ctacggagag g 21
<210> 3
<211> 21
<212> DNA
<213> 人工合成
<400> 3
tctctgactc gtgcttcgat g 21
<210> 4
<211> 21
<212> DNA
<213> 人工合成
<400> 4
gggaatttga ttcggaataa t 21
<210> 5
<211> 21
<212> DNA
<213> 人工合成
<400> 5
actaatttga ctaagccgta t 21
<210> 6
<211> 21
<212> DNA
<213> 人工合成
<400> 6
acgccgaata atcgtgtgca g 21
<210> 7
<211> 21
<212> DNA
<213> 人工合成
<400> 7
tttgcgccga atggtactcg g 21
<210> 8
<211> 21
<212> DNA
<213> 人工合成
<400> 8
atgccgaaga gtccgatgtc g 21
<210> 9
<211> 21
<212> DNA
<213> 人工合成
<400> 9
atgcttcata agcctaatag t 21
<210> 10
<211> 21
<212> DNA
<213> 人工合成
<400> 10
cgtacgacgt atgggccgaa t 21
<210> 11
<211> 21
<212> DNA
<213> 人工合成
<400> 11
cgggcttctt cgcaggcgtc t 21
<210> 12
<211> 21
<212> DNA
<213> 人工合成
<400> 12
atgaatgata ttcggtctcg t 21
<210> 13
<211> 7
<212> PRT
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Ser Asn Ala Thr Arg Leu Val
1 5
<210> 14
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<212> PRT
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Pro Arg Ser Ser Thr Glu Arg
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Ser Leu Thr Arg Ala Ser Met
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Gly Asn Leu Ile Arg Asn Asn
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Thr Asn Leu Thr Lys Pro Tyr
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Thr Pro Asn Asn Arg Val Gln
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Phe Ala Pro Asn Gly Thr Arg
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Met Pro Lys Ser Pro Met Ser
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Met Leu His Lys Pro Asn Ser
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Arg Thr Thr Tyr Gly Pro Asn
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Arg Ala Ser Ser Gln Ala Ser
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Met Asn Asp Ile Arg Ser Arg
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<212> DNA
<213> AAV衣壳蛋白突变体1的核酸序列
<400> 25
atggctgccg atggttatct tccagattgg ctcgaggaca accttagtga aggaattcgc 60
gagtggtggg ctttgaaacc tggagcccct caacccaagg caaatcaaca acatcaagac 120
aacgctcgag gtcttgtgct tccgggttac aaataccttg gacccggcaa cggactcgac 180
aagggggagc cggtcaacgc agcagacgcg gcggccctcg agcacgacaa ggcctacgac 240
cagcagctca aggccggaga caacccgtac ctcaagtaca accacgccga cgccgagttc 300
caggagcggc tcaaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaaaaaga ggcttcttga acctcttggt ctggttgagg aagcggctaa gacggctcct 420
ggaaagaaga ggcctgtaga gcagtctcct caggaaccgg actcctccgc gggtattggc 480
aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540
tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600
cttacaatgg cttcaggtgg tggcgcacca gtggcagaca ataacgaagg tgccgatgga 660
gtgggtagtt cctcgggaaa ttggcattgc gattcccaat ggctggggga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca atcacctcta caagcaaatc 780
tccaacagca catctggagg atcttcaaat gacaacgcct acttcggcta cagcaccccc 840
tgggggtatt ttgacttcaa cagattccac tgccacttct caccacgtga ctggcagcga 900
ctcatcaaca acaactgggg attccggcct aagcgactca acttcaagct cttcaacatt 960
caggtcaaag aggttacgga caacaatgga gtcaagacca tcgccaataa ccttaccagc 1020
