CN117693592A - 用于治疗遗传性疾患的体内核酸酶介导的基因靶向的组合物和方法 - Google Patents
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Abstract
本公开提供了用于治疗遗传性疾患的双载体系统。所述系统包括：(a)基因编辑载体，其包含表达盒，所述表达盒包含编码核酸酶的核酸序列和指导所述核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；以及(b)供体载体，其包含编码用于从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，其中所述系统还包含指导所述核酸酶特异性靶向天然PCSK9基因座的序列；并且其中所述靶细胞中的天然PCSK9用所述双载体系统给药后任选地被消除或减少。
Description
背景技术
位点特异性核酸酶(例如CRISPR-Cas9或大范围核酸酶)在染色体中产生双链断裂(DSB)，导致了DNA修复。在供体DNA存在的情况下，发生同源性定向修复(HDR)，并用来自供体基因的新信息替换染色体中的遗传信息。
同源定向修复(HDR)是使用DNA模板通过同源重组修复DNA双链断裂(DSB)的过程。该模板可以来自细胞周期后期S期或G2期的细胞内，此时姐妹染色单体在有丝分裂完成之前可用。此外，可将外源修复模板递送到细胞中，最常见的是以合成的单链DNA供体寡核苷酸或供体质粒的形式，以在基因组中产生精确的变化。
安全港位点(SHS)是可以安全插入和表达基因或其他遗传元件的基因组基因座。这些SHS对于有效的人类疾病基因治疗；对于研究基因结构、功能和调控；以及对于细胞标记和示踪至关重要。
所需要的是用于基因编辑的改进的组合物和方法。
发明内容
本文提供了用于基因编辑的组合物、方法、系统和试剂盒，其允许天然PCSK9基因的敲低或消融以及外源转基因在PCSK9基因座中的插入和/或表达。
在第一方面，本文提供了用于治疗遗传性疾患的系统。该系统包括基因编辑组件，该组件包含表达盒，该表达盒包含编码靶向PCSK9基因的核酸酶的核酸序列和指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列。该系统还包括供体载体，该供体载体包含转基因盒，该转基因盒包含编码转基因的核酸序列和指导转基因在靶细胞中的表达的调控序列，该供体载体进一步包含该转基因盒5′和3′的同源定向重组(HDR)臂，其中该转基因不是PCSK9。核酸酶靶向PCSK9基因。在一些实施例中，核酸酶靶向PCSK9外显子7。在一些实施例中，大范围核酸酶是ARCUS大范围核酸酶。
在一些实施例中，基因编辑组件包含编码Cas9的序列。在某些实施例中，基因编辑载体进一步包含编码包含至少20个核苷酸的种子区的sgRNA的序列，其中sgRNA特异性结合PCSK9基因中的靶位点，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
在其它实施例中，供体载体进一步包含编码包含至少20个核苷酸的种子区的sgRNA的序列，其中sgRNA特异性结合PCSK9基因中的靶位点，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
在另一方面，本文提供了用于治疗遗传性疾患的系统。该系统包括基因编辑组件，其包含编码靶向PCSK9基因的核酸酶的核酸序列。该系统还包括供体载体，该供体载体包含转基因盒，该转基因盒包含编码转基因的核酸序列和指导转基因在靶细胞中的表达的调控序列，该供体载体进一步包含该转基因盒5′和3′的同源定向重组(HDR)臂，其中该转基因不是PCSK9。核酸酶靶向PCSK9基因。在某些实施例中，基因编辑组件以脂质纳米颗粒的形式提供。
在一些实施例中，基因编辑组件包含编码Cas9的序列。在某些实施例中，基因编辑载体进一步包含编码包含至少20个核苷酸的种子区的sgRNA的序列，其中sgRNA特异性结合PCSK9基因中的靶位点，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
在其它实施例中，供体载体的另外的组分包含编码包含至少20个核苷酸种子区的sgRNA的序列，其中sgRNA特异性结合PCSK9基因中的靶位点，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
在某些实施例中，转基因涉及肝代谢疾患。在某些实施例中，转基因是OTC、PKU、CTLN1或LDLR。
在某些实施例中，载体是腺相关病毒(AAV)载体，并且载体包含AAV 5′ITR和AAV3′ITR。
在另一个实施例中，用于治疗遗传性疾患的双载体系统包括基因编辑AAV，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含：5′ITR，编码大范围核酸酶的序列，所述大范围核酸酶在指导所述大范围核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列控制下靶向PCSK9，和3′ITR；以及供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR、5′同源定向重组(HDR)臂、转基因和指导转基因在靶细胞中的表达的调控序列，3′HDR臂和3′ITR，其中该转基因不编码PCSK9。
在另一个实施例中，用于治疗遗传性疾患的双载体系统包括基因编辑AAV，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR、5′核定位信号(NLS)、编码Cas9的序列和指导saCas9在包含PCSK9基因的靶细胞中的表达的调控序列、3′NLS和3′ITR；和供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR、5′同源定向重组(HDR)臂、转基因和指导转基因在靶细胞中的表达的调控序列，3′HDR臂、U6启动子、包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′，和3′ITR，其中该转基因不编码PCSK9。
在另一个实施例中，用于治疗遗传性疾患的双载体系统包括基因编辑AAV载体，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR、U6启动子、包含特异性结合该PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′，5′核定位信号(NLS)、编码Cas9的序列和指导Cas9在包含PCSK9基因的靶细胞中的表达的调控序列、3′NLS和3′ITR；和供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR、5′同源定向重组(HDR)臂、转基因和指导转基因在靶细胞中的表达的调控序列，3′HDR臂和3′ITR。
在一些实施例中，基因编辑AAV载体和供体AAV载体具有相同的AAV衣壳。在其它实施例中，基因编辑AAV载体和供体AAV载体具有不同的AAV衣壳。在一些实施例中，AAV衣壳选自AAV8、AAV9、rh10、AAV6.2、AAV3B、hu37、rh79和rh64。
在另一方面，提供了通过共同施用本文所述的双载体系统来治疗人类疾患的方法。
在另一方面，提供了在受试者中治疗肝代谢疾患的方法，该方法包括向患有肝代谢疾患的受试者共同施用基因编辑AAV载体，该载体包含编码核酸酶的序列和指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列，以及供体AAV载体，其包含转基因和指导转基因在靶细胞中的表达的调控序列，该供体载体进一步包含转基因盒5′和3′的同源定向重组(HDR)臂，其中该转基因不是PCSK9。在某些实施例中，肝脏代谢疾患是鸟氨酸氨甲酰基转移酶。在其它实施例中，家族性高胆固醇血症或苯丙酮尿症。在一个实施例中，受试者是新生儿。
在另一方面，提供了用于治疗遗传性疾患的系统。该系统包括脂质纳米颗粒(LNP)，其包含编码靶向PCSK9基因的核酸酶的mRNA序列；和供体AAV载体，其包含转基因和指导其在靶细胞中的表达的调控序列，该供体载体进一步包含转基因5′和3′的同源定向重组(HDR)臂，其中该转基因不是PCSK9。在一些实施例中，核酸酶靶向PCSK9外显子7。在一些实施例中，大范围核酸酶是ARCUS大范围核酸酶。
在其它实施例中，基因编辑载体编码Cas9。在某些实施例中，基因编辑载体还编码包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。在一些实施例中，其中该系统包括LNP，该LNP包含Cas9编码序列和gRNA两者。
在其它实施例中，供体载体还编码包含至少20个核苷酸的种子区的sgRNA的序列，其中sgRNA特异性结合PCSK9基因中的靶位点，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
在又一方面，提供了用于治疗遗传性疾患的双载体系统。该系统包括基因编辑载体，其包含表达盒，该表达盒包含编码核酸酶的核酸序列和指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；以及供体载体，其包含编码用于从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，其中该系统进一步包含指导核酸酶特异性靶向天然PCSK9基因座的序列；并且其中靶细胞中的天然PCSK9任选地在用双载体系统给药后被消除或减少。
在又一方面，提供了使用本文所述的系统治疗患者的方法，其中患者的天然PCSK9表达水平降低并且其中患者表达外源产物。
在又一方面，提供了工程化的编码鸟氨酸氨甲酰基转移酶的序列。还包括载体、表达盒和包含其的重组病毒。
本发明的其它方面和优点将从本发明的以下详细描述中变得明显。
附图说明
图1显示了rhPCSK9基因座的示意图，显示了外显子7内的供体剪接位点，以及包含目的的供体模板例如hFIX、hOTC的HDR供体载体。
图2显示了用于试点研究的时间线，该试点研究包括在新生NHP中通过ARCUS2或SaCas9在PCSK9基因座中进行的hFIX微型基因敲入。
图3A至3C显示用于SaCas9或ARCUS介导的基因校正的双AAV载体系统的示意图。图3A显示用于ARCUS2介导的基因校正的双AAVhu37载体系统的示意图，其中AAVhu37-供体载体包含hOTC供体模板序列。图3B显示用于SaCas9介导的基因校正的双AAVhu37载体系统的示意图(反式；AAVhu37-SaCas9)，其中SaCas9和sgRNA的表达盒位于两个单独的载体中，并且AAVhu37.sgRNA供体载体包含hOTC供体模板序列和U6.sgRNA盒。图3C显示用于SaCas9介导的基因校正的双AAVhu37载体系统的示意图(顺式；AAVhu37.PCSK9-sgRNA.SaCas9)，其中SaCas9和sgRNA的表达盒在同一载体中，并且hOTC供体载体在一个单独的载体中。
图4A至4H显示新生NHP中核酸酶介导的基因靶向的体内测试。如图4A、4B和5G所示，向动物施用1x1013GC/kg的AAVhu37.ARCUS2.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR或1x1013GC/kg的AAVhu37.SaCas9.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR.U6.sgR或1x1013GC/kg的AAVhu37.GFP.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR.U6.sgR。图4C显示新生NHP中指定的时间点的hFIX水平(以ng/mL作图)。图4D显示新生NHP中指定的时间点的PCSK9水平(以第0天基线的百分比作图)。图4E显示新生NHP中指定的时间点的ALT(丙氨酸氨基转移酶)水平(以U/L作图)。图4F显示新生NHP中指定的时间点的抗FIX IgG水平(以稀释因子作图，1/稀释)。图4G显示新生NHP中指定的时间点的PCSK9水平(以ng/mL作图)。图4H显示新生NHP中测量的体重(以g作图)。
图5A至5H显示对3个月大的幼年NHP给药的图4所描述的体内测试的结果。图5A显示幼年NHP中指定的时间点的hFIX水平(以ng/mL作图)。图5B显示幼年NHP中指定的时间点的PCSK9水平(以第0天基线的百分比作图)。图5C显示幼年NHP中指定的时间点的ALT(丙氨酸氨基转移酶)水平(以U/L作图)。图5D显示幼年NHP中指定的时间点的抗FIX IgG水平(以稀释因子作图，1/稀释)。图5E显示幼年NHP中指定的时间点的PCSK9水平(以ng/mL作图)。图5F显示幼年NHP中指定的时间点测量的体重(以g作图)。图5G是显示来自图4A-5G中所描述实验的数据的汇总表。图5H显示测试的新生和幼年NHP之间的各种数据的比较。
图6A至6G显示了在肝活检样品中的载体转导(GC)和转基因表达，该样品在如图4A-4H所描述处理的NHP中处理后的不同天数收集。图6A显示肝活检样品中的载体转导水平，以每个二倍体细胞的AAV基因组拷贝(GC)作图。图6B显示肝活检样品中转基因RNA的相对表达。图6C显示使用特异性探针检测肝活检中FIX和ARCUS的双重原位杂交(ISH)。图6D显示用于转导百分比的量化的数字化ISH图像。图6E显示通过ISH定量的FIX转基因的转导效率，并以转导百分比作图。
图7A至7L显示使用特异性探针检测在NHP中处理后第84天收集的肝活检中的FIX和ARCUS的双重原位杂交(ISH)；显示了不同放大倍数的图像(用AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX处理的NHP)。图7A显示肝活检中ISH检测的ARCUS，以4倍放大倍数观察。图7B显示肝活检中ISH检测的hFIX，以4倍放大倍数观察。图7C显示ISH检测的ARCUS和hFIX的叠加图像，以4倍放大倍数观察。图7D显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以4倍放大倍数观察。图7E显示肝活检中ISH检测的ARCUS，以10倍放大倍数观察。图7F显示肝活检中ISH检测的hFIX，以10倍放大倍数观察。图7G显示ISH检测的ARCUS和hFIX的叠加图像，以10倍放大倍数观察。图7H显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以10倍放大倍数观察。图7I显示肝活检中ISH检测的ARCUS表达，以20倍放大倍数观察。图7J显示肝活检中ISH检测的hFIX，以20倍放大倍数观察。图7K显示ISH检测的ARCUS和hFIX的叠加图像，以20倍放大倍数观察。图7L显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。
图8A至8M显示使用特异性探针检测在NHP中处理后第84天收集的肝活检中的FIX和ARCUS的双重原位杂交(ISH)；显示了不同放大倍数的图像(用AAVhu37.EGFP和AAVhu37.供体-HDR-hFIX.U6.sgR处理的NHP)。图8A显示肝活检中ISH检测的GFP-WRPE，以4倍放大倍数观察。图8B显示肝活检中ISH检测的hFIX，以4倍放大倍数观察。图8C显示ISH检测的GFP-WRPE和hFIX的叠加图像，以4倍放大倍数观察。图8D显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以4倍放大倍数观察。图8E显示了肝活检中ISH检测的GFP-WRPE，以10倍放大倍数观察。图8F显示肝活检中ISH检测的hFIX，以10倍放大倍数观察。图8G显示ISH检测的GFP-WRPE和hFIX的叠加图像，以10倍放大倍数观察。图8H显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以10倍放大倍数观察。图8I显示肝活检中ISH检测的GFP-WRPE表达，以20倍放大倍数观察。图8J显示肝活检中ISH检测的hFIX，以20倍放大倍数观察。图8K显示ISH检测的GFP-WRPE和hFIX的叠加图像，以20倍放大倍数观察。图8L显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。图8M显示在未处理的对照中ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。
图9显示用AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX.处理的NHP中ARCUS介导的在靶编辑。治疗后第84天，收集肝活检样品，并根据扩增子测序计算目标区域中存在的总插入缺失的百分比。
图10A和10B显示PCSK9-hE7-KI小鼠模型的示意图。图10A显示用人pcsk9外显子7替代的小鼠pcsk9外显子7的示意图(hE7含有ARCUS靶向序列)。人PCSK9外显子7序列显示于SEQ ID NO：44中。图10B显示PCSK9-hE7-KI小鼠模型与其他疾患小鼠模型，例如OTCspfash、KI-spfash模型杂交的示意图。首先通过用包含外显子7的人PCSK9基因的区域替换包括鼠Pcsk9基因的外显子7的区域而产生PCSK9-hE7-KI敲入小鼠模型。然后将PCSK9-hE7-KI小鼠与稀疏毛皮灰(spfash)小鼠杂交，由于Otc基因的外显子4的末端处剪接供体位点的G到A点突变，该小鼠表现出OTC表达降低至20倍低。来自该杂交的小鼠称为PCSK9-hE7-KI.spfash小鼠并如本文所述使用。缩写：bp、碱基对；E6，外显子6；E7：外显子7；E8，外显子8；HDR，同源依赖重组；PCSK9，前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(基因，人)；Pcsk9，前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(基因，小鼠)。
图11A-11I显示对于如图11I中所显示的载体，新生NHP中核酸酶介导的基因靶向的体内测试。图11A是显示对于如实例3中所描述的载体，新生NHP中核酸酶介导的基因靶向的体内测试的实验设计。动物21-111、21-122和21-113在给药前为AAV结合抗体(BAb)阳性。载体给药后，第0天收集21-178份样品，这将干扰Bab测定。c：列出了独立的ITRseq测定中鉴定的OT位点的数量。图11B显示对于图11A所示的各组的PCSK9水平，显示为ng/mL(顶行)或第0天的％(底行)。图11C显示对于如图11A中所显示的组的ALT水平，显示为U/L(顶行)，或AST，显示为U/L(底行)。图11D显示通过ISH或IF定量的OTC转基因的转导效率，并以转导的肝细胞百分比作图。图11E显示小鼠的体重。图11F显示通过定量PCR分析第84天肝脏中的载体GC。图11G显示第84天猕猴肝脏中的hOTC和核酸酶的表达，该表达是通过对从肝活检样品分离的总RNA进行定量PCR，然后进行逆转录而测量的，并且以通过GAPDH水平标准化的相对表达水平表示。图11H显示通过扩增子测序对rhPCSK9靶向的基因座进行的插入缺失分析。图11I是新生NHP中核酸酶介导的基因靶向的体内测试的时间线的示意图，包括针对实例3中所描述的实验测试的载体。
图12显示代表pcsk9-hE7敲入等位基因的人PCSK9序列、小鼠PCSK9(mPCSK9)和恒河猴PCSK9(rhPCSK9)的265bp序列的序列比对。缩写：GAPDH，3-磷酸甘油醛脱氢酶；GC，基因组拷贝；hOTC，人鸟氨酸氨甲酰基转移酶；OT，脱靶；PCR，聚合酶链式反应；rhPCSK9，前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(恒河猴基因)；RNA，核糖核酸。
图13显示用于ARCUS2介导的基因校正的双AAV载体系统的供体构建体的示意图，其中AAV供体载体包含hOTC供体模板序列。显示了构建体中的HDR臂与敲入小鼠模型(图10A-10B)、NHP和人靶区域的同源性。
图14A显示在PCSK9-hE7-KI.spf-ash幼崽(部分OTC缺陷模型)中进行的包括通过ARCUS2在PCSK9基因座中的hOTC微型基因敲入研究的时间线，如实例5中所描述。图14B显示对于图14A的研究每组将接受的载体和剂量。
图14C-14I显示用如图7中所示的载体处理的或未经处理的(KI WT)并喂食高蛋白(HP)饮食10天的小鼠的研究结果。图14C显示存活的概率。图14D显示以引入HP饮食之前的体重百分比表示的体重。图14E显示在HP饮食第10天的血浆NH3水平。图14F显示第48天的mPCSK9蛋白水平。图14G显示在第59天通过扩增子测序测量的插入缺失百分比。图14H显示在第59天测量的肝活检样品中的载体转导水平，以每个二倍体细胞的AAV基因组拷贝(GC)作图。图14I显示第8周时的OTC IF。
图15是实例10中描述的实验设计的示意图，其在PCSK9-hE7-KI.ldlr-/ldlr-.apobec-/apobec-幼崽(hoFH模型)中通过SaCas9在PCSK9基因座中产生hLDLR微型基因敲入。
图16是显示实例10中使用的载体的示意图。
图17显示实例10的实验设计。
图18A-18D显示实例10的实验结果。图18A显示shHDR+saCas9、mhHDR+saCas9、仅shHDR和未处理的小鼠的血清LDL水平。图18B显示shHDR+saCas9、mhHDR+saCas9、仅shHDR处理的小鼠的插入缺失百分比。图18C显示了第63天在肝脏中测量的每个二倍体基因组的hLDLR基因组拷贝。图18D显示shHDR+saCas9、mhHDR+saCas9、仅shHDR和未处理的小鼠在第63天的血清LDL水平。
图19显示对于实例10的小鼠在第63天采集的肝脏样品的免疫组织化学数据。
具体实施方式
本文提供了组合物、试剂盒和方法，其向患有某些遗传性疾患的患者提供稳定、长期的治疗效果，该遗传性疾患包括肝代谢疾患。组合物、试剂盒和方法使用靶向靶细胞PCSK9基因座的核酸酶，并且供体载体提供了包括外源产物的模板，该外源产物用于整合到PCSK9基因座中并从其表达，其中插入的核酸序列不编码PCSK9，并且内源PCSK9的表达被破坏并且表达水平降低。
PCSK9
前蛋白转化酶枯草杆菌蛋白酶9(PCSK9)是一种丝氨酸蛋白酶，其可降低肝脏和肝外低密度脂蛋白(LDL)受体(LDLR；606945)水平并增加血浆LDL胆固醇。PCSK9对于血浆胆固醇稳态的调节至关重要。PCSK9结合低密度脂质受体家族成员低密度脂蛋白受体(LDLR)、极低密度脂蛋白受体(VLDLR)、载脂蛋白E受体(LRP1/APOER)和载脂蛋白受体2(LRPg/APOER2)，并促进它们在细胞内酸性区室中的降解。人PCSK9的蛋白序列为NP_777596.2，如SEQ ID NO：23所示，其编码序列在SEQ ID NO：22中显示。
尽管已经靶向PCSK9基因以用于治疗胆固醇相关疾患，但本文证明了PSCK9基因座是用于基因靶向以插入非PCSK9转基因的其它基因的安全港。因此，本文提供的组合物、试剂盒和方法利用靶向PCSK9基因座的核酸酶，并使用供体模板将治疗性转基因插入到靶PCSK9基因座中。
本文提供的组合物、试剂盒和方法包括基因编辑组件(在一些实施例中，载体)和提供待在宿主细胞中的表达的治疗性转基因的供体载体。
基因编辑组件
本文提供的组合物、试剂盒和方法包括基因编辑组件，其包含核酸酶(或其编码序列)和指导核酸酶特异性靶向染色体1上的天然PCSK9基因座的序列。如本文所用，“靶PCSK9基因座”或“PCSK9基因基因座”是PCSK9编码区中需要插入异源转基因的任何位点。在某些实施例中，靶PCSK9基因座位于PCSK9编码序列的外显子7中。图12提供了人(h)、恒河猴(rh)和小鼠(m)PCSK9外显子7剪接位点的比对，其在本文中使用SaCas9和靶向PCSK9的大范围核酸酶(称为ARCUS)进行示例。
本文描述了组合物，特别是核酸酶，其可用于靶向基因以插入转基因，例如对PCSK9特异性的核酸酶。在某些实施例中，核酸酶不是天然存在的。在其它实施例中，核酸酶是非天然存在的，即在DNA结合结构域和/或切割结构域中工程化的。例如，可以改变天然存在的核酸酶的DNA结合结构域以结合选定的靶位点(例如，经工程化以结合与同源结合位点不同的位点的大范围核酸酶)。在其它实施例中，核酸酶包含异源DNA结合和切割结构域(例如，锌指核酸酶；TAL效应物核酸酶；具有异源切割结构域的大范围核酸酶DNA结合结构域)。
在某些实施例中，核酸酶是靶向PCSK9的大范围核酸酶。大范围核酸酶是内切脱氧核糖核酸酶，其特征在于大识别位点(12至40个碱基对的双链DNA序列)，例如，I-SceI。当与核酸酶结合时，可以在特定位置切割DNA。可将限制性酶引入到细胞中，用于基因编辑或用于原位基因组编辑。在某些实施例中，核酸酶是归巢核酸内切酶家族的成员LAGLIDADG(SEQID NO：31)。在某些实施例中，核酸酶是归巢核酸内切酶家族的成员I-CreI，其识别并切割22个碱基对识别序列SEQ ID NO：32-CAAAACGTCGTGAGACAGTTTG。参见，例如WO 2009/059195。描述了合理设计的单LAGLIDADG(SEQ ID NO：32)归巢核酸内切酶的方法，该方法能够全面地重新设计I-CreI和其它归巢核酸内切酶以靶向广大不同的DNA位点，包括哺乳动物、酵母、植物、细菌和病毒基因组中的位点(WO 2007/047859)。在一个实施例中，核酸酶由SEQ ID NO：19中第330位至第1424位所示的序列或与其具有至少95％、98％或99％同一性的序列编码。在一个实施例中，核酸酶蛋白序列是SEQ ID NO：20中所示的序列，或与其具有至少95％、98％或99％同一性的序列。此类核酸酶在本文中有时称为ARCUS核酸酶。术语“归巢核酸内切酶”与术语“大范围核酸酶”是同义的。参见WO 2018/195449，其描述了某些PCSK9大范围核酸酶，其以其整体并入本文。