acggtccagg tcttcacgga ctcagactat cagctcccgt acgtgctcgg gtcggctcac 1080
gagggctgcc tcccgccgtt cccagcggac gttttcatga ttcctcagta cgggtatctg 1140
acgcttaatg atggaagcca ggccgtgggt cgttcgtcct tttactgcct ggaatatttc 1200
ccgtcgcaaa tgctaagaac gggtaacaac ttccagttca gctacgagtt tgagaacgta 1260
cctttccata gcagctacgc tcacagccaa agcctggacc gactaatgaa tccactcatc 1320
gaccaatact tgtactatct ctctagaact attaacggtt ctggacagaa tcaacaaacg 1380
ctaaaattca gtgtggccgg acccagcaac atggctgtcc agggaagaaa ctacatacct 1440
ggacccagct accgacaaca acgtgtctca accactgtga ctcaaaacaa caacagcgaa 1500
tttgcttggc ctggagcttc ttcttgggct ctcaatggac gtaatagctt gatgaatcct 1560
ggacctgcta tggccagcca caaagaagga gaggaccgtt tctttccttt gtctggatct 1620
ttaatttttg gcaaacaagg aactggaaga gacaacgtgg atgcggacaa agtcatgata 1680
accaacgaag aagaaattaa aactactaac ccggtagcaa cggagtccta tggacaagtg 1740
gccacaaacc accagagtgc ccaatcgaat gcgacgcgtc tggttgcaca ggcgcagacc 1800
ggttgggttc aaaaccaagg aatacttccg ggtatggttt ggcaggacag agatgtgtac 1860
ctgcaaggac ccatttgggc caaaattcct cacacggacg gcaactttca cccttctccg 1920
ctgatgggag ggtttggaat gaagcacccg cctcctcaga tcctcatcaa aaacacacct 1980
gtacctgcgg atcctccaac ggccttcaac aaggacaagc tgaactcttt catcacccag 2040
tattctactg gccaagtcag cgtggagatc gagtgggagc tgcagaagga aaacagcaag 2100
cgctggaacc cggagatcca gtacacttcc aactattaca agtctaataa tgttgaattt 2160
gctgttaata ctgaaggtgt atatagtgaa ccccgcccca ttggcaccag atacctgact 2220
cgtaatctgt aa 2232
<210> 26
<211> 743
<212> PRT
<213> AAV衣壳蛋白突变体1的氨基酸序列
<400> 26
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ser Asn Ala Thr
580 585 590
Arg Leu Val Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 27
<211> 2232
<212> DNA
<213> AAV衣壳蛋白突变体2的核酸序列
<400> 27
atggctgccg atggttatct tccagattgg ctcgaggaca accttagtga aggaattcgc 60
gagtggtggg ctttgaaacc tggagcccct caacccaagg caaatcaaca acatcaagac 120
aacgctcgag gtcttgtgct tccgggttac aaataccttg gacccggcaa cggactcgac 180
aagggggagc cggtcaacgc agcagacgcg gcggccctcg agcacgacaa ggcctacgac 240
cagcagctca aggccggaga caacccgtac ctcaagtaca accacgccga cgccgagttc 300
caggagcggc tcaaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaaaaaga ggcttcttga acctcttggt ctggttgagg aagcggctaa gacggctcct 420
ggaaagaaga ggcctgtaga gcagtctcct caggaaccgg actcctccgc gggtattggc 480
aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540
tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600
cttacaatgg cttcaggtgg tggcgcacca gtggcagaca ataacgaagg tgccgatgga 660
gtgggtagtt cctcgggaaa ttggcattgc gattcccaat ggctggggga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca atcacctcta caagcaaatc 780
tccaacagca catctggagg atcttcaaat gacaacgcct acttcggcta cagcaccccc 840
tgggggtatt ttgacttcaa cagattccac tgccacttct caccacgtga ctggcagcga 900
ctcatcaaca acaactgggg attccggcct aagcgactca acttcaagct cttcaacatt 960
caggtcaaag aggttacgga caacaatgga gtcaagacca tcgccaataa ccttaccagc 1020
acggtccagg tcttcacgga ctcagactat cagctcccgt acgtgctcgg gtcggctcac 1080
gagggctgcc tcccgccgtt cccagcggac gttttcatga ttcctcagta cgggtatctg 1140
acgcttaatg atggaagcca ggccgtgggt cgttcgtcct tttactgcct ggaatatttc 1200
ccgtcgcaaa tgctaagaac gggtaacaac ttccagttca gctacgagtt tgagaacgta 1260
cctttccata gcagctacgc tcacagccaa agcctggacc gactaatgaa tccactcatc 1320
gaccaatact tgtactatct ctctagaact attaacggtt ctggacagaa tcaacaaacg 1380
ctaaaattca gtgtggccgg acccagcaac atggctgtcc agggaagaaa ctacatacct 1440
ggacccagct accgacaaca acgtgtctca accactgtga ctcaaaacaa caacagcgaa 1500
tttgcttggc ctggagcttc ttcttgggct ctcaatggac gtaatagctt gatgaatcct 1560
ggacctgcta tggccagcca caaagaagga gaggaccgtt tctttccttt gtctggatct 1620
ttaatttttg gcaaacaagg aactggaaga gacaacgtgg atgcggacaa agtcatgata 1680
accaacgaag aagaaattaa aactactaac ccggtagcaa cggagtccta tggacaagtg 1740
gccacaaacc accagagtgc ccaaccgagg agttctacgg agagggcaca ggcgcagacc 1800
ggttgggttc aaaaccaagg aatacttccg ggtatggttt ggcaggacag agatgtgtac 1860
ctgcaaggac ccatttgggc caaaattcct cacacggacg gcaactttca cccttctccg 1920
ctgatgggag ggtttggaat gaagcacccg cctcctcaga tcctcatcaa aaacacacct 1980
gtacctgcgg atcctccaac ggccttcaac aaggacaagc tgaactcttt catcacccag 2040
tattctactg gccaagtcag cgtggagatc gagtgggagc tgcagaagga aaacagcaag 2100
cgctggaacc cggagatcca gtacacttcc aactattaca agtctaataa tgttgaattt 2160
gctgttaata ctgaaggtgt atatagtgaa ccccgcccca ttggcaccag atacctgact 2220
cgtaatctgt aa 2232
<210> 28
<211> 743
<212> PRT
<213> AAV衣壳蛋白突变体2的氨基酸序列
<400> 28
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Pro Arg Ser Ser
580 585 590
Thr Glu Arg Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 29
<211> 2232
<212> DNA
<213> AAV衣壳蛋白突变体3的核酸序列
<400> 29
atggctgccg atggttatct tccagattgg ctcgaggaca accttagtga aggaattcgc 60
gagtggtggg ctttgaaacc tggagcccct caacccaagg caaatcaaca acatcaagac 120
aacgctcgag gtcttgtgct tccgggttac aaataccttg gacccggcaa cggactcgac 180
aagggggagc cggtcaacgc agcagacgcg gcggccctcg agcacgacaa ggcctacgac 240
cagcagctca aggccggaga caacccgtac ctcaagtaca accacgccga cgccgagttc 300
caggagcggc tcaaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaaaaaga ggcttcttga acctcttggt ctggttgagg aagcggctaa gacggctcct 420
ggaaagaaga ggcctgtaga gcagtctcct caggaaccgg actcctccgc gggtattggc 480
aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540
tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600
cttacaatgg cttcaggtgg tggcgcacca gtggcagaca ataacgaagg tgccgatgga 660
gtgggtagtt cctcgggaaa ttggcattgc gattcccaat ggctggggga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca atcacctcta caagcaaatc 780
tccaacagca catctggagg atcttcaaat gacaacgcct acttcggcta cagcaccccc 840
tgggggtatt ttgacttcaa cagattccac tgccacttct caccacgtga ctggcagcga 900
ctcatcaaca acaactgggg attccggcct aagcgactca acttcaagct cttcaacatt 960
caggtcaaag aggttacgga caacaatgga gtcaagacca tcgccaataa ccttaccagc 1020
acggtccagg tcttcacgga ctcagactat cagctcccgt acgtgctcgg gtcggctcac 1080
gagggctgcc tcccgccgtt cccagcggac gttttcatga ttcctcagta cgggtatctg 1140
acgcttaatg atggaagcca ggccgtgggt cgttcgtcct tttactgcct ggaatatttc 1200
ccgtcgcaaa tgctaagaac gggtaacaac ttccagttca gctacgagtt tgagaacgta 1260
cctttccata gcagctacgc tcacagccaa agcctggacc gactaatgaa tccactcatc 1320
gaccaatact tgtactatct ctctagaact attaacggtt ctggacagaa tcaacaaacg 1380
ctaaaattca gtgtggccgg acccagcaac atggctgtcc agggaagaaa ctacatacct 1440
ggacccagct accgacaaca acgtgtctca accactgtga ctcaaaacaa caacagcgaa 1500