“锌指核酸酶”(ZFN)是通过将锌指DNA结合结构域与DNA切割结构域融合而产生的人工限制性酶。可以将锌指结构域工程化以靶向特定的所需DNA序列，这使得锌指核酸酶能够靶向复杂基因组内的独特序列。通过利用内源DNA修复机制，这些试剂可以用于精确地改变高等生物的基因组，并且用作基因组编辑领域中的重要工具。转录激活因子样效应子核酸酶(TALEN)是限制性酶，其可以被工程化以切割特定的DNA序列。所述转录激活因子样效应子核酸酶是通过将TAL效应子DNA结合结构域融合到DNA切割结构域(切割DNA链的核酸酶)而制成的。在另一个实施例中，编码序列编码锌指核酸酶或转录激活子样(TAL)效应物核酸酶(TALEN)。
在某些实施例中，核酸酶是CRISPR相关核酸酶(Cas)，任选地为Cas9。“Cas9”(CRISPR相关蛋白9)是指RNA引导的DNA核酸内切酶家族，其特征在于两个特征核酸酶结构域，RuvC(切割非编码链)和HNH(编码链)。Cas9的合适的细菌来源包括金黄色葡萄球菌(Staphylococcus aureus)(SaCas9)，化脓性链球菌(Streptococcus pyogenes)(SpCas9)和脑膜炎奈瑟菌(Neisseria meningitides)[KM Estelt等人，NatMeth，10：1116-1121(2013)]。野生型编码序列可用于本文所述的构建体中。可选地，优化细菌密码子以用于在人类中的表达，例如使用多种已知的人类密码子优化算法中的任何一种。可选地，这些序列可以全部或部分合成产生。可以任选地用具有类似特性的其他核酸内切酶来替代。参见，例如，公共CRISPR数据库(db)，可通过http：//crispr.u-psud.fr/crispr访间。
在某些实施例中，组合物、试剂盒和方法中核酸酶编码序列包含在基因编辑载体中。基因编辑载体包括表达盒，该表达盒包含编码核酸酶的核酸序列和指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列。
如本文所用的，“载体”是包含核酸序列的生物或化学部分，其可以被引入到合适的宿主细胞中以复制或表达所述核酸序列。常见的载体包括非病毒载体和病毒载体。如本文所用的，非病毒系统可以选自纳米颗粒、电穿孔系统和新型生物材料、裸DNA、噬菌体、转座子、质粒、粘粒(Phillip McClean，www.ndsu.edu/pubweb/～mcclean/-plsc731/cloning/cloning4.htm)和人工染色体(Gong，Shiaoching，等人，“Agene expressionatlas of the central nervous system based on bacterial artificial chromosomes(基于细菌人工染色体的中枢神经系统基因表达图谱).”Nature 425.6961(2003)：917-925)。
如本文所使用的，“表达盒”是指包括生物学上有用的核酸序列(例如，编码蛋白质、酶或其它有用的基因产物的基因cDNA、mRNA等)和与其可操作地连接的调控序列的核酸分子，所述调控序列指导或调节核酸序列和其基因产物的转录、翻译和/或表达。如本文所用的，“可操作地连接的”序列包括与核酸序列邻接的调控序列和以反式或在远处起作用以控制该序列的调控序列。此类调控序列通常包含例如启动子、增强子、内含子、Kozak序列、聚腺苷酸化序列和TATA信号中的一者或多者。表达盒可以含有基因序列上游(5′端)的调控序列，例如一个或多个启动子、增强子、内含子等，和一个或多个增强子，或基因序列下游(3′端)的调控序列，例如包含聚腺苷酸化位点的3′非翻译区，以及其他元件。在其它实施例中，术语“转基因”是指来自插入到靶细胞中的外源的一个或多个DNA序列。通常，用于产生病毒载体的此类表达盒含有本文所描述的基因产物的编码序列，所述编码序列侧接病毒基因组的包装信号和其它表达控制序列，如本文描述的序列。在某些实施例中，载体基因组可以含有两个或更多个表达盒。
除了核酸酶的编码序列之外，在某些实施例中，基因编辑载体包括指导核酸酶在宿主细胞中的表达的调控序列。在某些实施例中，调控元件包括启动子。在某些实施例中，当设计系统用于治疗以肝细胞中的突变或表型为特征的代谢疾患时，可以设计基因编辑载体为使得核酸酶在肝特异性启动子的控制下表达。本文所描述的示例性质粒和载体使用肝特异性启动子甲状腺素结合球蛋白(TBG)，其特征在于SEQ ID NO：41的序列。在其它实施例中，缩短形式的TBG是有用的，其为一种本文称为TBG-S1的变体，其特征在于SEQ ID NO：11的序列。在另一个实施例中，使用具有SEQ ID NO：12的序列的杂合肝启动子(HLP)。
在一些实施例中，期望地是利用具有低转录活性的启动子或弱启动子。在一个实施例中，启动子是弱化型的肝特异性甲状腺素结合球蛋白(TBG)启动子。在一个实施例中，弱启动子在天然启动子或TBG-S1序列的5′或3′末端被截短。在另一个实施例中，启动子仅保留来自TBG-S1启动子的3′末端的113个核苷酸，并且被称为F113(也称为TBG-S1-F113)(SEQ ID NO：19，第206位至第318位核苷酸)。美国临时专利申请第63/016，145号，于2020年4月27日提交，第63/033,738号，于2020年6月2日提交，以及第63/089,796号，于2020年10月9日提交，PCT/US21/29386和PCT/US21/29403，均于2021年4月27日提交，每篇标题为“COMPOSITIONS AND METHODS FOR REDUCING NUCLEASE EXPRESSION AND OFF-TARGETACTIVITY USING A PROMOTER WITH LOW TRANSCRIPTIONAL ACTIVITY(使用具有低转录活性的启动子降低核酸酶表达和脱靶活性的组合物和方法)”，其全部内容通过引用并入本文。
可选地，可以使用其他肝特异性启动子，例如α1抗胰蛋白酶(A1AT)、人白蛋白(Miyatake等人，J.Virol.，71：512432(1997))和乙型肝炎病毒核心启动子(Sandig等人，Gene Ther.，3：10029(1996)，TTR极小增强子/启动子，α-抗胰蛋白酶启动子，LSP(845个核苷酸)。参见，例如，肝特异性基因启动子数据库，Cold Spring Harbor，http：//rulai.schl.edu/LSPD。可选地，可以使用其他组织特异性启动子，例如肌肉特异性启动子，例如肌肉肌酸激酶(MCK)启动子或肌肉杂合(MH)启动子。可选地，其他启动子，例如组成型启动子(CMV、CBG、CB7等)、可调节(诱导型)启动子[参见，例如WO 2011/126808和WO 2013/049493，其通过引用并入本文]或响应于生理信号的启动子可以用于本文所描述的载体中。任选地，如果选择可调节系统，则可能需要第三载体以提供调控功能。
除了启动子之外，基因编辑盒、表达盒和/或载体还可以含有一种或多种合适的“调控元件”或“调控序列”，其包括但不限于增强子；转录因子；转录终止子；高效的RNA处理信号，例如剪接信号和聚腺苷酸化信号(聚A)；稳定细胞质mRNA的序列，例如土拨鼠肝炎病毒(WHP)转录后调控元件(WPRE)；增强翻译效率的序列(即Kozak共有序列)；增强蛋白质稳定性的序列；以及当需要时，增强编码产物分泌的序列。合适的聚A序列的实例包括，例如SV40、牛生长激素(bGH)和TK聚A。合适的增强子的实例包括，例如甲胎蛋白增强子、TTR极小启动子/增强子、LSP(TH-结合球蛋白启动子/α1-微球蛋白/bikunin增强子)等。这些控制序列或调控序列可操作地连接至核酸酶编码序列或转基因编码序列。
在某些实施例中，该基因编辑载体包括TBG启动子、一个或多个αmic/bik增强子、ARCUS大范围核酸酶的编码序列、任选地包括WPRE，和聚A。在某些实施例中，表达盒包括SEQID NO：42的第211位至第2964位核苷酸。
在一些实施例中，基因编辑组件还包括将核酸酶引导至PCSK9靶基因座中的靶位点的序列。在某些实施例中，例如针对PCSK9特异性的大范围核酸酶，不需要进一步的序列来将核酸酶引导至靶位点。然而，例如，在Cas9的情况下，提供了一个额外的序列，称为“单引导RNA”或“sgRNA”，它对目标序列具有特异性。sgRNA可在与Cas9相同的载体(顺式)或不同的载体(反式)上提供。如本文所用的，sgRNA与gRNA支架结构组合，具有至少20个碱基的序列(或约24-28个碱基，有时称为种子区)用于特异性DNA结合(即，与靶DNA同源)。sgRNA的转录应精确地从其5′端开始。当靶向模板DNA链时，sgRNA的碱基配对区域与转录的序列具有相同的序列同一性。当靶向非模板DNA链时，sgRNA的碱基配对区域是转录序列的反向互补。任选地，基因编辑载体可以含有多于一种的sgRNA。sgRNA位于被Cas9(或Cpf1)酶特异性识别的原型间隔子相邻基序(PAM)的5′。通常，sgRNA“紧邻”PAM序列的5′，即，不存在间隔子或插入序列。在一个实施例中，sgRNA“种子”编码序列是AAGTTGGTCCCCAAAGTCCC(SEQ IDNO：8)，其对于通过SaCas9靶向人和猕猴PCSK9的外显子7是有用的。然而，本领域技术人员可以设计其他sgRNA。
在某些实施例中，sgRNA包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。在一些实施例中，种子区域与PCSK9基因中的靶位点具有100％互补性。在其他的实施例中，与靶位点相比，种子区域包含1、2、3、4或5个错配。
sgRNA处于RNA聚合酶启动子和/或终止子的控制之下。在某些实施例中，RNA聚合酶启动子是Pol III启动子，例如U6启动子。在另一实施例中，启动子是H1启动子。示例性U6启动子的序列可见于SEQ ID NO：10。在其它实施例中，sgRNA和RNA聚合酶启动子位于供体载体中。
在其它实施例中，例如，其中核酸酶是Cas9，基因编辑组件还包括一种或多种核定位信号(NLS)。在一种实施例中，NLS位于Cas9的编码序列的侧翼。在某些实施例中，NLS具有SEQ ID NO：5的第4241位至第4288位的序列。参见，例如，Lu等人，Types of nuclearlocalization signals and mechanisms of protein import into the nucleus(核定位信号的类型和蛋白质导入细胞核的机制)，Cell Commun Signal(2021年5月)19：60，其通过引用并入本文。
在某些实施例中，核酸酶编码序列作为信使RNA(mRNA)提供。mRNA可以包含5′非翻译区、3′非翻译区，和/或编码或翻译序列。在某些实施例中，Cas9的编码序列作为mRNA提供。
mRNA可以是天然存在或非天然存在的mRNA。mRNA可以包含一个或多个经修饰的核碱基、核苷或核苷酸。在一些实施例中，本发明组合物中的mRNA包含至少一种修饰，其赋予核酸提高或增强的稳定性，包括例如在体内对核酸酶消化的改善的抗性。mRNA可以包含任何数量的碱基对，包含数十、数百或数千个碱基对。任何数量的(例如，全部、一些或无)核碱基、核苷或核苷酸可以是典型种类的类似物、其为取代的、修饰的或以其他方式非天然存在的。在某些实施例中，可以修饰全部特定核碱基类型。例如，mRNA中的全部胞嘧啶可以是5-甲基胞嘧啶。如本文所用的，术语“修饰”和“修饰的”作为涉及本文提供的核酸的术语，包括至少一种改变，其优选地增强稳定性并使mRNA比野生型或天然存在的mRNA形式更稳定(例如，对核酸酶消化有抗性)。如本文所用的，术语“稳定的”和“稳定性”作为涉及本发明核酸特别是关于mRNA的术语，是指对例如通常能够降解此类mRNA的核酸酶(即，核酸内切酶或核酸外切酶)的降解提高的或增强的抗性。提高的稳定性可包括，例如对靶细胞或组织内的内源酶(例如，核酸内切酶或核酸外切酶)或条件的水解或其它破坏的较低的敏感性，从而提高或增强此类mRNA在靶细胞、组织、受试者和/或细胞质中的停留。本文提供的稳定化的mRNA分子相对于其天然存在的未修饰的对应物(例如mRNA的野生型形式)表现出更长的半衰期。术语“修饰”和“修饰的”作为与本发明mRNA相关的术语，还考虑了改善或增强mRNA核酸的翻译的变化形式，包括，例如，包含在蛋白质翻译的起始中起作用的序列(例如Kozak共有序列)。
在一些实施例中，本文描述的mRNA已经历化学或生物修饰以使其更稳定。mRNA的示例性修饰包括碱基的缺失(例如，通过缺失或通过一个核苷酸取代另一个核苷酸)或碱基的修饰，例如，碱基的化学修饰。本文所用的短语“化学修饰”包括引入不同于天然存在的mRNA中所见的那些化学性质的修饰，例如共价修饰，如修饰的核苷酸(例如核苷酸类似物，或包括在此类mRNA分子中非天然存在的侧基)的引入。
在一些实施方案中，mRNA序列中的C和/或U残基的数量减少。在另一个实施方案中，通过用编码特定氨基酸的一个密码子取代编码相同或相关氨基酸的另一个密码子来减少C和/或U残基的数量。对本发明的mRNA核酸的可考虑的修饰还包括掺入假尿苷(ψ)或5-甲基胞嘧啶(m5C)。可以通过本领域的普通技术人员容易了解的方法对本发明的mRNA进行取代和修饰。
在某些实施例中，mRNA包括5′帽结构、链终止核苷酸、茎环，和/或聚腺苷酸化信号。帽结构或帽种类是包括通过接头连接的两个核苷部分的化合物，并且可以选自天然存在的帽、非天然存在的帽或帽类似物或抗反向帽类似物。mRNA可以替代地或另外地包含链终止核苷。
在某些实施例中，mRNA包括茎环，例如组蛋白茎环。茎环可包括1、2、3、4、5、6、7、8或更多个核苷酸碱基对。茎环可以位于mRNA的任何区域中。例如，茎环可位于非翻译区(5′非翻译区或3′非翻译区)、编码区、或聚A序列或尾中、之前或之后。
在某些实施例中，mRNA包括聚A序列。聚A序列可以完全或主要由腺嘌呤核苷酸或其类似物或衍生物组成。在某些实施例中，聚A序列是位于mRNA的3′非翻译区附近的尾。
mRNA可编码任何目的多肽，例如，核酸酶，包括任何天然存在的或非天然存在的或其它修饰的多肽。由mRNA编码的多肽可以是任何大小的，并且可以具有任何二级结构或活性。在一些实施例中，mRNA编码的多肽在细胞中的表达时可具有治疗效果。
供体载体
该组合物、试剂盒和方法包括供体载体，其提供治疗性转基因的编码序列。在某些实施例中，供体载体含有表达盒，该表达盒包含编码转基因的核酸序列和指导转基因在靶细胞中的表达的调控序列。在某些实施例中，转基因编码在肝代谢疾患或其它遗传性疾患中异常表达的蛋白质。转基因编码PCSK9以外的蛋白质。此类蛋白质包括但不限于OTC、低密度脂蛋白受体(LDLr)、因子IX如SEQ ID NO：55或56中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％和99％同一性的序列，和因子VIII，例如SEQ ID NO：53或54中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列。
可通过供体载体递送的其它示例性基因包括，但不限于，与1A型糖原贮积病或缺乏症(GSD1)相关的葡萄糖-6-磷酸酶、与磷酸烯醇式丙酮酸羧激酶(PEPCK)缺乏症相关的PEPCK；细胞周期蛋白依赖性激酶样5(CDKL5)，也称为丝氨酸/苏氨酸激酶9(STK9)，与癫痫发作和严重的神经发育损伤有关；半乳糖-1磷酸尿苷酰转移酶，与半乳糖血症相关，如SEQID NO：63或64中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；苯丙氨酸羟化酶(PAH)，与苯丙酮尿症(PKU)相关；与原发性高尿草酸盐1型相关的基因产物，包括羟酸氧化酶1(GO/HAO1)，如SEQ ID NO：49或50所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，以及AGXT如SEQ ID NO：47或48所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，支链α-酮酸脱氢酶，包括BCKDH、BCKDH-E2、BAKDH-E1a和BAKDH-E1b，与枫糖尿病相关；与酪氨酸血症1型有关的富马酰乙酰乙酸水解酶；与甲基丙二酸血症相关的甲基丙二酰-辅酶A变位酶；中链酰基辅酶A脱氢酶，与中链乙酰辅酶A缺乏有关；鸟氨酸氨甲酰基转移酶(OTC)，与鸟氨酸氨甲酰基转移酶缺乏有关；精氨琥珀酸合成酶(ASS1)，如SEQ ID NO：69或70所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，其与瓜氨酸血症相关；卵磷脂-胆固醇酰基转移酶(LCAT)缺乏；甲基丙二酸盐血症(MMA)；与C1型尼曼-皮克病相关的NPC1；丙酸血症(PA)；低密度脂蛋白受体(LDLR)蛋白，与家族性高胆固醇血症(FH)相关，如SEQ ID NO：73或74中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，LDLR变体，如WO 2015/164778中所述的那些，或具有SEQ ID NO：或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；ApoE和ApoC蛋白，与痴呆相关；脂蛋白脂酶(LPL)(脂蛋白脂酶缺乏症)如SEQ ID NO：67或68所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，UDP-葡萄糖醛酸转移酶，与Crigler-Najjar病相关的；腺苷脱氨酶，与严重联合免疫缺陷疾病相关；次黄嘌呤鸟嘌呤磷酸核糖转移酶，与痛风和Lesch-Nyan综合征相关的；生物酰亚胺酶，与生物酰亚胺酶缺乏相关；与法布里病相关的α-半乳糖苷酶A(a-Gal A)，例如SEQ ID NO：75或76所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；β-半乳糖苷酶(GLB1)，与GM1神经节苷脂贮积症相关；与威尔逊氏病相关的ATP7B；与戈谢病2型和3型相关的β-葡糖脑苷脂酶，如SEQ ID NO：51或52所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；70kDa的过氧化物酶体膜蛋白，与Zellweger综合征相关；与异染性脑白质营养不良相关的芳基硫酸酯酶A(ARSA)、与克拉伯病相关的半乳糖脑苷脂酶(GALC)、与庞皮病相关的α-葡糖苷酶(GAA)，如SEQ ID NO：79或80所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；与尼曼皮克病A型相关的鞘磷脂酶(SMPD1)基因；肌肽酶(CN1)；次黄嘌呤-鸟嘌呤磷酸核糖基转移酶(HGPRT)；红细胞生成素(EPO)；氨甲酰磷酸合成酶(CPS1)，N-乙酰谷氨酸合成酶(NAGS)；精氨琥珀酸裂合酶(ASL)(精氨酸琥珀酸尿)，如SEQ ID NO：57或58中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；和精氨酸酶(AG)；与成人发病型II型瓜氨酸血症(CTLN2)有关的精氨琥珀酸合酶(WO 2018/144709，在此引入作为参考)；与尿素循环障碍有关的氨甲酰磷酸合酶1(CPS1)；运动神经元存活(SMN)蛋白，与脊髓性肌萎缩相关；神经酰胺酶，与Farber脂肪肉芽肿相关；b-己糖胺酶，与GM2神经节苷脂贮积症和Tay-Sachs和Sandhoff疾患相关；天冬氨酰氨基葡糖苷酶，与天冬氨酰-氨基葡糖尿有关；与岩藻糖苷酶有关的α-岩藻糖苷酶；与α-甘露糖苷贮积症相关的α-甘露糖苷酶；胆色素原脱氨酶，与急性间歇性卟啉病(AIP)有关；用于治疗α-1抗胰蛋白酶缺乏(肺气肿)的α-1抗胰蛋自酶，如SEQ ID NO：77或78所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列；促红细胞生成素，用于治疗地中海贫血或肾衰竭引起的贫血；血管内皮生长因子、血管生成素-1和成纤维细胞生长因子，用于治疗缺血性疾患；血栓调节素和组织因子途径抑制剂，用于治疗如在例如动脉粥样硬化、血栓形成或栓塞中所见的血管闭塞；用于治疗帕金森病的芳香族氨基酸脱羧酶(AADC)和酪氨酸羟化酶(TH)；用于治疗充血性心力衰竭的β肾上腺素能受体、受磷酸蛋白的反义形式或突变形式、肌浆/内质网腺苷三磷酸酶-2(SERCA2)和心脏腺苷酸环化酶；用于治疗各种癌症的肿瘤抑制基因，如p53；用于治疗炎性和免疫疾患和癌症的细胞因子，如多种白介素之一；肌养蛋白或小肌养蛋白和肌营养相关蛋白或小肌营养相关蛋白，用于治疗肌营养不良；和用于治疗糖尿病的胰岛素或GLP-1。
用于递送的合适转基因的实例包括，例如，与家族性高胆固醇血症相关的转基因(例如VLDLr、LDLr、ApoE，参见，例如WO 2020/132155、WO 2018/152485、WO 2017/100682，其通过引用并入本文)、肌营养不良症、囊性纤维化和罕见病或孤儿病。此类罕见病的实例可以包含脊髓性肌萎缩症(SMA)、亨廷顿氏病、雷特综合征(Rett Syndrome)(例如，甲基CpG结合蛋白2(MeCP2)；UniProtKB-P51608)、肌萎缩侧索硬化症(ALS)、杜氏肌营养不良、弗里德里希共济失调(Friedrichs Ataxia)(例如，共济蛋白)、颗粒蛋白前体(PRGN)(与非阿尔茨海默氏病的大脑变性相关，包含额颞叶痴呆(FTD)、进行性非流利性失语症(PNFA)和语义性痴呆)等等。其他有用的基因产物包括氨基甲酰合成酶I、鸟氨酸氨甲酰基转移酶(OTC)、精氨酸琥珀酸合成酶、用于治疗精氨酸琥珀酸裂解酶缺陷的精氨酸琥珀酸裂解酶(ASL)、精氨酸酶、富马酰乙酸水解酶、苯丙氨酸羟化酶、α-1抗胰蛋白酶、恒河猴甲胎蛋白(AFP)、恒河猴绒毛膜促性腺激素(CG)、葡萄糖-6-磷酸酶，例如SEQ ID NO：59或60中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，与遗传性血管性水肿相关的血浆蛋白酶C1抑制剂(SERPING1)如SEQ ID NO：61或62所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，与高半胱氨酸尿症相关的胆色素原脱氨酶、胱硫醚β-合酶，例如SEQ ID NO：65或66中所示的序列，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列，支链酮酸脱羧酶、白蛋白、异戊酰辅酶A脱氢酶、丙酰辅酶A羧化酶、甲基丙二酰辅酶A变位酶、戊二酰辅酶A脱氢酶、胰岛素、β-葡萄糖苷酶、丙酮酸羧酸盐、肝磷酸化酶、磷酸化酶激酶、甘氨酸脱羧酶、H蛋白、T蛋白、囊性纤维化跨膜调节剂(CFTR)序列和肌营养不良蛋白基因产物[例如，小肌营养不良蛋白或微肌营养不良蛋白]。其它有用的基因产物包含如可以用于酶替代疗法的酶，所述酶替代疗法可用于由于酶活性不足而导致的多种病状。例如，可以将含有甘露糖-6-磷酸的酶用于溶酶体贮积病的疗法中(例如，合适的基因包含编码β-葡糖醛酸酶(GUSB)的基因)。用于递送的合适的转基因的实例可以包含在AAV载体中递送的人共济蛋白，如例如在2020年12月18日的PCT/US20/66167、于2019年12月19日提交的美国临时专利申请第62/950,834号和于2021年1月11日提交的美国临时申请第63/136,059号中所描述的，所述文献均通过引用并入本文。用于递送的合适的转基因的另一个实例可以包含在AAV载体中递送的人酸-α-葡萄糖苷酶(GAA)，如例如在2020年4月30日的PCT/US20/30493，现在公开为WO2020/223362A1、2020年4月20日的PCT/US20/30484，现在公开为WO 2020/223356A1、于2019年4月30日提交的美国临时专利申请第62/840,911号、于2019年10月10日提交的美国临时申请第62.913,401号、于2020年5月14日提交的美国临时专利申请第63/024,941号和于2020年11月4日提交的美国临时专利申请第63/109,677号中所描述的，所述文献均通过引用并入本文。同样地，用于递送的合适的转基因的另一个实例可以包含在AAV载体中递送的人α-L-艾杜糖醛酸酶(IDUA)，如例如在2014年3月13日的PCT/US2014/025509，现在公开为WO 2014/151341，以及于2013年3月15日提交的美国临时专利申请第61/788,724号中所描述的，所述文献均通过引用并入本文。
其他有用的治疗产品包括在肌肉(包括心肌)中的表达的那些。由转基因编码的有用的治疗产物包括激素和生长和分化因子，其包括但不限于胰岛素、胰高血糖素、胰高血糖素样肽1(GLP-1)、生长激素(GH)、甲状旁腺激素(PTH)、生长激素释放因子(GRF)、卵泡刺激素(FSH)、黄体生成素(LH)、人绒毛膜促性腺激素(hCG)、血管内皮生长因子(VEGF)、血管生成素、血管抑制素、粒细胞集落刺激因子(GCSF)、促红细胞生成素(EPO)、结缔组织生长因子(CTGF)、碱性成纤维细胞生长因子(bFGF)、酸性成纤维细胞生长因子(aFGF)、表皮生长因子(EGF)、转化生长因子α(TGFa)、血小板衍化生长因子(PDGF)、胰岛素生长因子I和II(IGF-I和IGF-II)、转化生长因子β超家族中的任一种，包括TGFβ、活化素、抑制素或骨形态发生蛋白(BMP)BMP 1-15中的任一种、生长因子的调蛋白/神经调节蛋白/ARIA/神经鞘分化因子(NDF)家族中的任一种、神经生长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养因子NT-3和NT-4/5、睫状神经营养因子(CNTF)、胶质细胞系源性的神经营养因子(GDNF)、神经营养因子、集聚蛋白、信号素/脑衰蛋白家族中的任一种、轴突导向因子-1和轴突导向因子-2、肝细胞生长因子(HGF)、肝配蛋白、头蛋白、音猬因子和酪氨酸羟化酶。本文有用的其他转基因包括用于治疗I-VII型粘多糖贮积症的转基因(IDUA、IDS、GNA、HGSNAT、NAGLU、SGSH、GALNS、GLB1、ARSB、GUSB)。用于治疗MPSI的示例性序列可见于WO 2019/010335中，其通过引用并入本文。用于治疗MPSII的示例性序列可见于WO 2019/060662中，其通过引用并入本文。用于治疗MPSIIIa的示例性序列可见于WO 2019/108857，其通过引用并入本文。用于治疗MPSIIIb的示例性序列可见于WO 2019/108856，其通过引用并入本文。