tttgcttggc ctggagcttc ttcttgggct ctcaatggac gtaatagctt gatgaatcct 1560
ggacctgcta tggccagcca caaagaagga gaggaccgtt tctttccttt gtctggatct 1620
ttaatttttg gcaaacaagg aactggaaga gacaacgtgg atgcggacaa agtcatgata 1680
accaacgaag aagaaattaa aactactaac ccggtagcaa cggagtccta tggacaagtg 1740
gccacaaacc accagagtgc ccaatctctg actcgtgctt cgatggcaca ggcgcagacc 1800
ggttgggttc aaaaccaagg aatacttccg ggtatggttt ggcaggacag agatgtgtac 1860
ctgcaaggac ccatttgggc caaaattcct cacacggacg gcaactttca cccttctccg 1920
ctgatgggag ggtttggaat gaagcacccg cctcctcaga tcctcatcaa aaacacacct 1980
gtacctgcgg atcctccaac ggccttcaac aaggacaagc tgaactcttt catcacccag 2040
tattctactg gccaagtcag cgtggagatc gagtgggagc tgcagaagga aaacagcaag 2100
cgctggaacc cggagatcca gtacacttcc aactattaca agtctaataa tgttgaattt 2160
gctgttaata ctgaaggtgt atatagtgaa ccccgcccca ttggcaccag atacctgact 2220
cgtaatctgt aa 2232
<210> 30
<211> 743
<212> PRT
<213> AAV衣壳蛋白突变体3的氨基酸序列
<400> 30
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ser Leu Thr Arg
580 585 590
Ala Ser Met Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 31
<211> 2232
<212> DNA
<213> AAV衣壳蛋白突变体4的核酸序列
<400> 31
atggctgccg atggttatct tccagattgg ctcgaggaca accttagtga aggaattcgc 60
gagtggtggg ctttgaaacc tggagcccct caacccaagg caaatcaaca acatcaagac 120
aacgctcgag gtcttgtgct tccgggttac aaataccttg gacccggcaa cggactcgac 180
aagggggagc cggtcaacgc agcagacgcg gcggccctcg agcacgacaa ggcctacgac 240
cagcagctca aggccggaga caacccgtac ctcaagtaca accacgccga cgccgagttc 300
caggagcggc tcaaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaaaaaga ggcttcttga acctcttggt ctggttgagg aagcggctaa gacggctcct 420
ggaaagaaga ggcctgtaga gcagtctcct caggaaccgg actcctccgc gggtattggc 480
aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540
tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600
cttacaatgg cttcaggtgg tggcgcacca gtggcagaca ataacgaagg tgccgatgga 660
gtgggtagtt cctcgggaaa ttggcattgc gattcccaat ggctggggga cagagtcatc 720
accaccagca cccgaacctg ggccctgccc acctacaaca atcacctcta caagcaaatc 780
tccaacagca catctggagg atcttcaaat gacaacgcct acttcggcta cagcaccccc 840
tgggggtatt ttgacttcaa cagattccac tgccacttct caccacgtga ctggcagcga 900
ctcatcaaca acaactgggg attccggcct aagcgactca acttcaagct cttcaacatt 960
caggtcaaag aggttacgga caacaatgga gtcaagacca tcgccaataa ccttaccagc 1020
acggtccagg tcttcacgga ctcagactat cagctcccgt acgtgctcgg gtcggctcac 1080
gagggctgcc tcccgccgtt cccagcggac gttttcatga ttcctcagta cgggtatctg 1140
acgcttaatg atggaagcca ggccgtgggt cgttcgtcct tttactgcct ggaatatttc 1200
ccgtcgcaaa tgctaagaac gggtaacaac ttccagttca gctacgagtt tgagaacgta 1260
cctttccata gcagctacgc tcacagccaa agcctggacc gactaatgaa tccactcatc 1320
gaccaatact tgtactatct ctctagaact attaacggtt ctggacagaa tcaacaaacg 1380
ctaaaattca gtgtggccgg acccagcaac atggctgtcc agggaagaaa ctacatacct 1440
ggacccagct accgacaaca acgtgtctca accactgtga ctcaaaacaa caacagcgaa 1500
tttgcttggc ctggagcttc ttcttgggct ctcaatggac gtaatagctt gatgaatcct 1560
ggacctgcta tggccagcca caaagaagga gaggaccgtt tctttccttt gtctggatct 1620
ttaatttttg gcaaacaagg aactggaaga gacaacgtgg atgcggacaa agtcatgata 1680