在一些实施例中，转基因盒包括启动子、转基因编码序列和聚A序列。在一些实施例中，启动子是肝特异性启动子，例如TBG启动子、TBG-S1启动子、HLP启动子或本文描述的其他启动子。在其它实施例中，提供不具有启动子的转基因，并将其插入天然PSCK9启动子下游的基因组中。
转基因盒、表达盒和/或(编辑或供体)载体可以含有一个或多个合适的“调控元件”或“调控序列”，其包括但不限于，增强子；转录因子；转录终止子；有效的RNA加工信号，例如剪接和多聚腺苷酸化信号(聚A)；稳定细胞质mRNA的序列，例如土拨鼠肝炎病毒(WHP)转录后调控元件(WPRE)；增强翻译效率的序列(即Kozak共有序列)；增强蛋白质稳定性的序列；以及当需要时，增强编码产物分泌的序列。合适的聚A序列的实例包括，例如SV40、牛生长激素(bGH)和TK聚A。合适的增强子的实例包括，例如甲胎蛋白增强子、TTR极小启动子/增强子、LSP(TH-结合球蛋白启动子/α1-微球蛋白/bikunin增强子)等。这些控制序列或调控序列可操作地连接至核酸酶编码序列或转基因编码序列。
除了转基因盒之外，在某些实施例中，供体载体还包括转基因盒的5′和3′的同源定向重组(HDR)臂，以促进转基因同源定向重组到内源基因组中。同源臂针对靶PCSK9基因座，并且可以具有不同的长度。在一些实施例中，HDR臂各自的长度为约100bp至约1000bp。在其它实施例中，HDR臂各自为约130bp至约500bp。在其它实施例中，HDR臂各自为约100bp至约300bp。在其它实施例中，HDR臂各自为约100bp至约400bp。在其它实施例中，HDR臂各自为约250bp至约500bp。在其它实施例中，HDR臂各自为约300bp至约500bp。在某些实施例中，HDR臂各自为约100bp、125bp、150bp、175bp、200bp、225bp、250bp、275bp、300bp、325bp、350bp、375bp、400bp、425bp、450bp、450bp、475bp或500bp。在一个实施例中，HDR臂是130bp。在另一个实施例中，HDR臂是137bp。在其它的实施例中，HDR臂为约130bp至140bp。在另一个实施例中，HDR臂为约500bp。在另一个实施例中，不存在HDR臂。理想情况下，HDR臂与靶PCSK9基因座具有高水平的互补性，尽管不需要100％的互补性。在一些实施例中，在每个HDR臂中，允许1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更多个错配。用于靶向PCSK9外显子7的合适的HDR臂序列显示于SEQ ID No：24-29中。在一个实施例中，HDR臂序列选自SEQ ID No：24-29。
本文还提供了用于将OTC转基因盒核酸酶介导的位点特异性整合到基因组中PCSK9安全港中的组合物、试剂盒和方法，其为具有OTC缺陷的患者提供长期治疗益处。提供了OTC的工程化的编码序列，本文称为hOTCco2，并显示在SEQ ID NO：17中。提供了具有SEQID NO：17的序列的核酸或具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或至少99.9％同一性的序列的核酸。在一个实施例中，核酸与SEQ ID NO：30所示的天然OTC编码序列具有小于80％、小于79％、小于78％、小于77％、小于76％、小于75％、小于74％、小于73％、小于72％、小于71％或小于70％的同一性。
用于治疗OTC的其它序列描述于WO 2015/138348和WO 2015/138357中，其通过引用并入本文。用于治疗PKU的示例性序列描述于WO 2018/126112中，其通过引用并入本文。其它序列在SEQ ID NO：71或72中显示，或与之具有至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性的序列。
病毒和非病毒载体
本文所述的(基因编辑和供体)表达盒或编码序列可以被工程化成任何合适的遗传元件，例如载体，以用于递送至靶细胞，例如肝细胞。如本文所用的，“载体”是包含核酸序列的生物或化学部分，其可以被引入到合适的宿主细胞中以复制或表达所述核酸序列。常见的载体包括非病毒载体和病毒载体。如本文所用的，非病毒系统可以选自纳米颗粒、电穿孔系统和新型生物材料、裸DNA、噬菌体、转座子、质粒、粘粒(Phillip McClean，www.ndsu.edu/pubweb/～mcclean/-plsc731/cloning/cloning4.htm)和人工染色体(Gong,Shiaoching，等人，“A gene expression atlas of the central nervous systembased on bacterial artificial chromosomes(基于细菌人工染色体的中枢神经系统基因表达图谱).”Nature 425.6961(2003)：917-925)。在一个实施例中，如本文所述或本领域已知的，核酸通过非病毒载体或脂质纳米颗粒递送。
在某些实施例中，基因编辑组件封装在脂质纳米颗粒(LNP)中。参见，例如，Conway等人，Non-viral Delivery of Zinc Finger Nuclease mRNA Enables Highly EfficientIn Vivo Genome Editing of Multiple Therapeutic Gene Targets(锌指核酸酶mRNA的非病毒递送实现多个治疗基因靶标的高效体内基因组编辑)，Molecular Therapy，27(4)：866-877(2019年4月)，其通过引用并入本文)。如本文所用，短语“脂质纳米颗粒”是指包含一种或多种脂质(例如，阳离子脂质、非阳离子脂质和PEG修饰的脂质)的转移载剂。优选地，脂质纳米颗粒被配制成将一种或多种mRNA以递送到一种或多种靶细胞(例如，肝和/或肌肉)。合适的脂质的实例包含例如磷脂酰化合物(例如，磷脂酰甘油、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、鞘脂、脑苷脂和神经节苷脂)。还考虑使用聚合物作为转移媒剂，无论是单独使用还是与其它转移媒剂组合使用。合适的聚合物可以包含例如聚丙烯酸酯、聚氰基丙烯酸烷基酯、聚交酯、聚交酯-聚乙交酯共聚物、聚己内酯、葡聚糖、白蛋白、明胶、藻酸盐、胶原、壳聚糖、环糊精、树枝状大分子和聚乙烯亚胺。在一个实施例中，基于转移载体促进mRNA转染靶细胞的能力来选择转移载剂。用于mRNA的有用的脂质纳米颗粒包含阳离子脂质以包封和/或增强mRNA向靶细胞中的递送，该靶细胞将充当蛋白质产生的储库。如本文所用的，短语“阳离子脂质”是指在选定pH如生理pH下携带净正电荷的许多脂质种类中的任一种。可以通过包含采用一种或多种阳离子脂质、非阳离子脂质和经PEG修饰的脂质的不同比率的多组分脂质混合物来制备所考虑的脂质纳米颗粒。文献中已经描述了若干阳离子脂质，其中许多是可商购获得的。参见例如，WO2014/089486、US2018/0353616A1和US 8,853,377B2，所述文献通过引用并入本文。在某些实施例中，使用常规程序进行LNP配制，该常规程序包括胆固醇、可电离的脂质、辅助脂质、PEG-脂质和在包封的核酸周围形成脂质双层的聚合物(Kowalski等人，2019，Mol。Ther.27(4)：710-728)。在一些实施例中，LNP包含阳离子脂质(即N-[1-(2，3-二油酰氧基)丙基]-N，N，N-三甲基氯化铵(DOTMA)，或1，2-二油酰-3-三甲基铵-丙烷(DOTAP))与辅助脂质DOPE。在一些实施例中，LNP包括可电离脂质Dlin-MC3-DMA可电离脂质，或基于二酮哌嗪的可电离脂质(cKK-E12)。在一些实施例中，聚合物包括聚乙烯亚胺(PE1)或聚(β-氨基)酯(PBAE)。参见，例如，W02014/089486、US2018/0353616A1、US2013/0037977A1、W02015/074085A1、US9670152B2和US 8,853,377B2，所述文献通过引用并入本文。在某些实施例中，其中基因编辑组件包括Cas9mRNA，LNP还包括gRNA。
本文中有用的某些LNP包括WO 2021/077066和WO 2021/055892中描述的那些，每一篇均通过引用以其整体并入本文。有用的LNP包括那些显示出增强的肝脏递送的LNP。可以改变LNP制剂以增强肝递送。例如，类型和可电离的脂质：mRNA比率，mRNA：sgRNA比率、可电离的脂质、磷脂、胆固醇和PEG-脂质的摩尔比等可以变化。在一个实施例中，LNP是Kauffman，K.J；Dorkin，J.R.；Yang，J.H.；Heartlein，M.W.；DeRosa，F.；Mir，F.F.；Fenton，O.S.；Anderson，D.G.，Optimization of lipid nanoparticle formulations for mRNAdelivery in vivo with fractional factorial and definitive screening designs(利用部分因子和确定性筛选设计优化用于体内mRNA递送的脂质纳米颗粒制剂).Nanoletters 2015，15(11)，7300-7306，其通过引用并入本文。在某些实施例中，LNP被设计为具有可电离的脂质：mRNA重量比在5∶1到25∶1之间变化。在某些实施例中，可电离的脂质∶mRNA重量比为1∶1、2∶1、3∶1、4∶1、5∶1、6∶1、7∶1、8∶1、9∶1、10∶1、12.5∶1、15∶1、20∶1或25∶1。在某些实施例中，mRNA∶sgRNA重量比为1∶1、1∶2、2∶1、1∶4、1∶5、5∶1、4∶1、3∶1或2∶1。
已描述了其他LNP，并且在本文中是有用的。参见，例如，WO 2016/118724、US 10,413,618B2、US 10,723,692B2和US8754062B2，其均通过引用并入本文。
本文的某些实例说明了在AAV载体基因组中使用含有基因编辑组件(核酸酶)编码序列和转基因编码序列的AAV载体。然而，本文描述的构建体的使用不限于AAV构建体并且可以用于其他载体。在某些实施例中，可以将载体基因组包装到不同的载体中(例如，重组的博卡病毒)。在某些实施例中，可以将表达盒包装到不同的病毒载体中、非病毒载体中和/或不同的递送系统中。在某些实施例中，在LNP中提供基因编辑组件。
“质粒”或“质粒载体”在本文中通常由载体名称前面和/或后面的小写字母p表示。可根据本发明使用的质粒、其他克隆和表达载体、其特性及其构建/操作方法对于本领域技术人员而言是显而易见的。在一个实施例中，将本文所描述的核酸序列或本文所描述的表达盒经工程化到用于产生病毒载体和/或递送至宿主细胞的合适的遗传元件(载体)中，例如裸DNA、噬菌体、转座子、粘粒、附加体等，这些遗传元件转移其上携带的核酸酶序列。所选载体可以通过任何合适的方法，包含转染、电穿孔、脂质体递送、膜融合技术、高速DNA包被的团粒、病毒感染和原生质体融合递送。用于制备此类构建体的方法对核酸操纵技术人员而言是已知的并且包含基因工程、重组工程以及合成技术。参见，例如，Sambrook等人，Molecular Cloning：ALaboratory Manual(分子克隆：实验室手册)，Cold Spring HarborPress，Cold Spring Harbor，NY。
在某些实施例中，表达盒位于用于包装到病毒衣壳中的载体基因组中。例如，对于AAV载体基因组，表达盒的组分在5′末端和3′末端侧翼为AAV反向末端重复序列。例如，5′AAV ITR、表达盒、3′AAV ITR。在其它实施例中，可以选择自身互补AAV。在其它实施例中，可以使用逆转录病毒系统、慢病毒载体系统或腺病毒系统。
AAV载体
在某些实施例中，基因编辑载体和/或供体载体作为重组AAV提供。“重组AAV”或“rAAV”是DNA酶抗性病毒颗粒，其含有两个元件，AAV衣壳和包装在AAV衣壳内的至少含有非AAV编码序列的载体基因组。除非另有说明，该术语可与短语“rAAV载体”或“AAV载体”互换使用。rAAV是“复制缺陷型病毒”或“病毒载体”，因为其缺少任何功能性AAV rep基因或功能性AAV cap基因并且不能产生子代。在某些实施例中，仅AAV序列是AAV反向末端重复序列(ITR)，通常定位在载体基因组的5′和3′最端处，以允许定位在ITR之间的基因和调控序列包装在AAV衣壳内。
AAV衣壳的来源可以是许多天然存在的和可获得的腺相关病毒以及工程化的AAV中的任一种。在一个实施例中，基因编辑载体和/或供体载体的AAV衣壳的来源是相同的。在另一个实施例中，基因编辑载体和/或供体载体的AAV衣壳的来源是不同的。腺相关病毒(AAV)病毒载体是一种AAV DNA酶抗性颗粒，其具有AAV蛋白衣壳，该AAV蛋白衣壳包装有核酸序列以用于递送至靶细胞。AAV衣壳由60个衣壳(cap)蛋白亚基、VP1、VP2和VP3组成，它们以二十面体对称排列，比率大约为1∶1∶10至1∶1∶20，这取决于所选的AAV。可以选择各种AAV作为上述AAV病毒载体衣壳的来源。参见，例如，美国公开专利申请号2007-0036760-A1；美国公开专利申请号2009-0197338-A1；EP 1310571。还参见，WO 2003/042397(AAV7和其它猿猴类AAV)、美国专利7790449和美国专利7282199(AAV8)、WO 2005/033321和US 7,906,111(AAV9)以及WO 2006/110689、WO 2003/042397(rh.10)和WO 2018/160582(AAVhu68)。这些文档还描述了可以选择用于产生AAV的其它AAV，并且通过引用并入。
除非另有说明，否则本文所描述的AAV衣壳、ITR和其它所选的AAV组分可以容易地选自任何AAV，包含但不限于通常被鉴定为AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV8bp、AAV7M8、AAVAnc80、AAVrh10、AAVrh79和AAVPHP.B的AAV，以及任何已知的或提及的AAV或尚待发现的AAV的变体，或其变体或混合物。参见，例如，WO 2005/033321，其通过引用并入本文。在一个实施例中，AAV衣壳是AAV1衣壳或其变体、AAV8衣壳或其变体、AAV9衣壳或其变体、AAVhu.68衣壳或其变体、AAVrh.10衣壳或其变体、AAVrh64R1衣壳或其变体、AAVhu.37衣壳或其变体、或AAV3B或其变体。在一个实施例中，衣壳是AAVhu.37衣壳。还参见WO 2019/168961和WO 2019/169004，其全部内容通过引用并入本文。在一个实施例中，AAV衣壳是AAVrh79衣壳或其变体。在一个实施例中，AAV衣壳是AAVrh.90或其变体。
在其他实施例中，rAAV包括AAVhu37衣壳。AAVhu37衣壳包含：vp1蛋白的异源群体，其是编码SEQ ID NO：38的氨基酸序列的核酸序列的产物，vp2蛋白的异源群体，其是编码SEQ ID NO：38的至少约第138至738位氨基酸的氨基酸序列的核酸序列的产物，和vp3蛋白的异源群体，其是编码SEQ ID NO：38的至少第204至738位氨基酸的核酸序列的产物，其中：vp1、vp2和vp3蛋白含有具有氨基酸修饰的亚群，其包含SEQ ID NO：38中天冬酰胺-甘氨酸对中的至少两个高度脱酰胺的天冬酰胺(N)，且任选地进一步包含含有其它脱酰胺氨基酸的亚群，其中脱酰胺化导致氨基酸改变。AAVhu37的特征在于具有高度脱酰胺的残基，例如，在基于AAVhu37 VP1(SEQ ID NO：38)的编号的位置N57、N263、N385和/或N514处。
其它残基中已观察到脱酰胺化，如以下表中和例如2019年9月6号公布的WO 2019/168961中所示，其通过引用并入本文。在某些实施例中，如使用质谱法用胰蛋白酶所测定的，AAVhu37衣壳在以下提供的范围内的一个或多个位置被修饰。在某些实施例中，如本文所描述的修饰以下位置中的一个或多个位置或N之后的甘氨酸。例如，在某些实施例中，可以修饰G为S或A，例如，在第58位、第264位、第386位或第515位处。在一个实施例中，AAVhu37衣壳在位置N57/G58处修饰为N57Q或G58A以提供在该位置处脱酰胺化减少的衣壳。在另一个实施例中，N57/G58被改变为NS57/58或NA57/58。然而，在某些实施例中，当NG改变为NS或NA时观察到脱酰胺化的增加。在某些实施例中，NG对的N被修饰为Q，同时保留G。在某些实施例中，NG对的两个氨基酸都被修饰。在某些实施例中，N385Q导致该位置的脱酰胺化显著减少。在某些实施例中，N499Q导致该位置的脱酰胺化显著增加。
在某些实施例中，AAVhu37可具有这些或其它脱酰胺化的残基，例如，通常小于10％和/或可具有其它修饰，包括甲基化(例如，～R487)(在给定残基处通常小于5％，更通常小于1％)、异构化(例如，在D97处)(在给定残基处通常小于5％，更通常小于1％)、磷酸化(例如，当存在时，在约10％至约60％，或约10％至约30％，或约20％至约60％范围内)(例如，在S149、～S153、～S474、～T570、～S665中的一个或多个处)、或氧化(例如，在W248、W307、W307、M405、M437、M473、W480、W480、W505、M526、M544、M561、W621、M637和/或W697中的一个或多个处)。任选地，W可以氧化成犬尿氨酸。
还有其它位置可具有这些或其它修饰(例如乙酰化或进一步的脱酰胺化)。在某些实施例中，在SEQ ID NO：37中提供了编码AAVhu37 vp1衣壳蛋白的核酸序列。在其它实施例中，可选择与SEQ ID NO：37具有70％至99.9％同一性的核酸序列以表达AAVhu37衣壳蛋白。在某些其它实施例中，所述核酸序列与SEQ ID NO：37至少约75％相同、至少80％相同、至少85％、至少90％、至少95％、至少97％相同或至少99％相同。然而，可以选择编码SEQ ID NO：38的氨基酸序列的其它核酸序列以用于产生rAAVhu37衣壳。在某些实施例中，核酸序列具有SEQ ID NO：37的核酸序列或与编码SEQ ID NO：38的SEQ ID NO：37至少70％至至少99％相同、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。在某些实施例中，该核酸序列具有SEQ ID NO：37的核酸序列或与编码SEQ ID NO：38的vp2衣壳蛋白(约第138位至第738位氨基酸)的SEQ ID NO：37的第412位至约第2214位核苷酸至少70％至99％、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。在某些实施例中，核酸序列具有SEQ ID NO：37的约第61 0位至约第2214位的核酸序列或与编码SEQ ID NO：38的vp3衣壳蛋白(约第204位至第738位氨基酸)的SEQID NO：37的核苷酸至少70％至99％、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。参见，EP 2345731B1和其中的SEQ ID NO：88，其通过引用并入。
在其他实施例中，rAAV包括AAV8衣壳。AAV8衣壳包含：一种VP同种型的异源群体，其是如下表中所定义的脱酰胺化的，如使用质谱法基于衣壳中VP蛋白的总量所测定。合适的修饰包含上文的段落中所描述的标记为脱酰胺化的调节的修饰，其并入本文中。在某些实施例中，如使用质谱法所确定的，AAV衣壳在以下提供的范围内的一个或多个位置被修饰。在某些实施例中，如本文所描述的修饰以下位置中的一个或多个位置或N之后的甘氨酸。在某些实施例中，将人工NG引入到与上表所鉴定的位置之一不同的位置中。在某些实施例中，如本文所描述的修饰以下位置中的一个或多个位置或N之后的甘氨酸。例如，在某些实施例中，G可以被修饰为S或A，例如，在第58位、第67位、第95位、第216位、第264位、第386位、第411位、第460位、第500位、第515位或第541位处。当NG57/58被改变为NS 57/58或NA57/58时，观察到脱酰胺化的显著减少。然而，在某些实施例中，当NG改变为NS或NA时观察到脱酰胺化的增加。在某些实施例中，NG对的N被修饰为Q，同时保留G。在某些实施例中，NG对的两个氨基酸都被修饰。在某些实施例中，N385Q导致该位置的脱酰胺化显著减少。在某些实施例中，N499Q导致该位置的脱酰胺化显著增加。在某些实施例中，在位于N263处的对处进行NG突变(例如，至N263A)。在某些实施例中，在位于N514处的对处进行NG突变(例如，至N514A)。在某些实施例中，在位于N540的对(例如，N540A)处进行NG突变。在某些实施例中，对含有多个突变的AAV突变体和这些位置的突变中的至少一个进行工程化。在某些实施例中，在第N57位没有进行突变。在某些实施例中，在第N94位没有进行突变。在某些实施例中，在第N305位没有进行突变。在某些实施例中，在第G386位没有进行突变。在某些实施例中，在第Q467位没有进行突变。在某些实施例中，在第N479位没有进行突变。在某些实施例中，在第N653位没有进行突变。在某些实施例中，衣壳被修饰以减少除“NG”对之外的位置处的“N”或“Q”。残基编号基于公开的AAV8序列，其在SEQ ID NO：36中再次出现。
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在某些实施例中，rAAV包含AAVrh79衣壳，如2019年9月6日公布的WO 2019/169004中所描述，其通过引用并入本文。在一个实施例中，AAVrh79衣壳包含AAVrh79 vp1蛋白、AAVrh79 vp2蛋白和AAVrh79 vp3蛋白的异源群体。在一个实施例中，通过从编码SEQ IDNO：34的第1位至第738位的预测的氨基酸序列的核酸序列表达产生AAVrh79衣壳。任选地，共表达vp3蛋白的序列，来自除vp1-独特区域(约第1位至第137位氨基酸)或vp2-独特区域(约第1位至第203位氨基酸)之外的核酸序列，vpl蛋白由SEQ ID NO：33产生，或vp1蛋白由与SEQ ID NO：33至少70％相同的编码SEQ ID NO：34的第1位至第738位的预测的氨基酸序列的核酸序列产生。在其它的实施例中，AAVrh79 vp2蛋白通过从编码SEQ ID NO：34的至少大约第138位至第738位氨基酸的预测的氨基酸序列的核酸序列表达产生，vp2蛋白从包含SEQ ID NO：33的至少第412位至第2214位核苷酸的序列产生，或vp2蛋白从与SEQ ID NO：33的至少第412位至第2214位核苷酸至少70％相同的编码SEQ ID NO：34的至少大约第138位至第738位的预测的氨基酸序列的核酸序列产生，AAVrh79 vp3蛋白通过从编码SEQ ID NO：34的至少大约第204位至第738位的预测的氨基酸序列的核酸序列表达产生，vp3蛋白从包含SEQ ID NO：33的至少第610位至第2214位核苷酸的序列产生，或vp3蛋白从与SEQ ID NO：33的至少大约第610位至第2214位核苷酸至少70％相同的编码SEQ ID NO：34的至少大约第204至第738位氨基酸的预测的氨基酸序列的核酸序列产生。
在某些实施例中，AAVrh79衣壳包含：vp1蛋白的异源群体，其是编码SEQ ID NO：34的氨基酸序列的核酸序列的产物，vp2蛋白的异源群体，其是编码SEQ ID NO：34的至少约第138位至第738位的氨基酸序列的核酸序列的产物，和vp3蛋白的异源群体，其是编码SEQ IDNO：34的至少第204位至第738位氨基酸的核酸序列的产物。
AAVrh79 vp1、vp2和vp3蛋白含有具有氨基酸修饰的亚群，其包含SEQ ID NO：34中天冬酰胺-甘氨酸对中的至少两个高度脱酰胺的天冬酰胺(N)，并任选进一步包含含有其它脱酰胺氨基酸的亚群，其中脱酰胺化导致氨基酸改变。相对于SEQ ID NO：34的编号，观察到在N-G对N57、N263、N385和/或N514处高水平的脱酰胺化。在其它残基中已经观察到脱酰胺化，如下表和实例中所示。在某些实施例中，AAVrh79可具有其它脱酰胺的残基，例如，通常小于10％和/或可具有其它修饰，包括甲基化(例如，～R487)(在给定残基处通常小于5％，更通常小于1％)、异构化(例如，在D97处)(在给定残基处通常小于5％，更通常小于1％)、磷酸化(例如，当存在时，在约10％至约60％，或约10％至约30％，或约20％至约60％范围内)(例如，在S149、～S153、～S474、～T570、～S665中的一个或多个处)、或氧化(例如，在W248、W307、W307、M405、M437、M473、W480、W480、W505、M526、M544、M561、W621、M637和/或697中的一个或多个处)。任选地，W可以氧化成犬尿氨酸。
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在某些实施例中，如使用质谱法用胰蛋白酶测定的，AAVrh79衣壳在以下提供的范围内在前表中鉴定的一个或多个位置被修饰。在某些实施例中，如本文所描述的修饰以下位置中的一个或多个位置或N之后的甘氨酸。残基数基于本文所提供的AAVrh79序列。参见，SEQ ID NO：34。
在某些实施例中，在SEQ ID NO：33中提供了编码AAVrh79 vp1衣壳蛋白的核酸序列。在其它实施例中，可选择与SEQ ID NO：33具有70％至99.9％同一性的核酸序列以表达AAVrh79衣壳蛋白。在某些其它实施例中，核酸序列与SEQ ID NO：33至少约75％相同、至少80％相同、至少85％、至少90％、至少95％、至少97％相同、至少99％相同或至少99.9％相同。然而，可以选择编码SEQ ID NO：34的氨基酸序列的其它核酸序列以用于产生rAAV衣壳。在某些实施例中，核酸序列具有SEQ ID NO：33的核酸序列，或与编码SEQ ID NO：34的SEQID NO：33至少70％至99％相同、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。在某些实施例中，该核酸序列具有SEQ ID NO：33的核酸序列，或与SEQ ID NO：33的编码SEQ ID NO：34的vp2衣壳蛋白(约第138位至第738位氨基酸)的约第412位至约第2214位核苷酸至少70％至99.％、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。在某些实施例中，核酸序列具有SEQ ID NO：33的约第610位至约第2214位的核酸序列，或与SEQ ID NO：33的编码SEQ ID NO：34的vp3衣壳蛋白(约第204位至第738位氨基酸)的核苷酸至少70％至99.％、至少75％、至少80％、至少85％、至少90％、至少95％、至少97％、至少99％相同的序列。
本发明还包括编码突变体AAVrh79的核酸序列，其中一个或多个残基已被改变以减少脱酰胺化，或本文鉴定的其它修饰。此类核酸序列可用于产生突变型rAAVrh79衣壳。
在某些实施例中，rAAV包含AAVrh.90衣壳，如2020年11月5日公布的WO 2020/223232中所述，其通过引用并入本文。在另一方面，提供了重组腺相关病毒(rAAV)，其包含：(A)AAVrh.90衣壳，其包含以下的一种或多种：(1)AAVrh.90衣壳蛋白，其包含：选自以下的AAVrh.90vp1蛋白的异源群体：由编码SEQ ID NO：40的第1位至第738位的预测的氨基酸序列的核酸序列表达产生的vp1蛋白、由SEQ ID NO：39产生的vp1蛋白、或由与SEQ ID NO：39至少70％相同的编码SEQ ID NO：40的第1位至第738位的预测的氨基酸序列的核酸序列产生的vp1蛋白；选自以下的AAVrh.90vp2蛋白的异源群体：由编码SEQ ID NO：40的至少约第138位至第738位氨基酸的预测氨基酸序列的核酸序列表达产生的vp2蛋白，由包含SEQ IDNO：39的至少第412位至第2214位核苷酸的序列产生的vp2蛋自，或由与SEQ ID NO：39的至少第412位至第2214位核苷酸至少70％相同的编码SEQ ID NO：40的至少约第138位至第738位氨基酸的预测氨基酸序列的核酸序列产生的vp2蛋白；选自以下的AAVrh.90vp3蛋白的异源群体：由编码SEQ ID NO：40的至少约第204位至第738位的预测氨基酸序列的核酸序列表达产生的vp3蛋白、由包含SEQ ID NO：39的至少第610位至第2214位核苷酸的序列产生的vp3蛋白、或由与SEQ ID NO：39的至少第610位至第2214位至少70％相同的编码SEQ ID NO：40的至少约第204位至第738位的预测氨基酸序列的核酸序列产生的vp3蛋白；和/或(2)vp1蛋白的异源群体，其为编码SEQ ID NO：40的氨基酸序列的核酸序列的产物，vp2蛋白的异源群体，其为编码SEQ ID NO：40的至少约第138位至第738位氨基酸的氨基酸序列的核酸序列的产物，和vp3蛋白的异源群体，其为编码SEQ ID NO：40的至少第204位至第738位氨基酸的核酸序列的产物，其中：vp1、vp2和vp3蛋白含有具有氨基酸修饰的亚群，其包含SEQ ID NO：40中天冬酰胺-甘氨酸对中的至少两个高度脱酰胺化的天冬酰胺(N)，且任选地进一步包含含有其它脱酰胺化氨基酸的亚群，其中脱酰胺化导致氨基酸改变；和(B)在AAVrh.90衣壳中的载体基因组，所述载体基因组包含含有AAV反向末端重复序列和编码产物的非AAV核酸序列的核酸分子，所述核酸序列与指导该产物在宿主细胞中的表达的序列可操作地连接。
在某些实施例中，AAVrh.90vp1、vp2和vp3蛋白含有具有氨基酸修饰的亚群，其在SEQ ID NO：40的天冬酰胺-甘氨酸对中包含至少两个高度脱酰胺的天冬酰胺(N)，并且任选地进一步包含含有其它脱酰胺氨基酸的亚群，其中脱酰胺化导致氨基酸改变。相对于SEQID NO：40的编号，观察到在N-G对N57、～N263、～N385和/或～N514处的高水平的脱酰胺化。如以下表中所示，在其它残基中观察到脱酰胺化。在某些实施例中，AAVrh.90可具有其它脱酰胺化的残基(例如～N305、～N499和/或～N599，通常为小于20％)和/或可具有其它修饰，包括磷酸化(例如当存在时，在约2％至约30％，或约2％至约20％，或约2％至约10％范围内)(例如在S149处)或氧化(例如在～W23、～M204、～M212、W248、W282、M405、M473、W480、W505、M526、～N544、M561和/或～M607中的一个或多个处)。任选地，W可以氧化成犬尿氨酸。
在某些实施例中，如使用胰蛋白酶质谱所测定，在提供的范围内，在上表中鉴定的一个或多个位置中修饰AAVrh.90衣壳。在某些实施例中，如本文所述地修饰一个或多个位置或N之后的甘氨酸。残基数基于本文所提供的AAVrh.90序列。参见，SEQ ID NO：40。
在某些实施例中，AAVrh.90衣壳包含：vp1蛋白的异源群体，其是编码SEQ ID NO：40的氨基酸序列的核酸序列的产物，vp2蛋白的异源群体，其是编码SEQ ID NO：40的至少约第138位至第738位的氨基酸序列的核酸序列的产物，和vp3蛋白的异源群体，其是编码SEQID NO：40的至少第204位至第738位氨基酸的核酸序列的产物。
在某些实施例中，选择细小病毒载体衣壳用于肝向性，并且所治疗的患者患有肝代谢疾患。在某些实施例中，选择细小病毒载体衣壳用于心脏向性，并且所治疗的患者患有心脏疾患。在某些实施例中，选择细小病毒载体衣壳用于骨骼肌中的细胞的向性，并且所治疗的患者患有肌肉疾患。
如本文所使用的，“载体基因组”是指包装在形成病毒颗粒的rAAV衣壳内部的核酸序列。此类核酸序列含有AAV反向末端重复序列(ITR)。在本文的实例中，载体基因组从5′到3′至少包含AAV 5′ITR，含有转基因或编码序列的表达盒，该转基因或编码序列与指导其表达的调控序列可操作地连接，以及AAV 3′ITR。ITR是在载体生产期间负责基因组复制和包装的遗传元件，并且是产生rAAV所需的唯一病毒顺式元件。在一个实施例中，ITR来自与供应衣壳的AAV不同的AAV。在一个优选的实施例中，来自AAV2的ITR序列或其缺失的形式(ΔITR)可以为了方便而使用。然而，可以选择来自其它AAV来源的ITR。在ITR的来源来自AAV2并且AAV衣壳来自另一个AAV来源的情况下，所得载体可以被称为假型的。通常，AAV载体基因组包括AAV 5′ITR，编码基因产物的核酸序列和任何调控序列以及AAV 3′ITR。然而，这些元件的其它构型可以是合适的。在一个实施例中，提供了自身互补AAV。已经描述了被称为ΔITR的5′ITR的缩短版本，其中缺失了D序列和末端解析位点(trs)。在某些实施例中，载体基因组包含130个碱基对的缩短的AAV2 ITR，其中外部“a”元件被删除。在使用内部A元件作为模板的载体DNA扩增期间，缩短的ITR回复到145个碱基对的野生型长度。在其它实施例中，使用了全长AAV 5′和3′ITR。在其他的实施例中，可以选择全长的或工程化的ITR。可以选择来自AAV2的ITR、不同于衣壳来源或除全长ITR之外的AAV。ITR来自与生产过程中提供rep功能的AAV相同的AAV来源或反式互补AAV。进一步地，可以使用其它ITR。合适的ITR序列的实例示于序列表中，例如SEQ ID NO：42，第1位至第130位和第3052位至第3181位核苷酸。此外，载体基因组包含直接调节基因产物表达的调控序列(例如，通过调节转录和/或翻译而直接地或间接地调节)。在本文中更详细地讨论载体基因组的合适组分。
在某些实施例中，基因编辑载体基因组包括TBG启动子、一种或多种αmic/bik增强子、ARCUS大范围核酸酶的编码序列、任选的WPRE和聚A。在某些实施例中，表达盒包含SEQID NO：42的第211位至第2964位核苷酸，侧翼为5′和3′ITR。
为了用于制备AAV病毒载体(例如，重组(r)AAV)，可将表达盒载于任何合适的载体上，例如质粒，将其递送到包装宿主细胞中。可将用于本发明的质粒进行工程化，以使它们适于在原核细胞、昆虫细胞、哺乳动物细胞等中进行体外复制和包装。合适的转染技术和包装宿主细胞是已知的和/或可以由本领域的技术人员容易地设计。
用于产生和分离适合于用作载体的AAV的方法是本领域已知的。一般参见，例如，Grieger和Samulski，2005，“Adeno-associated virus as a gene therapy vector：Vector development，production and clinical applications，(作为基因治疗载体的腺相关病毒：载体开发、生产和临床应用)”Adv.Biochem.Engin/Biotechnol.99：119-145；Buning等人，2008，“Recent developments in adeno-associated virus vectortechnology，(腺相关病毒载体技术的最新进展)”J.Gene Med.10：717-733；以及下文引用的参考文献，这些参考文献中的每个参考文献通过引用整体并入本文。为了将转基因包装到病毒粒子中，ITR是与含有表达盒的核酸分子相同的构建体中顺式所需的仅有的AAV组分。cap和rep基因可在反式中提供。
术语“AAV中间体”或“AAV载体中间体”是指缺少包装在其中的所期望的基因组序列的组装的rAAV衣壳。这些也可以被称为“空”衣壳。此类衣壳可以不含有表达盒的可检测基因组序列，或者含有不足以实现基因产物的表达的仅部分包装的基因组序列。这些空衣壳是无功能性的以将目的基因转移至宿主细胞。
可以使用已知的技术产生本文所描述的重组腺相关病毒(AAV)。参见，例如，WO2003/042397；WO 2005/033321、WO 2006/110689；US 7588772 B2。此类方法涉及培养含有对AAV衣壳蛋白进行编码的核酸序列的宿主细胞；功能性rep基因；至少由AAV反向末端重复序列(ITR)和转基因构成的表达盒；以及足够的辅助功能以允许将表达盒包装到AAV衣壳蛋白中。已经描述了产生衣壳的方法、其编码序列以及用于产生rAAV病毒载体的方法。参见，例如，Gao等人，Proc.Natl.Acad.Sci.U.SA.100(10)，6081-6086(2003)和US2013/0045186A1。
在一个实施例中，提供了一种可用于产生重组AAV的产生细胞培养物。此类细胞培养物含有在宿主细胞中表达AAV衣壳蛋白的核酸；适合于包装到AAV衣壳中的核酸分子，例如，含有AAV ITR和编码基因产物的非AAV核酸序列的载体基因组，该基因产物与指导产物在宿主细胞中表达的序列可操作地连接；以及足够的AAV rep功能和腺病毒辅助功能，以允许将核酸分子包装到重组AAV衣壳中。在一个实施例中，细胞培养物由哺乳动物细胞(例如，人胚肾293细胞以及其它细胞)或昆虫细胞(例如，杆状病毒)构成。
任选地，rep功能由AAV而不是提供衣壳的AAV提供。例如，rep可以是但不限于AAV1rep蛋白、AAV2 rep蛋白、AAV3 rep蛋白、AAV4 rep蛋白、AAV5 rep蛋白、AAV6 rep蛋白、AAV7rep蛋白、AAV8 rep蛋白；或rep 78、rep 68、rep 52、rep 40、rep68/78和rep40/52；或其片段；或其它来源。任选地，rep和cap序列在细胞培养物中位于同一遗传元件上。Rep序列与cap基因之间可以存在间隔子。这些AAV或突变体AAV衣壳序列中的任一种都可以在外源性调控控制序列的控制下，所述外源性调控控制序列指导其在宿主细胞中表达。
在一个实施例中，在合适的细胞培养物(例如，HEK 293)细胞中制造细胞。用于制造本文所描述的基因疗法载体的方法包含本领域众所周知的方法，如产生用于产生基因疗法载体的质粒DNA、产生载体以及纯化载体。在一些实施例中，基因疗法载体是AAV载体，并且所产生的质粒是编码AAV基因组和目的基因的AAV顺式质粒、含有AAV rep和cap基因的AAV反式质粒以及腺病毒辅助质粒。载体产生过程可以包括方法步骤，如开始细胞培养、进行细胞传代、接种细胞、用质粒DNA转染细胞、将转染后介质交换为无血清介质以及采集含载体的细胞和介质。所采集的含载体的细胞和介质在本文中被称为粗细胞采集物。在又一个系统中，通过用基于杆状病毒的载体进行感染来将基因疗法载体引入到昆虫细胞中。关于这些生产系统的综述，一般参见例如Zhang等人，2009，“Adenovirus-adeno-associatedvirus hybrid for large-scale recombinant adeno-associated virus production(用于大规模重组腺相关病毒生产的腺病毒-腺相关病毒杂合体)”Human Gene Therapy 20：922-929，其各自的内容通过引用整体并入本文。制备和使用这些和其它AAV生产系统的方法也描述于以下美国专利中，其各自的内容以全文引用的方式并入本文中：5,139,941；5,741,683；6,057,152；6,204,059；6,268,213；6,491,907；6,660,514；6,951,753；7,094,604；7,172,893；7,201,898；7,229,823；和7,439,065。
此后，粗细胞采集物可以是本主题的方法步骤，如浓缩载体采集物、渗滤载体采集物、微流化载体采集物、核酸酶消化载体采集物、过滤经微流化的中间体、通过色谱粗纯化、通过超速离心法粗纯化、通过切向流过滤进行缓冲液交换和/或调配和过滤以制备大量载体。
在高盐浓度下进行两步亲和色谱法纯化，随后使用阴离子交换树脂色谱法来纯化载体药物产物并去除空衣壳。这些方法在国际专利公开WO 2017/160360中有更详细的描述，其通过引用并入本文。用于AAV8的纯化方法的国际专利公开WO 2017/100676，和用于rh10的纯化方法的国际专利公开WO 2017/100704，和用于AAV1的纯化方法的国际专利公开WO 2017/100674，均通过引用并入本文。
为了计算空颗粒和完整颗粒的含量，将所选样品(例如，在本文的实例中经过碘克沙醇(iodixanol)梯度纯化的制剂，其中GC#＝颗粒#)的VP3带体积相对于加载的GC颗粒进行作图。所得线性等式(y＝mx+c)用于计算测试制品峰的带状体积中的颗粒的数量。然后将加载的每20μL颗粒数量(pt)乘以50，以得到颗粒(pt)/mL。将Pt/mL除以GC/mL得到颗粒与基因组拷贝的比率(pt/GC)。Pt/mL-GC/mL得到空pt/mL。空pt/mL除以pt/mL并且x 100得到空颗粒的百分比。
通常，用于测定具有包装的基因组的空衣壳和AAV载体颗粒的方法是本领域已知的。参见例如Grimm等人，Gene Therapy(1999)6：1322-1330；Sommer等人，Molec.Ther.(2003)7：122-128。为了测试变性的衣壳，该方法包括使经处理的AAV原种经受SDS-聚丙烯酰胺凝胶电泳(由能够分离三种衣壳蛋白的任何凝胶组成，例如在缓冲液中含有3％-8％三乙酸盐的梯度凝胶)，然后运行凝胶直到分离出样品材料，并且将凝胶印迹到尼龙或硝酸纤维素膜(优选地尼龙)上。然后，将抗AAV衣壳抗体用作结合变性的衣壳蛋白的初级抗体，优选抗AAV衣壳单克隆抗体，最优选B1抗AAV-2单克隆抗体(Wobus等人，J.Virol.(2000)74：9281-9293)。然后使用次级抗体，该次级抗体与初级抗体结合并且含有一种用于检测与初级抗体的结合的装置，更优选地是含有与其共价结合的检测分子的抗IgG抗体，最优选地是与辣根过氧化物酶共价连接的绵羊抗小鼠IgG抗体。一种用于检测结合的方法用于半定量地确定初级抗体与次级抗体之间的结合，优选地是能够检测放射性同位素发射、电磁辐射或比色变化的检测方法，最优选地是化学发光检测试剂盒。例如，对于SDS-PAGE，可以从柱级分中取得样品并在含有还原剂(例如DTT)的SDS-PAGE上样缓冲液中加热，并在预浇注的梯度聚丙烯酰胺凝胶(例如，Novex)上解析衣壳蛋白。可以根据制造商的说明使用SilverXpress(加利福尼亚州英杰公司)或其它合适的染色方法(即SYPRO红宝石色或考马斯染色)进行银染色。在一个实施例中，可以通过定量实时PCR(Q-PCR)测量柱级分中的AAV载体基因组(vg)的浓度。将样品稀释并用DNA酶I(或另一种合适的核酸酶)消化以去除外源性DNA。在核酸酶失活后，使用引物和对引物之间的DNA序列具有特异性的TaqManTM荧光探针进一步稀释和扩增样品。在Applied Biosystems Prism 7700序列检测系统上测量每种样品达到所定义的荧光水平所需的周期的数量(阈值周期，Ct)。含有与AAV载体中所含序列相同的序列的质粒DNA用于在Q-PCR反应中产生标准曲线。从样品获得的周期阈值(Ct)的值用于通过相对于质粒标准曲线的Ct值对其进行归一化来确定载体基因组效价。也可以使用基于数字PCR的端点测定。
一方面，使用了经优化的q-PCR方法，该方法利用了广谱丝氨酸蛋白酶，例如蛋白酶K(如可从凯杰公司(Qiagen)商购获得)。更具体地，经优化的qPCR基因组效价测定与标准测定类似，不同之处在于在DNA酶I消化之后，将样品用蛋白酶K缓冲液稀释并用蛋白酶K处理，然后进行热失活。合适地，以等于样品大小的量用蛋白酶K缓冲液稀释样品。蛋白酶K缓冲液可以浓缩2倍或更多倍。通常，蛋白酶K处理为约0.2mg/mL，但是可以在0.1mg/mL至约1mg/mL之间变化。处理步骤通常在约55℃下进行持续约15分钟，但是可以在较低温度(例如，约37℃至约50℃)下进行持续较长的时间段(例如，约20分钟至约30分钟)，或者在较高的温度(例如，至多约60℃)下进行持续较短的时间段(例如，约5至10分钟)。类似地，热失活通常在约95℃下持续约15分钟，但是温度可以降低(例如，约70℃到约90℃)并且时间延长(例如，约20分钟到约30分钟)。然后将样品稀释(例如，1000倍)，并如标准测定中所描述的进行TaqMan分析。
另外地或可替代地，可以使用液滴数字PCR(ddPCR)。例如，已经描述了用于通过ddPCR确定单链和自身互补AAV载体基因组效价的方法。参见例如，M.Lock等人，Hum GeneTher Methods(人类基因疗法方法).2014年4月；25(2)：115-25.doi：10.1089/hgtb.2013.131.电子版2014年2月14日。ddPCR方法直接测量包壳的载体基因组的浓度。用DNA酶I处理样品以消化样品中存在的任何未衣壳化的DNA，然后用蛋白酶K处理以破坏衣壳。然后将样品稀释以适合测定范围。将样品与ddPCR Supermix混合，并使用靶向PCSK9基因(M2PCSK9)特异性的大范围核酸酶的序列特异性引物结合与该相同区域杂交的荧光标记探针完成检测。在Bio-Rad液滴发生器中处理20微升ddPCR反应混合物，并将ddPCR反应混合物分配至≥10,000个液滴中。液滴生成后，对ddPCR反应混合物进行PCR扩增，并使用Bio-Rad液滴读取器读取扩增的ddPCR反应混合物。
感染单位(IU)测定法可用于测定RC32细胞(表达HeLa细胞的rep2)中rAAV载体的有效摄取和复制。与先前公布的相似，已经采用了96孔终点形式。简言之，通过rAAV BDS的系列稀释和Ad5的均一稀释对RC32细胞进行共感染，其中每个rAAV稀释具有12个重复。感染后72小时，裂解细胞，进行qPCR以检测输入的rAAV载体扩增。将进行终点稀释50％组织培养感染剂量(TCID50)的计算(Spearman-Karber)以确定以IU/mL表示的感染滴度。由于“感染性”值取决于每个颗粒与细胞的接触、受体结合、内化、转运至细胞核和基因组复制，因此它们受测定几何结构和适当受体的存在以及所用细胞系中的结合后途径的影响。受体和结合后途径通常不在永生化细胞系中维持，因此感染性测定滴度不是存在的“感染性”颗粒的数目的绝对量度。然而，包壳的GC与“感染单位”的比率(描述为GC/IU比率)可以用作批次之间产品一致性的量度。
简而言之，用于从基因组缺陷型AAV中间体中分离具有包装的基因组序列的rAAV颗粒的方法涉及使包括重组AAV病毒颗粒和AAV衣壳蛋白中间体的悬浮液经受高效液相色谱法，其中AAV病毒颗粒和AAV中间体与在高pH下平衡的强阴离子交换树脂结合，并经受盐梯度，同时监测洗脱液在约260和约280下的紫外线吸光度。可以基于所选AAV调整pH。参见，例如，WO2017/160360(AAV9)、WO2017/100704(AAVrh10)、WO 2017/100676(例如，AAV8)和WO2017/100674(AAV1)，其通过引用并入本文。在此方法中，当A260/A280的比率达到拐点时，从洗脱的级分中收集AAV完整衣壳。在一个实例中，对于亲和色谱法步骤，可以将经过渗滤的产物应用于有效捕获AAV2血清型的Capture SelectTM Poros-AAV2/9亲和树脂(生命科技公司(Life Technologies))上。在这些离子条件下，显著百分比的残留的细胞DNA和蛋白质流过柱，而AAV颗粒则被有效捕获。
双载体系统
在另一方面，提供了用于治疗遗传性疾患的双载体系统。该系统包括(a)基因编辑组件，其包括编码靶向PCSK9的核酸酶的核酸序列，和任选地，指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；和(b)供体载体，其包含编码用于从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，且其中该系统进一步包含指导核酸酶特异性靶向天然PCSK9基因座的序列。该系统任选地包含允许靶细胞中的天然PCSK9用该双载体系统给药后被消除或减少的组件，例如，通过使用具有诱导型启动子的诱导剂。在一个实施例中，基因编辑组件包含在基因编辑载体中，该基因编辑载体包含表达盒，该表达盒包含编码核酸酶的核酸序列和指导该核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列。双载体的组分如本文所述。
虽然如果基因编辑组件与供体载体的比率为约1至约1，则该系统可能是有效的，但期望的是供体模板载体以超过基因编辑组件的量存在。在一个实施例中，编辑载体(a)与供体载体(b)的比率为约1∶3至约1∶100，或约1∶10。即使基因编辑酶(例如，Cas9或大范围核酸酶)由除AAV载体以外的来源额外地或替代地提供，也可维持该基因编辑酶与供体模板的这种比率。
在一个实施例中，双载体系统包括基因编辑AAV载体，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR；编码大范围核酸酶的序列，该大范围核酸酶在指导该大范围核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列控制下靶向PCSK9；和3′ITR；和(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR、5′同源定向重组(HDR)臂；转基因和指导转基因在靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
在另一个实施例中，双载体系统包括基因编辑AAV，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR；5′核定位信号(NLS)；编码Cas9的序列和指导SaCas9在包含PCSK9基因的靶细胞中的表达的调控序列；3′NLS；和3′ITR；和包含AAV衣壳和第二载体基因组的供体AAV载体，该第二载体基因组包含5′ITR；5′同源定向重组(HDR)臂；转基因和指导该转基因在靶细胞中的表达的调控序列；3′HDR臂；U6启动子；包含特异性结合该PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被该Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；和3′ITR。
在另一个实施例中，双载体系统包括基因编辑AAV载体，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR；U6启动子；包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；5′核定位信号(NLS)；编码Cas9的序列和指导该Cas9在包含该PCSK9基因的靶细胞中的表达的调控序列；3′NLS；和3′ITR；和供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导该转基因在该靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
在本文描述的系统的某些实施例中，基因编辑AAV载体和供体AAV载体具有相同的AAV衣壳。在其它实施例中，基因编辑AAV载体和供体AAV载体具有不同的AAV衣壳。在一些实施例中，AAV衣壳选自AAV8、AAV9、rh10、AAV6.2、AAV3B、hu37、rh79和rh64。
在某些实施例中，核酸酶是Cas9核酸酶，并且Cas9选自金黄色葡萄球菌或化脓性链球菌Cas9。
在某些实施例中，核酸酶和/或转基因处于组织特异性启动子的控制之下。在某些实施例中，核酸酶和/或转基因处于组成型启动子的控制下。在某些实施例中，核酸酶和/或转基因处于诱导型启动子的控制下。在某些实施例中，核酸酶和/或转基因处于肝特异性启动子的控制之下，任选地为人甲状腺素结合球蛋白(TBG)启动子或杂合肝启动子(HLP)。在某些实施例中，该系统进一步包含诱导剂。
在另一个实施例中，该系统包括(a)基因编辑组件，其包括编码靶向PCSK9的核酸酶的核酸序列和指导该核酸酶在靶细胞中的表达的调控序列，该靶细胞包含包封在LNP中的PCSK9基因；和(b)供体载体，其包含包封在LNP中的编码从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，且其中该系统进一步包含指导核酸酶特异性靶向天然PCSK9基因座的序列。该系统任选地包含允许靶细胞中的天然PCSK9用该双载体系统给药后被消除或减少的组件，例如，通过使用具有诱导型启动子的诱导剂。