accaacgaag aagaaattaa aactactaac ccggtagcaa cggagtccta tggacaagtg 1740
gccacaaacc accagagtgc ccaagggaat ttgattcgga ataatgcaca ggcgcagacc 1800
ggttgggttc aaaaccaagg aatacttccg ggtatggttt ggcaggacag agatgtgtac 1860
ctgcaaggac ccatttgggc caaaattcct cacacggacg gcaactttca cccttctccg 1920
ctgatgggag ggtttggaat gaagcacccg cctcctcaga tcctcatcaa aaacacacct 1980
gtacctgcgg atcctccaac ggccttcaac aaggacaagc tgaactcttt catcacccag 2040
tattctactg gccaagtcag cgtggagatc gagtgggagc tgcagaagga aaacagcaag 2100
cgctggaacc cggagatcca gtacacttcc aactattaca agtctaataa tgttgaattt 2160
gctgttaata ctgaaggtgt atatagtgaa ccccgcccca ttggcaccag atacctgact 2220
cgtaatctgt aa 2232
<210> 32
<211> 743
<212> PRT
<213> AAV衣壳蛋白突变体4的氨基酸序列
<400> 32
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gly Asn Leu Ile
580 585 590
Arg Asn Asn Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
Claims (6)
1.一种具有心脏靶向性的异源肽，其特征在于，所述异源肽为如SEQ ID No:15所示的氨基酸序列组成的蛋白质。
2.一种AAV衣壳蛋白突变体，其特征在于，所述AAV衣壳蛋白突变体是将如权利要求1所述的异源肽插入AAV衣壳蛋白得到的；所述异源肽的插入位点位于AAV衣壳蛋白氨基酸588和589之间。
3.一种重组腺相关病毒病毒体，其特征在于，包括：
a.根据权利要求2所述的AAV衣壳蛋白突变体；和
b.编码异源基因产物的异源多核苷酸。
4.如权利要求3所述的重组腺相关病毒病毒体，其特征在于，所述基因产物是多肽。
5.如权利要求3所述的重组腺相关病毒病毒体，其特征在于，所述基因产物是干扰RNA、适配体、内切核酸酶、指导RNA中的一种。
6.如权利要求3所述的重组腺相关病毒病毒体在制备用于将基因产物递送至受试者心脏组织的药物中的用途。
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| WO2023215546A2 (en) * | 2022-05-06 | 2023-11-09 | Capsida, Inc. | Adeno-associated virus compositions having increased brain enrichment |
| CN115960177B (zh) * | 2022-10-09 | 2023-07-07 | 广州派真生物技术有限公司 | 腺相关病毒突变体及其应用 |
| CN116789739B (zh) * | 2022-12-08 | 2024-01-26 | 广州派真生物技术有限公司 | 腺相关病毒突变体及其应用 |
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| CN115925819B (zh) * | 2022-12-30 | 2023-10-13 | 广州派真生物技术有限公司 | 腺相关病毒突变体及其应用 |
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| CN116836237B (zh) * | 2023-06-16 | 2023-12-05 | 广州译码基因科技有限公司 | 提高视网膜靶向性的aav病毒衣壳蛋白突变体及其应用 |
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| CN116286986A (zh) * | 2016-07-29 | 2023-06-23 | 加利福尼亚大学董事会 | 具有变异衣壳的腺相关病毒病毒体和其使用方法 |
| CA3066623A1 (en) * | 2017-06-06 | 2019-12-13 | University Of Massachusetts | Self-regulating aav vectors for safe expression of mecp2 in rett syndrome |
| MX2020001997A (es) * | 2017-08-28 | 2020-07-20 | Univ California | Variantes de capside de virus adenoasociado y metodos de uso de estas. |
| WO2019060454A2 (en) * | 2017-09-20 | 2019-03-28 | 4D Molecular Therapeutics Inc. | CAPSID VARIANT ADENO-ASSOCIATED VIRUSES AND METHODS OF USE |
| JP2021521833A (ja) * | 2018-04-27 | 2021-08-30 | ウニベルジテート ハイデルベルク | 筋疾患の治療のための改変ａａｖカプシドポリペプチド |
| EP3820885A4 (en) * | 2018-07-11 | 2022-04-20 | The Brigham & Women's Hospital, Inc. | METHODS AND COMPOSITIONS FOR ADMINISTRATION OF DRUGS ACROSS THE BLOOD-BRAIN BARRIER |
| CN110950934B (zh) * | 2019-12-31 | 2022-11-04 | 复旦大学 | 一种腺相关病毒衣壳蛋白、载体及其构建方法与应用 |
| CN111349148A (zh) * | 2020-03-13 | 2020-06-30 | 辉大(上海)生物科技有限公司 | 一种腺相关病毒载体及其用途 |
| CN111574595B (zh) * | 2020-05-22 | 2022-10-04 | 中国医学科学院血液病医院(中国医学科学院血液学研究所) | 腺相关病毒突变体及其应用 |
| CN111850045B (zh) * | 2020-07-16 | 2022-03-08 | 四川大学 | 靶向心脏血管内皮的腺相关病毒载体及其应用 |
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