在另一个实施例中，该系统包括(a)基因编辑组件，其包括编码靶向PCSK9的核酸酶的核酸序列和指导该核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列，其中该基因编辑组件由AAV载体提供；和(b)供体载体，其包含包封在LNP中的编码从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，且其中该系统进一步包含指导核酸酶特异性靶向天然PCSK9基因座的序列。该系统任选地包含允许靶细胞中的天然PCSK9用该双载体系统给药后被消除或减少的组件，例如，通过使用具有诱导型启动子的诱导剂。
在另一个实施例中，该系统包括(a)基因编辑组件，其包括编码靶向PCSK9的核酸酶的核酸序列和指导该核酸酶在靶细胞中的表达的调控序列，该靶细胞包含包封在LNP中的PCSK9基因；和(b)供体载体，其包含编码从PCSK9基因座表达的外源产物的核酸序列，其中该供体载体是AAV载体，其中插入的核酸序列不编码PCSK9，并且其中该系统进一步包含指导核酸酶特异性靶向天然PCSK9基因座的序列。该系统任选地包含允许靶细胞中的天然PCSK9用该双载体系统给药后被消除或减少的组件，例如，通过使用具有诱导型启动子的诱导剂。
在一个实施例中，该双载体系统包括(a)LNP，其包含编码大范围核酸酶的mRNA，该大范围核酸酶在调控序列的控制下靶向PCSK9，该调控序列指导大范围核酸酶在包含PCSK9基因的靶细胞中的表达；和(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导该转基因在该靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
在另一个实施例中，双载体系统包括(a)LNP，其包含含有编码Cas9的序列的核酸和含有特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；和(b)供体AAV载体，包含AAV衣壳和载体基因组，该载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导该转基因在该靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。编码Cas9的序列作为mRNA提供。
在另一个实施例中，双载体系统包括基因编辑AAV载体，其包含AAV衣壳和第一载体基因组，该第一载体基因组包含5′ITR；U6启动子；包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；5′核定位信号(NLS)；编码Cas9的序列和指导该Cas9在包含该PCSK9基因的靶细胞中的表达的调控序列；3′NLS；和3′ITR；和供体AAV载体，其包含AAV衣壳和第二载体基因组，该第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导该转基因在该靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
药物组合物
在另一方面，提供了药物组合物，其包含含有rAAV基因编辑载体的第一rAAV原种，该rAAV基因编辑载体包含表达盒，该表达盒包含编码靶向PCSK9的核酸酶的核酸序列和指导核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；和包含rAAV供体载体的第二rAAV原种，该rAAV供体载体包含转基因盒，该转基因盒包含编码转基因的核酸序列和指导转基因在靶细胞中的表达的调控序列。该药物组合物含有任选的载体、赋形剂和/或防腐剂。在一些实施例中，供体载体进一步包括转基因盒的5′和3′的同源定向重组(HDR)臂。在一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAVrh79衣壳。在另一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAVrh.90衣壳。在另一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAVhu.37衣壳。在一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAV8衣壳。在一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAVrh.91衣壳。在一个实施例中，用于供体载体、基因编辑载体或两者的AAV衣壳是AAVhu.68衣壳。
如本文所用，“载体”包含任何和所有溶剂、分散培养基、媒剂、涂层、稀释剂、抗菌剂和抗真菌剂、等渗剂和吸收缓释剂、缓冲液、载体溶液、悬浮液、胶体等。此类培养基和药剂用于药物活性物质的用途在本领域是众所周知的。补充性活性成分也可以掺入到组合物中。短语“药学上可接受的”是指当向宿主施用时不会产生过敏或类似不良反应的分子实体和组合物。如脂质体、纳米胶囊、微颗粒、微球、脂质颗粒、囊泡等递送载剂可以用于将本发明的组合物引入到合适的宿主细胞中。具体地，rAAV载体递送的载体基因组可以被调配成用于递送或包封在脂质颗粒、脂质体、囊泡、纳米球或纳米颗粒等中。
在一个实施例中，组合物包含适合于递送到受试者的最终调配物，该组合物是例如缓冲到生理上相容的pH和盐浓度的水性液体悬浮液。任选地，调配物中存在一种或多种表面活性剂。在另一个实施例中，可以将组合物作为稀释以向受试者施用的浓缩物运输。在其它实施例中，可以在施用时将组合物冻干并重构。
本领域熟知的用于制备制剂的方法和试剂描述于例如“Remington′sPharmaceutical Sciences，”MackPublishing Company，Easton，Pa中。制剂可以包含，例如赋形剂、载体、稳定剂或稀释剂，例如无菌水、盐水、聚亚烷基二醇例如聚乙二醇、植物来源的油，或氢化萘、防腐剂(例如十八烷基二甲基苄基、氯化铵、氯化六甲铵、苯扎氯铵、苄索氯铵、苯酚、丁醇或苄醇、对羟基苯甲酸烷基酯例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、儿茶酚、间苯二酚、环己醇、3-戊醇和间甲酚)、低分子量多肽、蛋白质例如血清白蛋白、明胶或免疫球蛋白、亲水性聚合物例如聚乙烯吡咯烷酮、氨基酸例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸和赖氨酸、单糖、二糖和其它碳水化合物包括葡萄糖、甘露糖和糊精，螯合剂如EDTA、糖例如蔗糖、甘露醇、海藻糖或山梨醇；成盐反离子，如钠；金属复合物(例如Zn-蛋白复合物)；和/或非离子表面活性剂，如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
活性成分还可以被包封在例如通过凝聚技术或通过界面聚合制备的微胶囊中，例如分别为羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊，其包封在胶体药物递送系统(例如脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)中或包封在粗乳液中。此类技术公开于Remington′s Pharmaceutical Sciences，第16版，Osol，A.编辑(1980)。
可以从无毒的非离子型表面活性剂中选择合适的表面活性剂或表面活性剂的组合。在一个实施例中，选择终止于伯羟基的双官能嵌段共聚物表面活性剂，例如F68[BASF]，也称为泊洛沙姆188，其具有中性pH，平均分子量为8400。可以选择其它表面活性剂和其它泊洛沙姆，即非离子型三嵌段共聚物，所述非离子型三嵌段共聚物由侧接聚氧乙烯(聚(环氧乙烷))的两个亲水链的聚氧丙烯(聚(环氧丙烷))的中心疏水链、SOLUTOLHS15(聚乙二醇-15羟基硬脂酸酯)、LABRASOL(聚氧辛酸甘油酯)、聚氧10油醚、TWEEN(聚氧乙烯山梨聚糖脂肪酸酯)、乙醇和聚乙二醇构成。在一个实施例中，调配物含有泊洛沙姆。这些共聚物通常以字母“P”(对于泊洛沙姆)命名，后跟三个数字：前两位数字x100给出了聚氧丙烯核的近似分子量，并且最后一位数字x 10给出了聚氧乙烯含量的百分比。在一个实施例中，选择了泊洛沙姆188。表面活性剂可以以悬浮液的至多约0.0005％至约0.001％的量存在。
以足够的量施用载体以转染细胞并提供足够水平的基因转移和表达，以便提供治疗益处，而不会产生过度的副作用或具有医学上可接受的生理作用，这可以由医学领域的技术人员确定。常规的和药学上可接受的施用途径包括但不限于直接递送至所需器官(例如，肝脏(任选地通过肝动脉)、肺、心脏、眼、肾)、口服、吸入、鼻内、鞘内、气管内、动脉内、眼内、静脉内、肌内、皮下、皮内和其它肠胃外给药途径。如果期望，可以组合施用途径。
病毒载体的剂量主要取决于如所治疗的病状、患者的年龄、体重和健康状况等因素，并且因此在患者之间可能有所不同。例如，治疗有效的人类剂量的病毒载体通常在约25-约1000微升至约100mL的溶液的范围内，该溶液含有浓度为约1x109至1x1016的基因组病毒载体。调整剂量以平衡治疗益处与任何副作用，并且此类剂量可以根据采用重组载体的治疗应用而变化。可以监测转基因产物的表达水平以确定所得病毒载体的剂量频率，优选地含有微型基因的AAV载体。任选地，与出于治疗目的描述的剂量方案类似的剂量方案可以用于使用本发明的组合物进行免疫。
载体组合物可以配制成剂量单位，以包含约1.0x109GC至约1.0x1016GC(以治疗平均体重70kg的受试者)范围内的复制缺陷型病毒量，包括该范围内的所有整数或分数量，对于人类患者优选1.0x1012GC至1.0x1014GC。在一个实施例中，组合物被配制成每剂量包含至少1x109、2x109、3x109、4x109、5x109、6x109、7x109、8x109或9x109GC，包括在该范围内的所有整数或分数量。在另一个实施例中，将组合物调配成每剂量含有至少1x1010、2x1010、3x1010、4x1010、5x1010、6x1010、7x1010、8x1010或9x1010GC，包含范围内的所有整数或分数量。在另一个实施例中，将组合物调配成每剂量含有至少1x1011、2x1011、3x1011、4x1011、5x1011、6x1011、7x1011、8x1011或9x1011GC，包含范围内的所有整数或分数量。在另一个实施例中，组合物被配制成每剂量含有至少1x1012、2x1012、3x1012、4x1012、5x1012、6x1012、7x1012、8x1012或9x1012GC，包括在该范围内的所有整数或分数量。在另一个实施例中，组合物被配制成每剂量含有至少1x1013、2x1013、3x1013、4x1013、5x1013、6x1013、7x1013、8x1013或9x1013GC，包括在该范围内的所有整数或分数量。在另一个实施例中，组合物被配制成每剂量含有至少1x1014、2x1014、3x1014、4x1014、5x1014、6x1014、7x1014、8x1014或9x1014GC，包括在该范围内的所有整数或分数量。在另一个实施例中，组合物被配制成每剂量含有至少1x1015、2x1015、3x1015、4x1015、5x1015、6x1015、7x1015、8x1015或9x1015GC，包括在该范围内的所有整数或分数量。在一个实施例中，对于人类应用，剂量的范围可以为每剂量1x1010至约1x1012GC，包含所述范围内的所有整数或分数量。
这些上述剂量可以以各种体积的载剂、赋形剂或缓冲剂调配物施用，范围为约25到约1000微升或更大的体积，包含所述范围内的所有数字，这取决于待治疗区域的大小、所使用的病毒效价、施用途径以及所述方法的所期望的效果。
可以选择任何合适的施用途径。因此，药物组合物可以配制成任何合适的施用途径，例如，液体溶液或悬浮液的形式(例如，用于静脉内施用、用于口服施用等)。可选地，药物组合物可以是固体形式(例如，片剂或胶囊的形式，例如用于口服施用)。在一些实施例中，药物组合物可以是粉末、滴剂、气雾剂等形式。
在一个方面，本文提供了药物组合物，其在制剂缓冲液中包含至少细小病毒载体，该细小病毒载体包含如本文所述的至少一种基因编辑载体和至少一种供体载体。在某些实施例中，药物组合物包含不同载体群体的组合。在一个实施例中，提供了在制剂缓冲液中包含本文所述的单个rAAV群体的药物组合物。本文提供的方法提供了两种单独的含载体的悬浮液的共同施用。
方法
本文提供的组合物可用于治疗各种遗传性疾患，包括肝代谢疾患。在某些实施例中，组合物可用于治疗鸟氨酸氨甲酰基转移酶。在其它实施例中，组合物可用于治疗家族性高胆固醇血症。在其它实施例中，组合物可用于治疗苯丙酮尿症。
可治疗的示例性肝脏疾患或病症包括但不限于甲型肝炎、乙型肝炎、丙型肝炎、自身免疫性肝炎、原发性胆管炎、原发性硬化性胆管炎、血色素沉着病、威尔逊氏病、α-1抗胰蛋白酶缺乏症、肝癌、胆管癌、肝腺瘤、转甲状腺素蛋白(TTR)、基于前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)的疾患或病症，或其任何组合。其它疾患包括1A型糖原贮积病或缺陷(GSD1)、PEPCK缺陷、CDKL5缺陷、半乳糖血症、苯丙酮尿症(PKU)、1型原发性高草酸盐尿症、枫糖尿症、1型酪氨酸血症、甲基丙二酸血症、中链乙酰辅酶A缺陷、鸟氨酸氨甲酰基转移酶缺陷、瓜氨酸血症；卵磷脂-胆固醇酰基转移酶(LCAT)缺乏症，甲基丙二酸血症(MMA)，尼曼-匹克病，丙酸血症(PA)；家族性高胆固醇血症(FH)、痴呆、脂蛋白脂酶缺乏、Crigler-Najjar病、重症联合免疫缺陷病、痛风和Lesch-Nyan综合征、生物素蛋白酶缺乏、法布里病、GM1神经节苷脂贮积症、Wilson病、高歇病2型和3型、Zellweger综合征、异染性脑白质营养不良、克拉伯病、庞贝氏症、A型尼曼匹克症、精酰琥珀酸尿症、成人发病II型瓜氨酸血症、尿素循环障碍；Farber脂肉芽肿病、天冬氨酰-葡糖胺尿症、岩藻糖苷贮积症、α-甘露糖苷贮积症、急性间歇性卟啉症(AIP)、α-1抗胰蛋白酶缺陷(肺气肿)、由地中海贫血或肾衰竭引起的贫血、缺血性疾患、例如在动脉粥样硬化、血栓形成或栓塞中所见的血管闭塞、帕金森病、充血性心力衰竭、肌营养不良和糖尿病。
在本文所述的某些方法中，天然PCSK9表达被降低或消除，并且转基因从天然PCSK9基因座中的插入序列表达。在另一个实施例中，天然PCSK9表达被降低或消除，并且转基因被外源表达，即没有整合到受试者的基因组中。
本文提供了通过共同施用如本文所述的双载体系统来治疗人的疾患的方法。
在一个实施例中，提供了治疗受试者的肝代谢疾患的方法。该方法包括对患有肝代谢疾患的受试者共同施用基因编辑AAV载体，该基因编辑AAV载体包含编码靶向PCSK9的核酸酶的序列和指导该核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；和包含转基因和指导转基因在靶细胞中的表达的调控序列的供体AAV载体。在另一个实施例中，该方法包括给患有肝代谢疾患的受试者共同施用LNP，该LNP包含编码Cas9核酸酶和sgRNA的序列，该sgRNA在包含PCSK9基因的靶细胞中靶向PCSK9；和供体AAV载体，其包含转基因和指导转基因在靶细胞中的表达的调控序列。在一个实施例中，受试者是新生儿。
在某些实施例中，基因编辑AAV载体和供体载体通过相同的途径基本上同时递送。在其它实施例中，首先递送基因编辑载体。在其它实施例中，首先递送供体载体。
在一个实施例中，rAAV的剂量为每剂约1x109GC至约1x1015基因组拷贝(GC)(以治疗平均体重70kg的受试者)，并且优选地1.0x1012GC至2.0x1015GC用于人类患者。在另一个实施例中，剂量小于约1x1014GC/kg受试者体重。在某些实施例中，向患者施用的剂量为至少约1.0x109GC/kg、约1.5x109GC/kg、约2.0x109GC/kg、约2.5x109GC/kg、约3.0x109GC/kg、约3.5x109GC/kg、约4.0x109GC/kg、约4.5x109GC/kg、约5.0x109GC/kg、约5.5x109GC/kg、约6.0x109GC/kg、约6.5x109GC/kg、约7.0x109GC/kg、约7.5x109GC/kg、约8.0x109GC/kg、约8.5x109GC/kg、约9.0x109GC/kg、约9.5x109GC/kg、约1.0x1010GC/kg、约1.5x1010GC/kg、约2.0x1010GC/kg、约2.5x1010GC/kg、约3.0x1010GC/kg、约3.5x1010GC/kg、约4.0x1010GC/kg、约4.5x1010GC/kg、约5.0x1010GC/kg、约5.5x1010GC/kg、约6.0x1010GC/kg、约6.5x1010GC/kg、约7.0x1010GC/kg、约7.5x1010GC/kg、约8.0x1010GC/kg、约8.5x1010GC/kg、约9.0x1010GC/kg、约9.5x1010GC/kg、约1.0x1011GC/kg、约1.5x1011GC/kg、约2.0x1011GC/kg、约2.5x1011GC/kg、约3.0x1011GC/kg、约3.5x1011GC/kg、约4.0x1011GC/kg、约4.5x1011GC/kg、约5.0x1011GC/kg、约5.5x1011GC/kg、约6.0x1011GC/kg、约6.5x1011GC/kg、约7.0x1011GC/kg、约7.5x1011GC/kg、约8.0x1011GC/kg、约8.5x1011GC/kg、约9.0x1011GC/kg、约9.5x1011GC/kg、约1.0x1012GC/kg、约1.5x1012GC/kg、约2.0x1012GC/kg、约2.5x1012GC/kg、约3.0x1012GC/kg、约3.5x1012GC/kg、约4.0x1012GC/kg、约4.5x1012GC/kg、约5.0x1012GC/kg、约5.5x1012GC/kg、约6.0x1012GC/kg、约6.5x1012GC/kg、约7.0x1012GC/kg、约7.5x1012GC/kg、约8.0x1012GC/kg、约8.5x1012GC/kg、约9.0x1012GC/kg、约9.5x1012GC/kg、约1.0x1013GC/kg、约1.5x1013GC/kg、约2.0x1013GC/kg、约2.5x1013GC/kg、约3.0x1013GC/kg、约3.5x1013GC/kg、约4.0x1013GC/kg、约4.5x1013GC/kg、约5.0x1013GC/kg、约5.5x1013GC/kg、约6.0x1013GC/kg、约6.5x1013GC/kg、约7.0x1013GC/kg、约7.5x1013GC/kg、约8.0x1013GC/kg、约8.5x1013GC/kg、约9.0x1013GC/kg、约9.5x1013GC/kg或约1.0x1014GC/kg受试者体重。
可以使用本文描述的组合物治疗的合适疾患的其他实例是家族性高胆固醇血症、肌营养不良、囊性纤维化和罕见病或孤儿病。此类罕见病的实例可以包含脊髓性肌萎缩症、亨廷顿氏病(Huntingdon′s Disease)、雷特综合征(Rett Syndrome)、肌萎缩侧索硬化症(ALS)、杜氏肌营养不良(Duchenne Type Muscular dystrophy)、弗里德里希共济失调(Friedrichs Ataxia)、2型脊髓小脑性共济失调(SCA2)/ALS；颗粒蛋白前体(PRGN)(与非阿尔茨海默氏病的大脑变性相关，包含额颞叶痴呆(FTD)、进行性非流利性失语症(PNFA)和语义性痴呆)等。参见例如，www.orpha.net/consor/cgi-bin/Disease_Search_List.php；rarediseases.info.nih.gov/diseases。由本文描述的转基因指示的其他疾患也可以使用本文描述的方法来治疗。
以足够的量施用载体以转染细胞并提供足够水平的基因转移和表达，以便提供治疗益处，而不会产生过度的副作用或具有医学上可接受的生理作用，这可以由医学领域的技术人员确定。期望的施用途径包括直接递送至期望的器官(例如，肝(任选地经由肝动脉)、肺、心脏、眼、肾)、口服、吸入、鼻内、气管内、鞘内、动脉内、眼内、静脉内、肌内、皮下、皮内和其他肠胃外施用途径。如果期望，可以组合施用途径。
如果产生足够量的功能酶或蛋白质以改善患者的状况，则本文所述的系统可以是治疗上有用的。在某些实施例中，低至健康患者的5％的基因表达水平将为患者提供足够的治疗效果，以便患者可用非基因疗法治疗。在其它实施例中，基因表达水平是在人(或其它动物受试者)中观察到的正常范围(水平)的至少约5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％，至高达100％。例如，“功能酶”是指编码野生型酶(例如，鸟鸟氨酸氨甲酰基转移酶)的基因，该基因提供野生型酶或其天然变体或多晶型物的至少约5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％，或约相同、或大于100％的生物活性水平，该天然变体或多晶型物不与疾患相关。更特别地，由于杂合患者可具有低至约50％或更低的酶功能水平，有效治疗可不需要将酶活性替代至“正常”范围内或非缺陷患者的水平。类似地，不具有可检测量的酶的患者可以通过将酶功能递送至低于100％的活性水平而得到拯救，并且可以任选地随后经受进一步的治疗。在某些实施例中，当基因功能通过供体模板递送时，患者可以表达比在“正常的”健康受试者中发现的更高的水平。在其它实施例中，当需要降低基因表达时，多达20％降低至50％降低，或高达约100％降低，可提供所需的益处。如本文所述，本文所述的疗法可与其它治疗，即，用于受试者(患者)诊断的护理标准联合使用。
在一个实施例中，该方法进一步包括向受试者施用免疫抑制联合疗法。例如，如果检测到针对AAV衣壳的不期望的高水平的中和抗体，则可在递送rAAV或所公开的组合物之前开始这种免疫抑制性联合疗法。在某些实施例中，作为预防措施，联合疗法也可以在递送rAAV之前开始。在某些实施例中，例如如果在治疗后观察到不期望的免疫应答，则在递送rAAV后开始免疫抑制联合疗法。
用于这种联合疗法的免疫抑制剂包括但不限于糖皮质激素、类固醇、抗代谢物、T细胞抑制剂、大环内酯(例如雷帕霉素或雷帕霉素类似物)和细胞抑制剂，包括烷化剂、抗代谢物、细胞毒性抗生素、抗体或对亲免素有活性的试剂。免疫抑制剂可以包含强的松、氮芥、亚硝基脲、铂化合物、甲氨蝶呤、硫唑嘌呤、巯嘌呤、氟尿嘧啶、更生霉素(dactinomycin)、蒽环霉素(anthracycline)、丝裂霉素C、博来霉素(bleomycin)、光神霉素(mithramycin)、IL-2受体(CD25)或CD3定向抗体、抗IL-2抗体、环孢素、他克莫司(tacrolimus)、西罗莫司(sirolimus)、IFN-β、IFN-γ、阿片类或TNF-α(肿瘤坏死因子-α)结合剂。在某些实施例中，在rAAV施用之前，可以从第0天、第1天、第2天、第7天或第更多天开始免疫抑制疗法，或者在rAAV施用之后，可以从第0天、第1天、第2天、第3天、第7天或第更多天开始免疫抑制疗法。这种疗法可以包括在同一天使用单一药物(例如泼尼松龙)或两种或多种药物(例如泼尼松龙、莫夫替尔(MMF)和/或西罗莫司(即雷帕霉素))的共同施用。可以在基因疗法施用之后以相同的剂量或经过调整的剂量继续使用这些药物中的一种或多种药物。根据需要，此类疗法可以持续约1周(7天)、两周、三周、约60天或更长时间。在某些实施例中，选择无他克莫司的方案。
在另一个实施例中，该方法包括与标准OTC疗法的共同治疗。OTC缺乏的治疗主要集中在血氨水平的饮食管理上，以避免高氨血症或在高氨血症发作期间(NORD，2021)从血液中除去过量的氨。患有OTC缺乏的个体遵守限制其蛋白质摄入的饮食限制以控制血氨水平。在婴儿中必须小心平衡饮食限制，婴儿需要消耗足够的蛋白质以确保适当的生长，同时避免过量的蛋白质摄入，过量的蛋白质摄入可能引发高氨血症的发作(Berry和Steiner， 2001)。因此，婴儿接受补充了必需氨基酸的高热量、低蛋白饮食。在高氨血症发作中，可能会在24小时内去除患者饮食中的所有蛋白质(NORD，2021)。
有几种药物设计以刺激从血流中除去氮。苯丁酸钠(Buphenyl)被美国食品和药物管理局(FDA)批准用于治疗OTC缺乏患者的慢性高氨血症。一旦代谢，Buphenyl转化为苯乙酸盐，苯乙酸盐与谷氨酰胺结合形成苯乙酰谷氨酰胺，经肾脏排出，为氮排泄提供了另一种途径。苯丁酸甘油酯(Ravicti)也被FDA批准用于治疗患有尿素循环障碍的患者的慢性高氨血症。与Buphenyl一样，Ravicti被转化为苯乙酸盐，并遵循相同的分泌氮的机制(Lichter-Konecki等人，1993；Gordon，2003；Magellan，2021)。最后，FDA批准Ammonul(苯乙酸钠和苯甲酸钠制剂)作为辅助疗法用于治疗患有尿素循环障碍的患者的急性高氨血症。Ammonul的苯乙酸钠组分遵循与Buphenyl和Ravicti产生的苯乙酸代谢物相同的氮排泄机制。Ammonul的苯甲酸钠组分与甘氨酸缀合形成马尿酸，马尿酸通过肾脏排泄并通过该过程去除氮。苯甲酸钠也作为口服制剂用于长期维持OTC缺乏，并且通常比Buphenyl和Ravicti更优选，因为认为它具有较少的副作用。(Lichter-Konecki等人，1993)。
一方面，提供了使用核酸酶表达盒治疗患有鸟氨酸氨甲酰基转移酶(OTC)缺乏的患者的方法，该核酸酶表达盒包含在如本文所述的启动子控制下识别人PCSK9基因内的位点的大范围核酸酶编码序列。该方法还包括施用携带SEQ ID NO：17的OTC转基因或与之具有至少90％同一性的序列的表达盒，如本文所述。这种表达盒可以通过病毒或非病毒载体递送。在某些实施例中，表达盒可以使用LNP来递送。天然人OTC编码序列如SEQ ID NO：30所示。SEQ ID NO：17和SEQ ID NO：30具有约75.89％的同一性。
在另一方面，提供了使用核酸酶表达盒治疗患有鸟氨酸氨甲酰基转移酶(OTC)缺乏症的患者的方法，该核酸酶表达盒包含识别人PCSK9基因内的位点的sgRNA和Cas9编码序列。该方法还包括施用携带SEQ ID NO：17的OTC转基因或与之具有至少90％同一性的序列的表达盒，如本文所述。这种表达盒可以通过病毒或非病毒载体递送。在某些实施例中，表达盒可以使用LNP来递送。
存在多种体内或体外测量OTC表达和活性水平的测定方法。参见，例如，X Ye，等人，1996，Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors(用腺病毒载体在鸟氨酸氨甲酰基转移酶缺乏的成年小鼠中进行长期的代谢校正).J Biol Chem 271：3639-3646)。例如，OTC酶活性可以使用液相色谱质谱稳定同位素稀释法来检测归一化为[1，2，3，4，5-13C5]瓜氨酸(98％13C)的瓜氨酸的形成来测量。该方法改编自先前开发的用于检测N-乙酰谷氨酸合酶活性的测定法[Morizono H，等人，Mammalian N-acetylglutamate synthase(哺乳动物N-乙酰谷氨酸合酶).Mol GenetMetab.2004；81(增刊1)：S4-11.]。将新鲜冷冻肝脏的薄片称重，并在含有10mM HEPES、0.5％Triton X-100、2.0mM EDTA和0.5mM DTT的缓冲液中短暂匀浆。调节均化缓冲液的体积以获得50mg/ml的组织。使用250μg肝组织在50mM Tris醋酸盐、4mM鸟氨酸、5mM氨基甲酰磷酸盐(pH 8.3)中测量酶活性。通过添加溶解在pH 8.3的50mM Tris-乙酸盐中的新鲜制备的50mM氨基甲酰磷酸来启动酶活性，在25℃下进行5分钟，并通过添加等体积的含于30％TCA中的5mM13C5-瓜氨酸来淬灭酶活性。通过5分钟的微量离心分离碎片，并将上清液转移至小瓶中进行质谱分析。在等度条件下将10μL样品注入Agilent 1100系列LC-MS中，流动相为93％溶剂A(1ml三氟乙酸于1L水中)：7％溶剂B(1ml三氟乙酸于1L 1∶9的水/乙腈中)。对对应于瓜氨酸的峰[176.1质量：电荷比(m/z)]和13C5-瓜氨酸(181.1m/z)的峰进行定量，并将它们的比率与每次测定运行的瓜氨酸的标准曲线获得的比率进行比较。将样品标准化至总肝组织或使用Bio-Rad蛋白质测定试剂盒(Bio-Rad，Hercules，CA)测定的蛋白质浓度。也可使用其它不需要肝活检的测定。一种这样的测定是血浆氨基酸测定，其中评估谷氨酰胺和瓜氨酸的比率，并且如果谷氨酰胺高(＞800微升/升)且瓜氨酸低(例如，个位数)，则怀疑尿素循环缺陷。可测量血浆氨水平，并且约100微摩尔/升的浓度指示OTCD。如果患者过度换气，则可以评估血气；呼吸性碱中毒在OTCD中是常见的。尿液中的乳清酸，例如，肌酸大于约20微摩尔/毫摩尔，指示OTCD，别嘌呤醇激发测试后尿中乳清酸升高也是如此。OTCD的诊断标准已在Tuchman等人，2008，Urea Cycle Disorders Consortium(UCDC)ofthe Rare Disease Clinical Research Network(RDCRN)(罕见病临床研究网络(RDCRN)的尿素循环障碍联合会(UCDC)中阐述)。Tuchman M等人，罕见病临床研究网络联合会。Cross-sectional multicenter study of patients with urea cycle disorders in theUnited States(对美国尿素循环障碍患者进行的横断面多中心研究).Mol GenetMetab.2008；94：397-402，其通过引用并入本文。还参见http：//www.ncbi.nlm.nih.gov/books/NBK154378/，其中提供了OTCD的现行护理标准的讨论。
在某些实施例中，如本文所述的药物组合物中的核酸酶表达盒、非病毒载体、病毒载体(例如rAAV)或其任何一种可用于患者中的基因编辑。在某些实施例中，该方法可用于非胚胎基因编辑。在某些实施例中，患者是婴儿(例如，出生至约9个月)。在某些实施例中，患者比婴儿大，例如12个月或更大。
如本文所用的，“一个(a)”、“一个(an)”或“该(the)”可以意指一个或多个。例如，“一个”细胞可以指单个细胞或多个细胞。
如本文所用，术语“特异性”是指核酸酶仅在被称为识别序列的特定碱基对序列上或仅在一组特定的识别序列上识别和切割双链DNA分子的能力。该组识别序列将共享某些保守位置或序列基序，但可以在一个或多个位置处简并。高度特异性的核酸酶只能切割一个或极少数的识别序列。可以通过本领域已知的任何方法确定特异性。
缩写“sc”是指自身互补。“自身互补AAV”是指其中由重组AAV核酸序列所携带的编码区已经被设计成形成分子内双链DNA模板的构建体。感染后，未等待细胞介导的第二条链合成，而是两条互补的半scAAV将缔合以形成易于立即复制和转录的一条双链DNA(dsDNA)。参见，例如，D M McCarty等人，“Self-complementary recombinant adeno-associatedvirus(scAAV)vectors promote efficient transduction independently of DNAsynthesis(自身互补的重组腺相关病毒(scAAV)载体独立于DNA合成而促进高效转导”，Gene Therapy，(2001年8月)，第8卷，第16期，第1248-1254页。自身互补AAV描述于，例如，美国专利第6,596,535号；第7,125,717号；和第7,456,683号中，其中的每一个以其整体通过引用并入本文。
如本文所使用的，术语“可操作地连接”是指与目的基因邻接的表达控制序列以及以反式或在远处起作用以控制目的基因的表达控制序列两者。
用于描述核酸序列或蛋白质的术语“外源的”是指核酸或蛋白质并非天然存在于其在染色体或宿主细胞中存在的位置。外源核酸序列还指衍生自并插入相同表达盒或宿主细胞的序列，但其以非天然状态存在，例如不同的拷贝数，或在不同的调控元件的控制下。
术语“异源性”当结合蛋白质或核酸使用时指示蛋白质或核酸包括在自然界中未发现彼此间的相同关系的两个或更多个序列或子序列。例如，核酸通常是重组地产生的，具有来自不相关基因的布置成产生新的功能性核酸的两个或更多个序列。例如，在一个实施例中，核酸具有来自一种基因的布置成指导编码序列从不同基因表达的启动子。
如本文所用，术语“宿主细胞”可以指其中载体(例如，重组AAV)由生产质粒产生的包装细胞系。在替代方案中，术语“宿主细胞”可以指其中需要转基因表达的任何靶细胞。因此，“宿主细胞”是指含有外源或异源核酸序列的原核或真核细胞，该核酸序列通过任何方法引入细胞中，例如电穿孔、磷酸钙沉淀、显微注射、转化、病毒感染、转染、脂质体递送、膜融合技术、高速DNA包被的沉淀、病毒感染和原生质体融合。在本文中的某些实施例中，术语“宿主细胞”是指用于体外评估本文所述的组合物的各种哺乳动物物种的细胞的培养物。在本文的其他实施例中，术语“宿主细胞”是指用于产生和包装病毒载体或重组病毒的细胞。在其它实施例中，术语“宿主细胞”旨在指针对如本文所述的疾患或疾患在体内治疗的受试者的靶细胞。在某些实施例中，术语“宿主细胞”是肝细胞(liver cell)或肝细胞(hepatocyte)。
“受试者”是哺乳动物，例如人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪或非人灵长类动物，例如猴、黑猩猩、狒狒或大猩猩。患者是指人。兽医受试者是指非人哺乳动物。在某些实施例中，该受试者在其PCSK9基因中没有缺陷。
“复制缺陷型病毒”或“病毒载体”是指合成的或人工的病毒颗粒，其中含有目的基因的表达盒包装在病毒衣壳或包膜中，其中也包装在病毒衣壳或包膜中的任何病毒基因组序列是复制缺陷型的；即，它们不能产生子代病毒体，但保留了感染靶细胞的能力。在一个实施例中，病毒载体的基因组不包含对复制所需的酶进行编码的基因(基因组可以被工程化成“无肠的(gutless)”-仅含有目的基因，其侧接扩增和包装人工基因组所需的信号)，但是这些基因可以在产生期间供应。因此，这被认为可以安全地用于基因疗法，因为除非存在复制所需的病毒酶，否则不会发生通过子代病毒粒子进行的复制和感染。
在核酸序列的上下文中，术语“序列同一性”、“序列同一性百分比”或“相同百分比”是指两个序列中的残基在比对以获得最大对应性时是相同的。期望序列同一性比较的长度可以超过基因组的全长、基因编码序列的全长或至少约500至5000个核苷酸的片段。然而，较小片段之间的同一性，例如至少约9个核苷酸，通常至少约20至24个核苷酸，至少约28至32个核苷酸，至少约36个或更多个核苷酸的同一性，也可以是期望的。类似地，对于氨基酸序列，在蛋白质的全长或其片段上，可以容易地确定“序列同一性百分比”。合适地，片段长度为至少约8个氨基酸，并且可以至多约700个氨基酸。本文描述了合适片段的实例。
当提及氨基酸或其片段时，术语“基本同源性”或“基本类似性”表示当与另一个氨基酸(或其互补链)的适当核苷酸插入或缺失进行最佳比对时，至少约95到99％的比对序列具有氨基酸序列同一性。优选地，同源性跨越全长序列或其蛋白质，例如，cap蛋白质、rep蛋白质或其片段，其长度为至少8个氨基酸，或更期望地，至少15个氨基酸。本文描述了合适片段的实例。
术语“高度保守的”意指至少80％同一性、优选地至少90％同一性，并且更优选地超过97％同一性。通过使用本领域技术人员已知的算法和计算机程序，本领域技术人员可以容易地确定同一性。
通常，当提及两种不同的腺相关病毒之间的“同一性”、“同源性”或“类似性”时，参考“比对”序列来确定“同一性”、“同源性”或“类似性”。“比对”序列或“比对”是指与参考序列相比，通常含有对丢失的或另外的碱基或氨基酸的校正的多个核酸序列或蛋白质(氨基酸)序列。在实例中，使用公开的AAV9序列作为参考点执行AAV比对。使用多种公开或可商购获得的多序列比对程序中的任一种进行比对。此类程序的实例包含“ClustalΩ”、“ClustalW”、“CAP序列组装”、“MAP”和“MEME”，这些程序可通过因特网上的Web服务器进行访问。此类程序的其它来源是本领域技术人员已知的。可替代地，也使用了载体NTI实用程序。本领域已知的许多算法可以用于测量核苷酸序列同一性，包含上述程序中所含有的算法。作为另一个实例，可以使用GCG 6.1版本的程序FastaTM比较多核苷酸序列。FastaTM提供了查询序列与搜索序列之间最佳重叠区的比对和序列同一性百分比。例如，核酸序列之间的序列同一性百分比可以是使用如GCG 6.1版本中所提供的采用其默认参数(字号6和评分矩阵的NOPAM系数)的FastaTM所确定的，所述程序通过引用并入本文。多个序列比对程序也可用于氨基酸序列，这些程序例如“ClustalΩ”、“Clustal X”、“MAP”、“PIMA”、“MSA”、“BLOCKMAKER”、“MEME”和“Match-Box”程序。通常，以默认设置使用这些程序中的任何程序，尽管本领域技术人员可以根据需要改变这些设置。可替代地，本领域技术人员可以利用另一种算法或计算机程序，所述算法或计算机程序提供至少与参考算法和程序所提供的同一性或比对水平相同的同一性或比对。参见，例如，J.D.Thomson等人，Nucl.Acids.Res.，“Acomprehensive comparison of multiple sequence alignments(多个序列比对的全面比较)”，27(13)：2682-2690(1999)。
如本文所用，术语“约”是指相对于参考整数和其间的值±10％的变化。例如，“约”40个碱基对包括±4个(即36-44个，其中包括整数36、37、38、39、40、41、42、43、44)。对于其它值，特别是当提及百分比(例如，90％同一性、约10％方差或约36％错配)时，术语“约”包括在包括整数和分数两者的范围内的所有值。
贯穿本公开，本发明的各个方面可以以范围形式呈现。应当理解的是，采用范围格式的描述仅为了方便和简洁起见，并且不应当解释为是对本发明的范围的硬性限制。因此，对范围的描述应被视为已经具体公开了所有可能的子范围以及所述范围内的单独数值。例如，对如从1到6等范围的描述应当被认为是具有明确公开的子范围，如1到3、1到4、1到5、2到4、2到6、3到6等；以及所述范围内的单独数字，例如，1、2、2.7、3、4、5、5.3和6。无论范围的宽度为多少，这都适用。
如贯穿本说明书和权利要求书所使用的，术语“包含”、“含有”、“包括”及其变体包括其他组件、元素、整数、步骤等。相反地，术语“由……组成(consisting)”及其变体不包括其他组件、元件、整数、步骤等。
除非在本说明书中另有定义，否则本文所使用的技术术语和科学术语具有与本领域的普通技术人员和参照公开文本所通常理解的相同含义，这为本领域的技术人员提供了本申请中使用的许多术语的通用指南。
实例
鸟氨酸氨甲酰基转移酶(OTC)缺乏症是一种X连锁的尿素循环障碍，与高死亡率相关。尽管对于晚期发作的OTC缺乏症是一种有前途的治疗方法，但腺相关病毒(AAV)新生儿基因疗法仅能提供短期的治疗效果，因为非整合的基因组在肝细胞增殖过程中丧失了。核酸酶介导的OTC微型基因盒在基因组安全港中的位点特异性整合将为OTC缺陷患者提供长期的治疗益处。用于基因靶向的安全港之一是PCSK9基因，如外显子7区域。核酸酶可以是靶向PCSK9(ARCUS2)的工程化大范围核酸酶或具有靶向PCSK9的特异性sgRNA的CRISPR/Cas9。供体载体含有包括肝特异性启动子如TBG启动子的微型基因、密码子优化的hOTC编码序列和聚A序列。核酸酶和供体模板二者都可以通过AAV载体(双AAV载体系统)递送。在新生非人灵长类动物(NHP)中单次静脉内注射双AAV载体12周后，在12％肝细胞中证实了持续的转基因表达和有效的基因靶向。供体载体中的微型基因侧翼是同源定向重组(HDR)臂。
第一次证实NHP在体内核酸酶介导的基因靶向PCSK9基因座以在双AAV载体单次注射后作为新生儿或幼儿表达治疗性蛋白。用于基因靶向人/NHP PCSK9基因座的含有OTC微型基因的供体载体的组合物并没有在治疗OTC缺乏的临床中经过测试。我们将测试hOTC供体载体在新生NHP中的基因靶向效率和在新生转基因OTC缺陷型小鼠中的效力。
许多代谢疾患需要早期干预和治疗；然而，由于新生儿阶段快速的肝脏增殖和AAV载体的非整合性，AAV介导的新生儿基因治疗是不稳定的。治疗性微型基因盒在安全港中的靶向整合将在基因组水平上持续表达治疗性基因，并且治疗效果将通过细胞分裂而维持。对于许多代谢疾患如OTC缺乏，需要在肝脏中获得足够的转导效率以获得临床益处。
我们描述了一种用于治疗鸟氨酸氨甲酰基转移酶缺乏(OTCD)的基因组编辑方法，该OTCD可引起婴儿期高氨血症的致死性发作。基因组编辑的目的是使治疗效果持久并在所有OTCD患者中实现而不依赖于他们的突变。我们提出通过用两种AAV载体治疗存活的新生儿来实现这一点：一种是递送核酸酶以在安全港位点产生双链断裂，第二种是递送OTC微型基因以敲入该位点。我们的假设是新生肝脏的分裂肝细胞将有助于OTC基因的有效敲入，并将通过稀释消除非整合的输入载体基因组。我们决定使用PCSK9基因作为安全位点，并使用称为ARCUS的大范围核酸酶靶向它，这是基于我们以前在成年猕猴中的工作，该工作显示AAV递送ARCUS后PCSK9的安全、有效和稳定的降低。我们对OTCD基因组编辑的初步研究是在OTC缺陷型小鼠中进行的，该小鼠通过内源PCSK9基因的外显子7的种系修饰而变得针对PCSK9ARCUS核酸酶敏感。将两种载体注射到新生小鼠中导致人OTC微型基因的有效敲入和当用高蛋白饮食攻击时针对致死性高氨血症的保护。在临床研究的准备中，我们评价了新生和幼年猕猴的关键安全性和功效参数。总共24只动物用AAV载体处理，分析包括在3个月和12个月时对肝活检的检查。在这些研究中，我们评价了以下参数对编辑效率和毒性的影响：转基因(人因子IX和人OTC)、驱动ARCUS的启动子、分支E衣壳、转基因侧翼的供体长度和给药时猕猴的年龄。我们在此报告16/24只动物的初步数据，其至少包括3个月的活检结果。我们发现，在任何经ARCUS处理的动物中，AAV载体的注射是相当安全的，没有转氨酶升高或肝脏组织病理学的证据。灵长类动物模型中功效的关键量度是转导效率，其通过原位杂交和免疫染色分别检测表达人OTC mRNA和蛋白质的细胞来测量。用在第一载体中使用具有TBG启动子的驱动ARCUS的新分支E衣壳和在供体载体上使用500bp侧翼同源臂的载体获得了最高和最一致的结果。用这种组合，我们实现了10.0±6.4％(N＝6)的转导，其高于我们认为可以为患者提供显著益处的阈值，即～5％的OTC表达细胞。初步数据表明，编辑水平在一年内是稳定的，并且当注射到长达3个月的猕猴中时，可以实现有效的靶向插入。PCSK9靶基因座的分子分析表明，绝大多数敲入的载体基因组是通过非同源末端连接(NHEJ)而不是同源定向修复(HDR)的。总之，新生儿型OTCD的大量未满足需求有必要考虑本报告中所述的实验疗法，如基因组编辑。
实例1-材料和方法
材料和方法
AAV载体是根据先前建立的程序和制造商的说明构建的。AAVhu37衣壳用于本文所描述的实验(如所指出的)。
所有动物程序均按照宾夕法尼亚大学的机构动物护理和使用委员会(theInstitutional Animal Care and Use Committee of the University ofPennsylvania)批准的方案。
实例2-试点研究：在新生儿NHPS中通过ARCUS2或SACAS9将HFIX微型基因敲入PCSK9基因座
在这项研究中，我们评估了新生非人类灵长类动物(NHP)中在靶(PSK9)SaCas9-或ARCUS介导的基因编辑和hFIX或OTC微型基因敲入效率。图1显示了rhPCSK9基因座的示意图，其显示了外显子7内的供体剪接位点，以及包含目的供体模板(例如hFIX、hOTC)的HDR供体载体。此外，图3A至3C显示用于SaCas9或ARCUS介导的基因校正的双AAV载体系统的示意图。图3A显示用于ARCUS2介导的基因校正的双AAVhu37载体系统的示意图，其中AAVhu37-供体载体包含hOTC供体模板序列。图3B显示用于Sa-Cas9介导的基因校正的双AAVhu37载体系统(反式；AAVhu37-SaCas9)的示意图，其中AAV.hu37.shRNA-供体载体包含hOTC供体模板序列。图3C显示用于Sa-Cas9介导的基因校正的双AAVhu37载体系统(顺式；AAVhu37.PCSK9-sgRN.SaCas9)的示意图，其中AAV.hu37-供体载体包含hOTC供体模板序列。
将包含基因编辑核酸酶和供体模板的上述双AAVhu37载体用于新生儿NHP中，以检测由SaCas9或ARCUS2介导的PCSK9基因座中的hFIX微型基因敲入。基因编辑AAVhu37载体以1x1013GC/kg的剂量递送，且供体模板AAVhu37载体以3x1013GC/kg递送。总而言之，有三个治疗NHP组：1)AAVhu37.EGFP和AAVhu37.供体-HDR-hFIX-U6.sgR；2)AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX；3)AAVhu37.SaCas9和AAVhu37.供体-HDR-hFIX-U6.sgR。图2显示了用于试点研究的时间线，该试点研究包括在新生NHP中通过ARCUS2或SaCas9在PCSK9基因座中进行的hFIX微型基因敲入。在该研究中，在第0天注射NHP，每2-4周采集一次血样(以检查血清化学、血浆中的hFIX表达、血清中的PCSK9水平、LDL水平和中和抗体(NAb)水平)，在第84天进行第一次肝活检(以检查载体基因组水平、基因表达水平、在靶或脱靶编辑和组织学)。
在新生儿和婴儿NHP中进行了核酸酶介导的基因靶向的体内测试。如图4A、4B和5G所示，给动物施用1x1013GC/kg的AAVhu37.ARCUS2.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR或1x1013GC/kg的AAVhu37.SaCas9.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR.U6.sgR或1x1013GC/kg的AAVhu37.GFP.WPRE和3x1013GC/kg的AAVhu37.hFIXco-HDR.U6.sgR。图4C显示在治疗后第0天至第13个月的指定时间点的hFIX水平(以ng/mL作图)。图4D显示治疗后第0天至第12个月的指定时间点的PCSK9水平(以第0天基线的百分比作图)。图4E显示治疗后第0天至第196天指定时间点的ALT(丙氨酸转氨酶)水平(以U/L作图)。图4F显示治疗后第0天至第196天的指定时间点的抗FIX IgG水平(以稀释因子作图，1/稀释)。图4G显示治疗后第0天至第196天的指定时间点的PCSK9水平(以ng/mL作图)。图4H显示治疗后第0天至第196天的指定时间点测量的体重(以g作图)。图5A显示幼年NHP中指定的时间点的hFIX水平(以ng/mL作图)。图5B显示幼年NHP中指定的时间点的PCSK9水平(以第0天基线的百分比作图)。图5C显示幼年NHP中指定的时间点的ALT(丙氨酸氨基转移酶)水平(以U/L作图)。图5D显示幼年NHP中指定的时间点的抗FIX IgG水平(以稀释因子作图，1/稀释)。图5E显示幼年NHP中指定的时间点的PCSK9水平(以ng/mL作图)。图5F显示幼年NHP中指定的时间点测量的体重(以g作图)。图5G是显示来自图4A-5G中所描述实验的数据的汇总表。图5H显示测试的新生和幼年NHP之间的各种数据的比较。
图6A至6E显示在NHP中显示的治疗后几天收集的肝活检样品中的载体转导(GC)和转基因表达。6A显示肝活检样品中的载体转导水平，以每个二倍体细胞的AAV基因组拷贝(GC)作图。图6B显示肝活检样品中转基因RNA的相对表达。图6C显示使用特异性探针检测肝活检中FIX和ARCUS的双重原位杂交(ISH)。图6D显示用于量化转导的数字化ISH图像。图6E显示通过ISH定量的FIX转基因的转导效率，并以转导百分比作图。图6F显示肝脏中的基因组拷贝。在两个时间点，在婴儿(3x)中均观察到高于新生儿的FIXco GC。第2次活检中比第1次活检中降低的FIXco GC(1.5-2x)。图6G显示肝活检中的转基因mRNA。FIXco mRNA在婴儿的3m和1y之间是稳定的，而FIXco mRNA在新生儿处理的动物的3m和1y之间降低至3倍低。图6H显示了对肝脏样品的分子分析结果。显示了通过扩增子测序测量的插入缺失和通过ITR测序测量的脱靶。此外，在第366天显示了动物20-196的纳米孔长读测序的结果。0.6％的读数显示在两侧掺入HDR。图6I是图6A-6H中描述的数据的汇总表。
图7A至7L显示使用特异性探针检测在NHP中处理后第84天收集的肝活检中的FIX和ARCUS的双重原位杂交(ISH)；显示了不同放大倍数的图像(用AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX处理的NHP)。图7A显示肝活检中ISH检测的ARCUS，以4倍放大倍数观察。图7B显示肝活检中ISH检测的hFIX，以4倍放大倍数观察。图7C显示ISH检测的ARCUS和hFIX的叠加图像，以4倍放大倍数观察。图7D显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以4倍放大倍数观察。图7E显示肝活检中ISH检测的ARCUS，以10倍放大倍数观察。图7F显示肝活检中ISH检测的hFIX，以10倍放大倍数观察。图7G显示ISH检测的ARCUS和hFIX的叠加图像，以10倍放大倍数观察。图7H显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以10倍放大倍数观察。图7I显示肝活检中ISH检测的ARCUS表达，以20倍放大倍数观察。图7J显示肝活检中ISH检测的hFIX，以20倍放大倍数观察。图7K显示ISH检测的ARCUS和hFIX的叠加图像，以20倍放大倍数观察。图7L显示ISH检测的ARCUS和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。载体转导(GC/二倍体基因组)的总结如下表1所示。
表1.
| GC/二倍体基因组 | |
| hFIX | 0.63 |
| ARCUS | 0.13 |
| 比率(FIX/ARCUS) | 4.8 |
| 载体剂量的比率(FIX/ARCUS) | 3.0 |
图8A至8M显示使用特异性探针检测在NHP中处理后第84天收集的肝活检中的FIX和ARCUS的双重原位杂交(ISH)；显示了不同放大倍数的图像(用AAVhu37.EGFP和AAVhu37.供体-HDR-hFIX.U6.sgR处理的NHP)。图8A显示肝活检中ISH检测的GFP-WRPE，以4倍放大倍数观察。图8B显示肝活检中ISH检测的hFIX，以4倍放大倍数观察。图8C显示ISH检测的GFP-WRPE和hFIX的叠加图像，以4倍放大倍数观察。图8D显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以4倍放大倍数观察。图8E显示了肝活检中ISH检测的GFP-WRPE，以10倍放大倍数观察。图8F显示肝活检中ISH检测的hFIX，以10倍放大倍数观察。图8G显示ISH检测的GFP-WRPE和hFIX的叠加图像，以10倍放大倍数观察。图8H显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以10倍放大倍数观察。图8I显示肝活检中ISH检测的GFP-WRPE表达，以20倍放大倍数观察。图8J显示肝活检中ISH检测的hFIX，以20倍放大倍数观察。图8K显示ISH检测的GFP-WRPE和hFIX的叠加图像，以20倍放大倍数观察。图8L显示ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。图8M显示在未处理的对照中ISH检测的GFP-WRPE和hFIX与DAPI(细胞核染色)的叠加图像，以20倍放大倍数观察。载体转导(GC/二倍体基因组)的总结如下表2所示。
表2.
图9显示用AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX.处理的NHP中ARCUS介导的在靶编辑。在处理后第84天，收集肝活检样品，并计算存在于靶区域中的总插入缺失的百分比。此外，在用AAVhu37.ARCUS2和AAVhu37.供体-HDR-hFIX处理的NHP中ARCUS介导的靶向编辑。在治疗后第84天，收集肝活检样品，并计算靶区域中存在的总插入缺失的频率，以独特的UMIOT读数相对于靶的频率作图。通过扩增子测序定量的插入缺失的总结在以下表3中显示。
表3.
实例3-新生儿NHPS中ARCUS2介导的HOTC基因靶向
新生儿(1-16天龄)或婴儿(3-4个月大)恒河猴用于不符合GLP的POC药理学研究。M2PCSK9大范围核酸酶靶向人和恒河猴PCSK9基因中存在的22bp序列。因此，恒河猴可用于评估在靶编辑(药理学)和安全性/毒理学。此外，新生和婴儿恒河猴具有与人类婴儿相似的解剖学和生理学特征，并将允许使用预期的临床ROA(IV)。预期解剖结构和ROA的相似性将导致代表性的向量分布和转导曲线，这将使得能够更准确地评估测试物品的药理学和毒性，包括在靶和脱靶编辑，以及临床病理学，这在新生小鼠中是不可能的。
在该研究中，给新生儿NHP施用ARCUS2核酸酶载体，和具有不同长度-500bp HDR臂或短HDR臂的供体载体。载体示意图如图11J中所示。图12A是显示来自实验的数据的汇总表。所有14个新生猕猴均良好耐受载体输注(即，无明显的临床后遗症)且随时间的推移体重增加(图11I)。除了在第14天一些动物中ALT水平的暂时和适度升高之外，肝酶水平在正常范围内(图11C)。
在第0天分析，在给药前从新生儿收集的血浆样品显示3只动物(21-111，21-113，21-122)具有高水平的(≥400)针对AAVrh79的抗体结合(图11A)。这些预先存在的抗AAVrh79抗体将阻断AAV基因转移。
在所有新生动物中，包括仅供体的对照动物中，随时间跟踪PCSK9水平。第0天的PCSK9水平在新生儿之间变化(图11B)。包括一只供体对照动物在内，九只动物在载体施用后显示PCSK9水平降低的趋势，而其余五只动物在给药后显示PCSK9水平的持久或暂时升高，图11B)。
在第84天，通过剖腹术进行肝活检。通过用hOTC和M2PCSK9特异性探针的双重ISH检测转基因mRNA，并通过OTC免疫荧光检测人OTC蛋白，然后在扫描的载玻片上量化，评价hOTC在肝脏中的转导效率(图11D)。给药时具有预先存在的抗AAVrh79结合抗体的三只动物(21-111、21-113和21-122)通过两种方法都显示某些OTC阳性肝细胞。两个仅供体对照动物显示了低水平的(≤1％)hOTC转导。在接受AAVrh79.TBG.PI.M2PCSK9.WPRE.bGH和AAVrh79.rhHDR.TBG.hOTCco.bGH供体载体(G6)共同施用的两只动物中检测到最高的转导效率(通过OTC免疫荧光测定11.9％和18.6％)。还发现阳性hOTC表达肝细胞成簇存在。这些水平高于对患者基本上有益的阈值，即～5％的OTC表达细胞。
在第84天进行分子分析对每只动物的肝活检样品进行检测，以测定每二倍体基因组的转基因拷贝数、mRNA表达水平、在靶编辑和脱靶编辑(图11F)。与转导效率分析一致，组6中的两只动物(21-157和21-175)具有最高的hOTC载体GC(图11F)、hOTC mRNA(图12I)和在靶插入缺失％(图11H)。动物中M2PCSK9载体GC比hOTC载体GC低2倍至7倍，而M2PCSK9 mRNA水平比hOTC mRNA水平低23倍和765倍(图11F和11G)。
在本研究中，通过ITR测序评估的脱靶活性在第84天的肝活检样品中鉴定了2至40个潜在脱靶。在多个动物中检测到一些脱靶位点，包括分别在研究2和研究3中的hFIX婴儿和hFIX新生动物。脱靶编辑将进一步通过潜在脱靶位点上的扩增子测序来表征。
总之，我们鉴定了M2PCSK9载体和hOTCco供体载体的组合，当将其共同施用至新生猕猴时，给药后3个月在肝脏中可达到12％-18.6％的转导效率，两者都高于对患者基本上有益的阈值，即～5％的OTC表达的肝细胞。在本研究中，对动物进行长期效率和安全性评价。我们将在给药后1年进行第二次肝活检以评价hOTC转导的稳定性、肝中的组织病理学和肝中的在靶和脱靶。
实例4-PCSK9-HE7-KI小鼠模型
由于人和猕猴PCSK9基因中的M2PCSK9靶向序列与鼠Pcsk9基因不保守，我们不能使用M2PCSK9在小鼠基因组基因座中进行基因组编辑。因此，我们委托Jackson实验室生成了敲入小鼠模型，该模型用含有外显子7的人PCSK9基因的区域取代了包括鼠Pcsk9基因外显子7的区域，命名为PCSK9-hE7-KI小鼠(图10A-10C)。该模型可以用于评价体内基因组编辑和基因靶向效率。然后我们将PCSK9-hE7-KI小鼠与稀疏毛皮灰(spfash)小鼠杂交。spfash小鼠在Otc基因的外显子4的末端处的剪接供体位点具有G到A的点突变，这导致Otc mRNA的异常剪接和OTC mRNA和蛋白质表达降低至20倍低。(Hodges和Rosenberg，1989)受影响的动物具有5-10％的残余OTC活性，并且可以在食物饮食中存活，但是它们发展高氨血症，当在高蛋白饮食中时，该高氨血症可以是致死性的(Yang等人，2016)。
PCSK9-hE7-KI.spfash小鼠模型可用于评价人OTC体内基因靶向的功效，证明靶向效率与功效的相关性。然而，由于新生小鼠的小尺寸，一旦它们达到足够的体重，仅可以在小鼠断奶后作为最终程序进行血液临床病理学评价和基因靶向的临床功效评价。
图12显示265bp序列的序列比对，代表PCSK9-hE7敲入等位基因的人PCSK9序列，小鼠PCSK9(mPCSK9)和恒河猴PCSK9(rhPCSK9)。在这个265bp区域中人和恒河猴序列之间存在6个错配。由于插入了各种LINE和LTR，啮齿类和灵长类序列在该窗口之外有差异。人和小鼠之间的外显子7中存在2个氨基酸的差异。通过测定ELISA，hE7-KI小鼠表达正常水平的mPCSK9。
实例5-在PCSK9-HE7-KI SPFASH幼崽中体内OTC基因靶向PCSK9基因座
这项正在进行的不符合GLP的药理学研究的目的是评估新生PCSK9-hE7-KI.spfash小鼠中M2PCSK9大范围核酸酶介导的人OTC基因的敲入是否可在单次共同施用表达M2PCSK9核酸酶的载体和人OTC供体载体后，通过预期的临床ROA(IV)在靶组织中实现治疗性人OTC表达以治疗OTC缺陷(肝)。图14A显示了实验设计的示意图，剂量组如图14B所示。
在第0天，新生(PND 1-2)雄性PCSK9-hE7-KI.spfash小鼠IV共同施用剂量为1.0x1013GC/kg的表达M2PCSK9大范围核酸酶的AAVrh79载体(AAVrh79.TBG.PI.M2PCSK9.WPRE.bGH)与剂量为3.0x1013GC/kg的三种不同的AAVrh79hOTCco供体载体之一的组合。在本研究中评价的M2PCSK9大范围核酸酶表达载体(AAVrh79.TBG.PI.M2PCSK9.WPRE.bGH)与先导临床候选者相同，而除了HDR臂之外，每个hOTCco供体载体与先导临床候选者相同。具体地，尽管临床候选物包括长形式的人HDR序列(AAVrh79.hHDR.TBG.hOTCco.bGH)，但是在本研究中评估的hOTCco供体载体包括小鼠-人杂合HDR序列(AAVrh79.mhHDR.TBG.hOTCco.bGH)、较短形式的人HDR序列(AAVrh79.shHDR.TBG.hOTCco.bGH)或无HDR序列(AAVrh79.TBG.hOTCco.bGH)。图13显示HDR臂与人、敲入小鼠和NHP序列的同源性的比较。作为阴性对照，对另外的年龄匹配的PCSK9-hE7-KI.spfash小鼠施用不表达大范围核酸酶的AAVrh79载体(AAVrh79 TBG PIEGFP.WPRE.bGH)与AAVrh79.mhHDR.TBG.hOTCco.bGH的组合。
生命期评估包括每天进行的生存力监测、体重测量、高蛋白饮食攻击后血浆PCSK9和血浆NH3以及尿乳清酸水平的评估、以及第120天的部分肝切除以评估三分之二部分肝切除术后人OTC转导的稳定性。在第49天和第170天，用10天高蛋白饮食攻击来自每个群组的亚组，然后在攻击结束时进行尸检。在尸检时，收集肝脏以评估人OTC基因的敲入，包括评估人OTC mRNA表达(原位杂交)、OTC蛋白表达(免疫染色)和通过染色和/或酶活性测定评估的OTC酶活性。分离肝脏DNA以评估在靶编辑(扩增子测序，牛津纳米孔长读测序)并评估载体基因组拷贝。
初步结果显示，用具有mhHDR臂的载体给药的小鼠显示与野生型小鼠相当的存活，其中shHDR处理的小鼠在10天高蛋白饮食攻击后达到80％的活力(图14C)。所有处理的小鼠维持的体重均优于KI-spf-ash未处理的小鼠(图14D)。mHDR处理的小鼠的血浆氨水平与未处理的小鼠相比显著降低(图14E)。
在第48天测量mPCSK9水平，所有处理的小鼠均显示了降低(图14F)。插入缺失百分比在HDR类型之间相当一致(图14G)。hOTC水平在用shHDR和mhHDR处理的小鼠中增高(图14H)。
实例6-体内OTC基因靶向新生恒河猴中的PCSK9基因座
这项正在进行的不符合GLP的药理学研究的目的是评估新生恒河猴中M2PCSK9大范围核酸酶介导的人OTC基因的敲入是否可在单次共同施用表达M2PCSK9核酸酶的载体和人OTC供体载体后，通过预期的临床ROA(IV)在靶组织中实现治疗性人OTC表达以治疗OTC缺陷(肝)。
在第0天，新生(1至16天龄)恒河猴IV共同施用剂量为1.0x1013GC/kg的表达M2PCSK9大范围核酸酶的两种不同的载体之一与剂量为3.0x1013GC/kg.的两种不同的AAVhOTCco供体载体之一的组合。仅接受剂量为3.0x1013GC/kg的AAV hOTCco供体载体的非核酸酶组被纳入作为仅供体对照。
对于靶向PCSK9基因的AAV载体，我们比较了在肝脏中的表达M2PCSK9的两种AAV载体构建体。AAV.TBG.PI.M2PCSK9.WPRE.bGH含有全长TBG启动子和两个拷贝的增强子元件，WPRE比含有短的和弱的启动子的AAV.TBG-S1-F113.PI.M2PCSK9.bGH表达的核酸酶水平更高。对于hOTC供体载体，我们比较了两种AAV.hOTCco供体载体，其在hOTCco转基因盒侧翼的同源臂的长度上不同。
在第0天IV施用NHP两种载体，并每天监测活力。生命中的评估包括体重的测量、血液的临床病理学和血浆的基因编辑分析。计划采用两种剖腹手术来分离肝组织，以分析基因组编辑效率、载体基因组拷贝、转基因表达、组织病理学、免疫染色和RNA ISH染色。将对NHP进行长期跟踪并进行尸检(日期待确定)，此时，将收集来自肝脏和其他主要器官的组织，用于评价基因组编辑效率、载体基因组拷贝、转基因表达、组织病理学、免疫染色和RNAISH染色。
实例7-评估PCSK9-HE7-KI.SPFASH幼崽中载体的功效并确定载体的比率
这项正在进行的不符合GLP的药理学研究的目的是评估在新生PCSK9-hE7-KI.spfash小鼠中为治疗OTC缺陷(肝)在通过预期的临床ROA(IV)单次共同施用表达M2PCSK9核酸酶的载体和人OTC供体载体后，达到M2PCSK9大范围核酸酶介导的人OTC基因敲入的最高效力所需的载体组分的比率。
在第0天，将对新生(PND 1-2)雄性PCSK9-hE7-KI.spfash小鼠IV共同施用三个剂量中之一的表达M2PCSK9大范围核酸酶的AAVrh79载体(AAVrh79.TBG.PI.M2PCSK9.WPRE.bGH)与三个剂量中之一的包括小鼠-人杂合HDR序列的hOTCco供体载体(AAVrh79.mhHDR.TBG.hOTCco.bGH)的组合。在本研究中评价的M2PCSK9大范围核酸酶表达载体(AAVrh79.TBG.PI.M2PCSK9.WPRE.bH)与临床候选物相同，而hOTCco供体载体除了HDR臂之外与临床候选物相同。具体地，尽管临床候选物包括长形式的人HDR序列(AAVrh79.hHDR.TBG.hOTCco.bGH)，但在本研究中评估的hOTCco供体载体包括小鼠-人杂合HDR序列(AAVrh79.mhHDR.TBG.hOTCco.bGH)。
选择供体载体(AAVrh79 mhHDR.TBG.hOTCco.bGH)内的小鼠-人杂合HDR序列用于该研究，以便能够评价该方法的药理学，其中供体序列与PCSK9-hE7-KI.spfash小鼠中的序列直接同源。
生命期评估包括每日进行的存活力监测、体重测量、高蛋白饮食激发后血浆NH3和尿液乳清酸水平的评估。在第81天，将用10天高蛋白饮食对小鼠进行攻击，随后在攻击结束时进行尸检。在尸检时，将收集肝脏以评估人OTC基因的敲入，包括评估人OTC mRNA表达(原位杂交)、OTC蛋白质表达(免疫染色)和通过染色和/或酶活性测定评估的OTC酶活性。还将分离肝脏DNA以评估在靶编辑(扩增子测序)并评估载体基因组拷贝。
实例8-评估PCSK9-HE7-KI.SPFASH幼崽中的效力和确定最小有效剂量
这项计划的不符合GLP的药理学研究的目的是评估在新生PCSK9-hE7-KI.spfash小鼠模型中IV施用的AAV的效力，并确定其MED。表达M2PCSK9大范围核酸酶的AAVrh79载体(AAVrh79.TBG.PI.M2PCSK9.WPRE.bGH)将是为计划的GLP遵从毒理学研究而制备的毒理学载体批次。代替使用包括长形式的人HDR序列(AAVrh79.hHDR.TBG.hOTCco.bGH)的测试物品，本研究将使用包括小鼠-人杂合HDR序列(AAVrh79.mhHDR.TBG.hOTCco.bGH)的hOTCco供体载体。该载体将以与临床候选者的毒理学载体批次的方法相当的方法来制备。
我们选择在供体载体(AAVrh79.mhHDR.TBG.hOTCco.bGH)中使用小鼠-人杂合HDR序列进行该研究，以使我们能够有效地研究该方法的药理学，其中供体序列与PCSK9-hE7-KI.spfash小鼠中的序列直接同源。
本研究将评价N＝60个新生儿(PND 1-2)的新生PCSK9-hE7-KI.spfash小鼠和作为对照的N＝15年龄匹配的雄性PCSK9-hE7-KI.WT(野生型)。该研究将包括一个尸检时间点(90天)。为了功效评价，将小鼠从第81天至第90天用10天疗程的高蛋白饮食攻击。将评估存活、身体状况和生物标志物变化。使用IV施用评估AAV的三个剂量水平。剂量水平将基于在先前的非临床研究中评估的剂量范围来选择。评估的剂量水平将包括预期的临床剂量。
生命内的评估包括每日活力检查、存活监测、体重测量、高蛋白饮食攻击后血清PCSK9水平、血浆NH3和尿液乳清酸水平的评估。尸检将在第90天进行。尸检时，将收集血液用于CBC/差异分析和血清临床化学分析。将收集组织列表用于组织病理学评估。收集肝脏来评价人OTC基因的敲入，包括评价人OTC mRNA表达(原位杂交)、OTC蛋白表达(免疫染色)和通过染色和/或酶活性测定来评价OTC酶活性。还将分离肝脏DNA以评估在靶编辑(扩增子测序)并评估载体基因组拷贝。
MED的测定是基于分析高蛋白饮食后的存活率、高蛋白饮食攻击结束时的血浆NH3水平、人OTCmRNA和蛋白表达、OTC酶活性、和与载剂处理的新生PCSK9-hE7-KI.spfash对照小鼠相比，AAV处理过的新生PCSK9-hE7-KI.spfash的在靶编辑。
实例9-PCSK9-HE7-KI.SPFASH幼崽中的毒理学研究
在新生(PND 1-2)PCSK9-hE7-KI.spfash小鼠中进行6个月的GLP遵从安全性研究以研究IV共同施用后测试物品的安全性、耐受性、药理学和药代动力学。在第60天和第180天进行期中分析，包括在靶编辑、脱靶编辑、转基因表达和组织病理学分析，因为这些时间点将允许在施用后有足够的时间使核酸酶依赖性基因插入以达到稳定的平台水平。新生PCSK9-hE7-KI.spfash小鼠将接受三种剂量水平的测试物品中之一，即，1.0x1012GC/kg核酸酶载体和3.0x1012GC/kg供体载体、3.3x1012GC/kg核酸酶载体和1.0x1013GC/kg供体载体，或1.0x1013GC/kg核酸酶载体和3.0x1013GC/kg；N＝20/剂，或载剂(磷酸盐缓冲盐水[PBS]；N＝20。在施用测试物品或载剂之后，生活中评估将包括每天监测痛苦和异常行为的迹象、体重测量和血液临床血清化学(具体为ALT、AST和总胆红素)的临床观察。
在施用测试物品后第60天，使组1、3、5和7安乐死，并且将对组织的综合列表进行组织病理学分析，该组织包括但不限于脑、脊髓、心脏、肝、脾、肾、肺、生殖器官、肾上腺和淋巴结。将酌情对器官进行称重。
收集肝样品，并分析其通过扩增子测序和AMP测序进行的在靶编辑、通过ITR测序和扩增子测序进行的脱靶编辑、载体生物分布和转基因表达。在肝样品中，通过PCR评价生物分布，通过RT-PCR分析大范围核酸酶RNA的表达。分析高度灌注的器官的大范围核酸酶RNA，并通过扩增子测序评估具有大范围核酸酶RNA可检测的表达的组织的在靶编辑。将对具有可检测的在靶编辑的组织关于脱靶编辑进行进一步评估。
对于载体生物分布，将开发对双载体M2PCSK9和hOTCco的转基因特异的qPCR检测。使用AAV顺式质粒作为靶序列的替代物，评估测定的检测效率、线性、精确度、再现性和限制。测定的量化下限(LLOQ)将在对测试组织或排泄物的测定开始之前确定。将实施鉴定计划以将转基因特异性测定与先前进行的鉴定研究相桥接。测试的基质将包括用于生物分布的预期靶标，肝脏。基于从生物分布研究过程中测试的所有样品中回收掺料的靶对照以及从之前进行的鉴定研究中减去的数据，将进一步评价基质效应。
实例10-PCSK9-HE7-KI.LDLR-/LDLR-.APOBEC-/APOBEC-幼崽(HOFH模型)中通过SACAS9在PCSK9基因座的HLDLR微型基因敲入
本研究旨在评估新生PCSK9-hE7-KI.ldlr-/ldlr-.apobec-/apobec小鼠中Cas9介导的人LDLR基因的敲入是否可在通过预期的临床ROA(IV)的单次共同施用表达SaCas9核酸酶的载体和人LDLR供体载体后，在靶组织中实现治疗性人LDLR表达以治疗家族性高胆固醇血症(肝)。使用图15中的实验设计生成小鼠模型。在小鼠模型中，小鼠PCSK9外显子7被包含SaCas9靶向序列的人PCSK9外显子7取代。
在第0天，新生PCSK9-hE7-KI.ldlr-/ldlr-.apobec-/apobec小鼠IV共同施用剂量为1.0x1013GC/kg的表达Cas9的AAVrh79载体(AAVrh79.U6.sgR3.PSCK9.APB2.HLP.SaCas9.bGH)，其与剂量为3.0x1013GC/kg的两种不同的AAVrh79 hLDLR供体载体中之一的组合。显示所使用的载体的示意图如图16中所示。具体地，在本研究中评估的供体载体之一包括小鼠-人杂合HDR序列(AAVrh79.mhHDR.hLDLR011)，另一个包括较短形式的人HDR序列(AAVrh79.shHDR.hLDLR011)。作为阴性对照，对另外的年龄匹配的PCSK9-hE7-KI.spfash小鼠施用不表达saCas9的AAVrh79载体与AAVrh79.shHDR.hLDLR011的组合。
生命期评估包括每天进行的活力监测，和在第42、63、90、120和150天评估血清LDL-c水平。在第63天进行部分肝切除术以评价人LDLR转导的稳定性，并在第150天进行尸检。在尸检时，收集肝脏以评价人LDLR基因的敲入，包括评价人LDLR mRNA表达(原位杂交)、LDLR蛋白表达(免疫染色)。分离肝脏DNA以评估在靶编辑(扩增子测序，牛津纳米孔长读测序)并评估载体基因组拷贝。实验设计显示于图17中。
初步结果显示，施用saCas9和供体载体的小鼠具有显著降低的血清LDL水平。2/3部分肝切除术后LDL没有变化，表明稳定的整合(图18A)。使用mhHDR和shHDR供体载体，插入缺失是一致的(图18B)。在第63天，shHDR处理的小鼠显示了稍高的hLDLR水平(图18C)，而对于mhHDR和shHDR(具有saCas9)载体，血清LDL水平是相似的(图18D)。
图19表示在部分肝切除术后第63天肝脏中hLDLR表达的免疫组织化学评价。
本说明书中引用的所有文献均通过引用并入本文，与此同时提交的序列表的序列和正文均通过引用并入本文。2021年4月27日提交的美国临时专利申请第63/180,603号；2021年9月9日提交的第63/242,474号；2021年9月14日提交的第63/244,205号；2022年1月21日提交的第63/301,933号；2022年4月15日提交的第63/331,385号，其全部内容通过引用并入本文。虽然已经参考特定实施例描述了本发明，但是应理解，在不脱离本发明的精神的情况下可以进行修改。此类修改旨在落入所附权利要求的范围内。
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序列表
<110> 宾夕法尼亚州大学信托人
<120> 用于治疗遗传性疾患的体内核酸酶介导的基因靶向的组合物和方法
<130> UPN-21-9650.PCT
<150> 63/180,603
<151> 2021-04-27
<150> 63/242,474
<151> 2021-09-09
<150> 63/244,205
<151> 2021-09-14
<150> 63/301,933
<151> 2022-01-21
<150> 63/331,385
<151> 2022-04-15
<160> 80
<170> 专利版本3.5
<210> 1
<211> 7429
<212> DNA
<213> 人工序列
<220>
<223> 生产质粒
U6.sgR.PCSK9.ABP2.TBG-S1.hSaCas9(pX601+3NLS).bGH
<220>
<221> LTR
<222> (1)..(168)
<223> AAV ITR
<220>
<221> 终止子
<222> (193)..(199)
<223> U6终止子
<220>
<221> misc_特征
<222> (199)..(275)
<223> gRNA支架
<220>
<221> misc_特征
<222> (276)..(295)
<223> PCSK9 sgRNA
<220>
<221> 启动子
<222> (297)..(545)
<223> U6启动子
<220>
<221> 增强子
<222> (557)..(656)
<223> α mic/bik增强子
<220>
<221> 增强子
<222> (663)..(762)
<223> α mic/bik增强子
<220>
<221> 启动子
<222> (777)..(952)
<223> TBG-S1
<220>
<221> misc_特征
<222> (956)..(958)
<223> 终止密码子突变
<220>
<221> misc_特征
<222> (973)..(1017)
<223> SV40 NLS
<220>
<221> 引物_结合
<222> (1160)..(1179)
<223> SA2-序列1
<220>
<221> 引物_结合
<222> (1647)..(1666)
<223> SA2-序列2
<220>
<221> 引物_结合
<222> (2170)..(2189)
<223> SA2-序列3
<220>
<221> 引物_结合
<222> (2680)..(2700)
<223> SA2-序列4
<220>
<221> 引物_结合
<222> (3130)..(3149)
<223> SA2-序列5
<220>
<221> misc_特征
<222> (4174)..(4221)
<223> NLS
<220>
<221> 聚A_信号
<222> (4233)..(4435)
<223> bGH聚A
<220>
<221> LTR
<222> (4456)..(4619)
<223> AAV ITR
<220>
<221> misc_特征
<222> (5382)..(6239)
<223> Amp-R
<220>
<221> misc_特征
<222> (6413)..(7001)
<223> 起源
<400> 1
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta aggctatttc 180
tagctctaaa acaaaaaaat ctcgccaaca agttgacgag ataaacacgg cattttgcct 240
tgttttagta gattctgttt ccagagtact aaaacgggac tttggggacc aacttcggtg 300
tttcgtcctt tccacaagat atataaagcc aagaaatcga aatactttca agttacggta 360
agcatatgat agtccatttt aaaacataat tttaaaactg caaactaccc aagaaattat 420
tactttctac gtcacgtatt ttgtactaat atctttgtgt ttacagtcaa attaattcca 480
attatctctc taacagcctt gtatcgtata tgcaaatatg aaggaatcat gggaaatagg 540
ccctccttaa gctagcaggt taatttttaa aaagcagtca aaagtccaag tggcccttgg 600
cagcatttac tctctctgtt tgctctggtt aataatctca ggagcacaaa cattccagat 660
ccaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 720
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccgg cgcgccactc 780
aaagttcaaa ccttatcatt ttttgctttg ttcctcttgg ccttggtttt gtacatcagc 840
tttgaaaata ccatcccagg gttaatgctg gggttaattt ataactaaga gtgctctagt 900
tttgcaatac aggacatgct ataaaaatgg aaagatgttg ctttctgaga gacagtgacc 960
gccaccatgg ccccaaagaa gaagcggaag gtcggtatcc acggagtccc agcagccaag 1020
cggaactaca tcctgggcct ggacatcggc atcaccagcg tgggctacgg catcatcgac 1080
tacgagacac gggacgtgat cgatgccggc gtgcggctgt tcaaagaggc caacgtggaa 1140
aacaacgagg gcaggcggag caagagaggc gccagaaggc tgaagcggcg gaggcggcat 1200
agaatccaga gagtgaagaa gctgctgttc gactacaacc tgctgaccga ccacagcgag 1260
ctgagcggca tcaaccccta cgaggccaga gtgaagggcc tgagccagaa gctgagcgag 1320
gaagagttct ctgccgccct gctgcacctg gccaagagaa gaggcgtgca caacgtgaac 1380
gaggtggaag aggacaccgg caacgagctg tccaccaaag agcagatcag ccggaacagc 1440
aaggccctgg aagagaaata cgtggccgaa ctgcagctgg aacggctgaa gaaagacggc 1500
gaagtgcggg gcagcatcaa cagattcaag accagcgact acgtgaaaga agccaaacag 1560
ctgctgaagg tgcagaaggc ctaccaccag ctggaccaga gcttcatcga cacctacatc 1620
gacctgctgg aaacccggcg gacctactat gagggacctg gcgagggcag ccccttcggc 1680
tggaaggaca tcaaagaatg gtacgagatg ctgatgggcc actgcaccta cttccccgag 1740
gaactgcgga gcgtgaagta cgcctacaac gccgacctgt acaacgccct gaacgacctg 1800
aacaatctcg tgatcaccag ggacgagaac gagaagctgg aatattacga gaagttccag 1860
atcatcgaga acgtgttcaa gcagaagaag aagcccaccc tgaagcagat cgccaaagaa 1920
atcctcgtga acgaagagga tattaagggc tacagagtga ccagcaccgg caagcccgag 1980
ttcaccaacc tgaaggtgta ccacgacatc aaggacatta ccgcccggaa agagattatt 2040
gagaacgccg agctgctgga tcagattgcc aagatcctga ccatctacca gagcagcgag 2100
gacatccagg aagaactgac caatctgaac tccgagctga cccaggaaga gatcgagcag 2160
atctctaatc tgaagggcta taccggcacc cacaacctga gcctgaaggc catcaacctg 2220
atcctggacg agctgtggca caccaacgac aaccagatcg ctatcttcaa ccggctgaag 2280
ctggtgccca agaaggtgga cctgtcccag cagaaagaga tccccaccac cctggtggac 2340
gacttcatcc tgagccccgt cgtgaagaga agcttcatcc agagcatcaa agtgatcaac 2400
gccatcatca agaagtacgg cctgcccaac gacatcatta tcgagctggc ccgcgagaag 2460
aactccaagg acgcccagaa aatgatcaac gagatgcaga agcggaaccg gcagaccaac 2520
gagcggatcg aggaaatcat ccggaccacc ggcaaagaga acgccaagta cctgatcgag 2580
aagatcaagc tgcacgacat gcaggaaggc aagtgcctgt acagcctgga agccatccct 2640
ctggaagatc tgctgaacaa ccccttcaac tatgaggtgg accacatcat ccccagaagc 2700
gtgtccttcg acaacagctt caacaacaag gtgctcgtga agcaggaaga aaacagcaag 2760
aagggcaacc ggaccccatt ccagtacctg agcagcagcg acagcaagat cagctacgaa 2820
accttcaaga agcacatcct gaatctggcc aagggcaagg gcagaatcag caagaccaag 2880
aaagagtatc tgctggaaga acgggacatc aacaggttct ccgtgcagaa agacttcatc 2940
aaccggaacc tggtggatac cagatacgcc accagaggcc tgatgaacct gctgcggagc 3000
tacttcagag tgaacaacct ggacgtgaaa gtgaagtcca tcaatggcgg cttcaccagc 3060
tttctgcggc ggaagtggaa gtttaagaaa gagcggaaca aggggtacaa gcaccacgcc 3120
gaggacgccc tgatcattgc caacgccgat ttcatcttca aagagtggaa gaaactggac 3180
aaggccaaaa aagtgatgga aaaccagatg ttcgaggaaa agcaggccga gagcatgccc 3240
gagatcgaaa ccgagcagga gtacaaagag atcttcatca ccccccacca gatcaagcac 3300
attaaggact tcaaggacta caagtacagc caccgggtgg acaagaagcc taatagagag 3360
ctgattaacg acaccctgta ctccacccgg aaggacgaca agggcaacac cctgatcgtg 3420
aacaatctga acggcctgta cgacaaggac aatgacaagc tgaaaaagct gatcaacaag 3480
agccccgaaa agctgctgat gtaccaccac gacccccaga cctaccagaa actgaagctg 3540
attatggaac agtacggcga cgagaagaat cccctgtaca agtactacga ggaaaccggg 3600
aactacctga ccaagtactc caaaaaggac aacggccccg tgatcaagaa gattaagtat 3660
tacggcaaca aactgaacgc ccatctggac atcaccgacg actaccccaa cagcagaaac 3720
aaggtcgtga agctgtccct gaagccctac agattcgacg tgtacctgga caatggcgtg 3780
tacaagttcg tgaccgtgaa gaatctggat gtgatcaaaa aagaaaacta ctacgaagtg 3840
aatagcaagt gctatgagga agctaagaag ctgaagaaga tcagcaacca ggccgagttt 3900
atcgcctcct tctacaacaa cgatctgatc aagatcaacg gcgagctgta tagagtgatc 3960
ggcgtgaaca acgacctgct gaaccggatc gaagtgaaca tgatcgacat cacctaccgc 4020
gagtacctgg aaaacatgaa cgacaagagg ccccccagga tcattaagac aatcgcctcc 4080
aagacccaga gcattaagaa gtacagcaca gacattctgg gcaacctgta tgaagtgaaa 4140
tctaagaagc accctcagat catcaaaaag ggcaaaaggc ctgctgccac caaaaaggcc 4200
ggccaggcaa aaaagaaaaa gtaatgacta gtgcctcgac tgtgccttct agttgccagc 4260
catctgttgt ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg 4320
tcctttccta ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc 4380
tggggggtgg ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg 4440
ctggggactc gagtagataa gtagcatggc gggttaatca ttaactacaa ggaaccccta 4500
gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca 4560
aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcagc 4620
cttaattaac ctaattcact ggccgtcgtt ttacaacgtc gtgactggga aaaccctggc 4680
gttacccaac ttaatcgcct tgcagcacat ccccctttcg ccagctggcg taatagcgaa 4740
gaggcccgca ccgatcgccc ttcccaacag ttgcgcagcc tgaatggcga atgggacgcg 4800
ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt gaccgctaca 4860
cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct cgccacgttc 4920
gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg atttagtgct 4980
ttacggcacc tcgaccccaa aaaacttgat tagggtgatg gttcacgtag tgggccatcg 5040
ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa tagtggactc 5100
ttgttccaaa ctggaacaac actcaaccct atctcggtct attcttttga tttataaggg 5160
attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa atttaacgcg 5220
aattttaaca aaatattaac gcttacaatt taggtggcac ttttcgggga aatgtgcgcg 5280
gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat 5340
aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc 5400
gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa 5460
cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac 5520
tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttccaatga 5580
tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac gccgggcaag 5640
agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca 5700
cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca 5760
tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa 5820
ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc 5880
tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca atggcaacaa 5940
cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa caattaatag 6000
actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct 6060
ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac 6120
tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa 6180
ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt 6240
aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat 6300
ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg 6360
agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc 6420
ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg 6480
tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag 6540
cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac ttcaagaact 6600
ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg 6660
gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc 6720
ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg 6780
aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa gggagaaagg 6840
cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag 6900
ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc 6960
gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct 7020
ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc 7080
ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc 7140
gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgccca atacgcaaac 7200
cgcctctccc cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg tttcccgact 7260
ggaaagcggg cagtgagcgc aacgcaatta atgtgagtta gctcactcat taggcacccc 7320
aggctttaca ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc ggataacaat 7380
ttcacacagg aaacagctat gaccatgatt acgccagatt taattaagg 7429
<210> 2
<211> 4619
<212> DNA
<213> 人工序列
<220>
<223> 载体基因组U6.sgR.PCSK9.ABP2.TBG-S1.hSaCas9(pX601+3NLS).bGH
<220>
<221> LTR
<222> (1)..(168)
<223> AAV ITR
<220>
<221> 终止子
<222> (193)..(199)
<223> U6终止子
<220>
<221> misc_特征
<222> (199)..(275)
<223> shRNA支架
<220>
<221> misc_特征
<222> (276)..(295)
<223> PCSK9 sgRNA
<220>
<221> 启动子
<222> (297)..(545)
<223> U6启动子
<220>
<221> 增强子
<222> (557)..(656)
<223> α mic/bik增强子
<220>
<221> 增强子
<222> (663)..(762)
<223> α mic/bik增强子
<220>
<221> 启动子
<222> (777)..(952)
<223> TBG-S1
<220>
<221> misc_特征
<222> (956)..(958)
<223> 终止密码子突变
<220>
<221> CDS
<222> (967)..(4221)
<223> SaCas9 (px601+3LNS)
<220>
<221> misc_特征
<222> (973)..(1017)
<223> SV40 NLS
<220>
<221> 引物_结合
<222> (1160)..(1179)
<223> Sa2-序列1
<220>
<221> 引物_结合
<222> (1647)..(1666)
<223> Sa2-序列2
<220>
<221> 引物_结合
<222> (2170)..(2189)
<223> Sa2-序列3
<220>
<221> 引物_结合
<222> (2680)..(2700)
<223> Sa2-序列4
<220>
<221> 引物_结合
<222> (3130)..(3149)
<223> Sa2-序列5
<220>
<221> misc_特征
<222> (4174)..(4221)
<223> NLS
<220>
<221> 聚A_信号
<222> (4233)..(4435)
<223> bGH聚A
<220>
<221> LTR
<222> (4456)..(4619)
<223> AAV ITR
<400> 2
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta aggctatttc 180
tagctctaaa acaaaaaaat ctcgccaaca agttgacgag ataaacacgg cattttgcct 240
tgttttagta gattctgttt ccagagtact aaaacgggac tttggggacc aacttcggtg 300
tttcgtcctt tccacaagat atataaagcc aagaaatcga aatactttca agttacggta 360
agcatatgat agtccatttt aaaacataat tttaaaactg caaactaccc aagaaattat 420
tactttctac gtcacgtatt ttgtactaat atctttgtgt ttacagtcaa attaattcca 480
attatctctc taacagcctt gtatcgtata tgcaaatatg aaggaatcat gggaaatagg 540
ccctccttaa gctagcaggt taatttttaa aaagcagtca aaagtccaag tggcccttgg 600
cagcatttac tctctctgtt tgctctggtt aataatctca ggagcacaaa cattccagat 660
ccaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 720
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccgg cgcgccactc 780
aaagttcaaa ccttatcatt ttttgctttg ttcctcttgg ccttggtttt gtacatcagc 840
tttgaaaata ccatcccagg gttaatgctg gggttaattt ataactaaga gtgctctagt 900
tttgcaatac aggacatgct ataaaaatgg aaagatgttg ctttctgaga gacagtgacc 960
gccacc atg gcc cca aag aag aag cgg aag gtc ggt atc cac gga gtc 1008
Met Ala Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly Val
1 5 10
cca gca gcc aag cgg aac tac atc ctg ggc ctg gac atc ggc atc acc 1056
Pro Ala Ala Lys Arg Asn Tyr Ile Leu Gly Leu Asp Ile Gly Ile Thr
15 20 25 30
agc gtg ggc tac ggc atc atc gac tac gag aca cgg gac gtg atc gat 1104
Ser Val Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp
35 40 45
gcc ggc gtg cgg ctg ttc aaa gag gcc aac gtg gaa aac aac gag ggc 1152
Ala Gly Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly
50 55 60
agg cgg agc aag aga ggc gcc aga agg ctg aag cgg cgg agg cgg cat 1200
Arg Arg Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His
65 70 75
aga atc cag aga gtg aag aag ctg ctg ttc gac tac aac ctg ctg acc 1248
Arg Ile Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr
80 85 90
gac cac agc gag ctg agc ggc atc aac ccc tac gag gcc aga gtg aag 1296
Asp His Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys
95 100 105 110
ggc ctg agc cag aag ctg agc gag gaa gag ttc tct gcc gcc ctg ctg 1344
Gly Leu Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu
115 120 125
cac ctg gcc aag aga aga ggc gtg cac aac gtg aac gag gtg gaa gag 1392
His Leu Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu
130 135 140
gac acc ggc aac gag ctg tcc acc aaa gag cag atc agc cgg aac agc 1440
Asp Thr Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser
145 150 155
aag gcc ctg gaa gag aaa tac gtg gcc gaa ctg cag ctg gaa cgg ctg 1488
Lys Ala Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu
160 165 170
aag aaa gac ggc gaa gtg cgg ggc agc atc aac aga ttc aag acc agc 1536
Lys Lys Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser
175 180 185 190
gac tac gtg aaa gaa gcc aaa cag ctg ctg aag gtg cag aag gcc tac 1584
Asp Tyr Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr
195 200 205
cac cag ctg gac cag agc ttc atc gac acc tac atc gac ctg ctg gaa 1632
His Gln Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu
210 215 220
acc cgg cgg acc tac tat gag gga cct ggc gag ggc agc ccc ttc ggc 1680
Thr Arg Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly
225 230 235
tgg aag gac atc aaa gaa tgg tac gag atg ctg atg ggc cac tgc acc 1728
Trp Lys Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr
240 245 250
tac ttc ccc gag gaa ctg cgg agc gtg aag tac gcc tac aac gcc gac 1776
Tyr Phe Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp
255 260 265 270
ctg tac aac gcc ctg aac gac ctg aac aat ctc gtg atc acc agg gac 1824
Leu Tyr Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp
275 280 285
gag aac gag aag ctg gaa tat tac gag aag ttc cag atc atc gag aac 1872
Glu Asn Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn
290 295 300
gtg ttc aag cag aag aag aag ccc acc ctg aag cag atc gcc aaa gaa 1920
Val Phe Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu
305 310 315
atc ctc gtg aac gaa gag gat att aag ggc tac aga gtg acc agc acc 1968
Ile Leu Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr
320 325 330
ggc aag ccc gag ttc acc aac ctg aag gtg tac cac gac atc aag gac 2016
Gly Lys Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp
335 340 345 350
att acc gcc cgg aaa gag att att gag aac gcc gag ctg ctg gat cag 2064
Ile Thr Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln
355 360 365
att gcc aag atc ctg acc atc tac cag agc agc gag gac atc cag gaa 2112
Ile Ala Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu
370 375 380
gaa ctg acc aat ctg aac tcc gag ctg acc cag gaa gag atc gag cag 2160
Glu Leu Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln
385 390 395
atc tct aat ctg aag ggc tat acc ggc acc cac aac ctg agc ctg aag 2208
Ile Ser Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys
400 405 410
gcc atc aac ctg atc ctg gac gag ctg tgg cac acc aac gac aac cag 2256
Ala Ile Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln
415 420 425 430
atc gct atc ttc aac cgg ctg aag ctg gtg ccc aag aag gtg gac ctg 2304
Ile Ala Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu
435 440 445
tcc cag cag aaa gag atc ccc acc acc ctg gtg gac gac ttc atc ctg 2352
Ser Gln Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu
450 455 460
agc ccc gtc gtg aag aga agc ttc atc cag agc atc aaa gtg atc aac 2400
Ser Pro Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn
465 470 475
gcc atc atc aag aag tac ggc ctg ccc aac gac atc att atc gag ctg 2448
Ala Ile Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu
480 485 490
gcc cgc gag aag aac tcc aag gac gcc cag aaa atg atc aac gag atg 2496
Ala Arg Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met
495 500 505 510
cag aag cgg aac cgg cag acc aac gag cgg atc gag gaa atc atc cgg 2544
Gln Lys Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg
515 520 525
acc acc ggc aaa gag aac gcc aag tac ctg atc gag aag atc aag ctg 2592
Thr Thr Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu
530 535 540
cac gac atg cag gaa ggc aag tgc ctg tac agc ctg gaa gcc atc cct 2640
His Asp Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro
545 550 555
ctg gaa gat ctg ctg aac aac ccc ttc aac tat gag gtg gac cac atc 2688
Leu Glu Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile
560 565 570
atc ccc aga agc gtg tcc ttc gac aac agc ttc aac aac aag gtg ctc 2736
Ile Pro Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu
575 580 585 590
gtg aag cag gaa gaa aac agc aag aag ggc aac cgg acc cca ttc cag 2784
Val Lys Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln
595 600 605
tac ctg agc agc agc gac agc aag atc agc tac gaa acc ttc aag aag 2832
Tyr Leu Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys
610 615 620
cac atc ctg aat ctg gcc aag ggc aag ggc aga atc agc aag acc aag 2880
His Ile Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys
625 630 635
aaa gag tat ctg ctg gaa gaa cgg gac atc aac agg ttc tcc gtg cag 2928
Lys Glu Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln
640 645 650
aaa gac ttc atc aac cgg aac ctg gtg gat acc aga tac gcc acc aga 2976
Lys Asp Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg
655 660 665 670
ggc ctg atg aac ctg ctg cgg agc tac ttc aga gtg aac aac ctg gac 3024
Gly Leu Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp
675 680 685
gtg aaa gtg aag tcc atc aat ggc ggc ttc acc agc ttt ctg cgg cgg 3072
Val Lys Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg
690 695 700
aag tgg aag ttt aag aaa gag cgg aac aag ggg tac aag cac cac gcc 3120
Lys Trp Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala
705 710 715
gag gac gcc ctg atc att gcc aac gcc gat ttc atc ttc aaa gag tgg 3168
Glu Asp Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp
720 725 730
aag aaa ctg gac aag gcc aaa aaa gtg atg gaa aac cag atg ttc gag 3216
Lys Lys Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu
735 740 745 750
gaa aag cag gcc gag agc atg ccc gag atc gaa acc gag cag gag tac 3264
Glu Lys Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr
755 760 765
aaa gag atc ttc atc acc ccc cac cag atc aag cac att aag gac ttc 3312
Lys Glu Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe
770 775 780
aag gac tac aag tac agc cac cgg gtg gac aag aag cct aat aga gag 3360
Lys Asp Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu
785 790 795
ctg att aac gac acc ctg tac tcc acc cgg aag gac gac aag ggc aac 3408
Leu Ile Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn
800 805 810
acc ctg atc gtg aac aat ctg aac ggc ctg tac gac aag gac aat gac 3456
Thr Leu Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp
815 820 825 830
aag ctg aaa aag ctg atc aac aag agc ccc gaa aag ctg ctg atg tac 3504
Lys Leu Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr
835 840 845
cac cac gac ccc cag acc tac cag aaa ctg aag ctg att atg gaa cag 3552
His His Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln
850 855 860
tac ggc gac gag aag aat ccc ctg tac aag tac tac gag gaa acc ggg 3600
Tyr Gly Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly
865 870 875
aac tac ctg acc aag tac tcc aaa aag gac aac ggc ccc gtg atc aag 3648
Asn Tyr Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys
880 885 890
aag att aag tat tac ggc aac aaa ctg aac gcc cat ctg gac atc acc 3696
Lys Ile Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr
895 900 905 910
gac gac tac ccc aac agc aga aac aag gtc gtg aag ctg tcc ctg aag 3744
Asp Asp Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys
915 920 925
ccc tac aga ttc gac gtg tac ctg gac aat ggc gtg tac aag ttc gtg 3792
Pro Tyr Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val
930 935 940
acc gtg aag aat ctg gat gtg atc aaa aaa gaa aac tac tac gaa gtg 3840
Thr Val Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val
945 950 955
aat agc aag tgc tat gag gaa gct aag aag ctg aag aag atc agc aac 3888
Asn Ser Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn
960 965 970
cag gcc gag ttt atc gcc tcc ttc tac aac aac gat ctg atc aag atc 3936
Gln Ala Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile
975 980 985 990
aac ggc gag ctg tat aga gtg atc ggc gtg aac aac gac ctg ctg aac 3984
Asn Gly Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn
995 1000 1005
cgg atc gaa gtg aac atg atc gac atc acc tac cgc gag tac ctg 4029
Arg Ile Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu
1010 1015 1020
gaa aac atg aac gac aag agg ccc ccc agg atc att aag aca atc 4074
Glu Asn Met Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile
1025 1030 1035
gcc tcc aag acc cag agc att aag aag tac agc aca gac att ctg 4119
Ala Ser Lys Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu
1040 1045 1050
ggc aac ctg tat gaa gtg aaa tct aag aag cac cct cag atc atc 4164
Gly Asn Leu Tyr Glu Val Lys Ser Lys Lys His Pro Gln Ile Ile
1055 1060 1065
aaa aag ggc aaa agg cct gct gcc acc aaa aag gcc ggc cag gca 4209
Lys Lys Gly Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala
1070 1075 1080
aaa aag aaa aag taatgactag tgcctcgact gtgccttcta gttgccagcc 4261
Lys Lys Lys Lys
1085
atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca ctcccactgt 4321
cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc attctattct 4381
ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata gcaggcatgc 4441
tggggactcg agtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4501
tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4561
aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcag 4619
<210> 3
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 3
Met Ala Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly Val Pro Ala
1 5 10 15
Ala Lys Arg Asn Tyr Ile Leu Gly Leu Asp Ile Gly Ile Thr Ser Val
20 25 30
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
35 40 45
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
50 55 60
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
65 70 75 80
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
85 90 95
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
100 105 110
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
115 120 125
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
130 135 140
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
145 150 155 160
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
165 170 175
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
180 185 190
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
195 200 205
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
210 215 220
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
225 230 235 240
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
245 250 255
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
260 265 270
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
275 280 285
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
290 295 300
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
305 310 315 320
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
325 330 335
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
340 345 350
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
355 360 365
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
370 375 380
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
385 390 395 400
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
405 410 415
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
420 425 430
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
435 440 445
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
450 455 460
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
465 470 475 480
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
485 490 495
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
500 505 510
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
515 520 525
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
530 535 540
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
545 550 555 560
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
565 570 575
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
580 585 590
Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
595 600 605
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
610 615 620
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
625 630 635 640
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
645 650 655
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
660 665 670
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
675 680 685
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
690 695 700
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
705 710 715 720
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
725 730 735
Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys
740 745 750
Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu
755 760 765
Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp
770 775 780
Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile
785 790 795 800
Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu
805 810 815
Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu
820 825 830
Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His
835 840 845
Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly
850 855 860
Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr
865 870 875 880
Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile
885 890 895
Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp
900 905 910
Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr
915 920 925
Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val
930 935 940
Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser
945 950 955 960
Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala
965 970 975
Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly
980 985 990
Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile
995 1000 1005
Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn
1010 1015 1020
Met Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser
1025 1030 1035
Lys Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn
1040 1045 1050
Leu Tyr Glu Val Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys
1055 1060 1065
Gly Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys
1070 1075 1080
Lys Lys
1085
<210> 4
<211> 7507
<212> DNA
<213> 人工序列
<220>
<223> 生产质粒 U6.sgR3.PCSK9.ABP2.HLP.hSaCas9(pX601+3NLS)bGH
<220>
<221> LTR
<222> (1)..(168)
<223> AAV ITR
<220>
<221> 终止子
<222> (193)..(199)
<223> U6终止子
<220>
<221> misc_特征
<222> (199)..(275)
<223> gRNA支架
<220>
<221> misc_特征
<222> (276)..(295)
<223> PCSK9 sgRNA
<220>
<221> 启动子
<222> (297)..(545)
<223> U6启动子
<220>
<221> 增强子
<222> (557)..(656)
<223> α mic/bik增强子
<220>
<221> 增强子
<222> (663)..(762)
<223> α mic/bik
<220>
<221> 启动子
<222> (777)..(1027)
<223> HLP
<220>
<221> misc_特征
<222> (1034)..(4288)
<223> SaCas9 (px601+3NLS)
<220>
<221> misc_特征
<222> (1040)..(1084)
<223> SV40 NLS
<220>
<221> 引物_结合
<222> (1227)..(1246)
<223> Sa2-序列1
<220>
<221> 引物_结合
<222> (1714)..(1733)
<223> Sa2-序列2
<220>
<221> 引物_结合
<222> (2237)..(2256)
<223> Sa2-序列3
<220>
<221> 引物_结合
<222> (2747)..(2767)
<223> Sa2-序列4
<220>
<221> 引物_结合
<222> (3197)..(3216)
<223> Sa2-序列5
<220>
<221> misc_特征
<222> (4241)..(4288)
<223> NLS
<220>
<221> LTR
<222> (4253)..(4686)
<223> AAV ITR
<220>
<221> 聚A_信号
<222> (4300)..(4502)
<223> bGH
<220>
<221> misc_特征
<222> (5449)..(6306)
<223> Amp-R
<220>
<221> misc_特征
<222> (6480)..(7068)
<223> 起源
<400> 4
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta aggctatttc 180
tagctctaaa acaaaaaaat ctcgccaaca agttgacgag ataaacacgg cattttgcct 240
tgttttagta gattctgttt ccagagtact aaaacgggac tttggggacc aacttcggtg 300
tttcgtcctt tccacaagat atataaagcc aagaaatcga aatactttca agttacggta 360
agcatatgat agtccatttt aaaacataat tttaaaactg caaactaccc aagaaattat 420
tactttctac gtcacgtatt ttgtactaat atctttgtgt ttacagtcaa attaattcca 480
attatctctc taacagcctt gtatcgtata tgcaaatatg aaggaatcat gggaaatagg 540
ccctccttaa gctagcaggt taatttttaa aaagcagtca aaagtccaag tggcccttgg 600
cagcatttac tctctctgtt tgctctggtt aataatctca ggagcacaaa cattccagat 660
ccaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 720
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccgg cgcgcctgtt 780
tgctgcttgc aatgtttgcc cattttaggg tggacacagg acgctgtggt ttctgagcca 840
gggggcgact cagatcccag ccagtggact tagcccctgt ttgctcctcc gataactggg 900
gtgaccttgg ttaatattca ccagcagcct cccccgttgc ccctctggat ccactgctta 960
aatacggacg aggacagggc cctgtctcct cagcttcagg caccaccact gacctgggac 1020
agtgaatgcc accatggccc caaagaagaa gcggaaggtc ggtatccacg gagtcccagc 1080
agccaagcgg aactacatcc tgggcctgga catcggcatc accagcgtgg gctacggcat 1140
catcgactac gagacacggg acgtgatcga tgccggcgtg cggctgttca aagaggccaa 1200
cgtggaaaac aacgagggca ggcggagcaa gagaggcgcc agaaggctga agcggcggag 1260
gcggcataga atccagagag tgaagaagct gctgttcgac tacaacctgc tgaccgacca 1320
cagcgagctg agcggcatca acccctacga ggccagagtg aagggcctga gccagaagct 1380
gagcgaggaa gagttctctg ccgccctgct gcacctggcc aagagaagag gcgtgcacaa 1440
cgtgaacgag gtggaagagg acaccggcaa cgagctgtcc accaaagagc agatcagccg 1500
gaacagcaag gccctggaag agaaatacgt ggccgaactg cagctggaac ggctgaagaa 1560
agacggcgaa gtgcggggca gcatcaacag attcaagacc agcgactacg tgaaagaagc 1620
caaacagctg ctgaaggtgc agaaggccta ccaccagctg gaccagagct tcatcgacac 1680
ctacatcgac ctgctggaaa cccggcggac ctactatgag ggacctggcg agggcagccc 1740
cttcggctgg aaggacatca aagaatggta cgagatgctg atgggccact gcacctactt 1800
ccccgaggaa ctgcggagcg tgaagtacgc ctacaacgcc gacctgtaca acgccctgaa 1860
cgacctgaac aatctcgtga tcaccaggga cgagaacgag aagctggaat attacgagaa 1920
gttccagatc atcgagaacg tgttcaagca gaagaagaag cccaccctga agcagatcgc 1980
caaagaaatc ctcgtgaacg aagaggatat taagggctac agagtgacca gcaccggcaa 2040
gcccgagttc accaacctga aggtgtacca cgacatcaag gacattaccg cccggaaaga 2100
gattattgag aacgccgagc tgctggatca gattgccaag atcctgacca tctaccagag 2160
cagcgaggac atccaggaag aactgaccaa tctgaactcc gagctgaccc aggaagagat 2220
cgagcagatc tctaatctga agggctatac cggcacccac aacctgagcc tgaaggccat 2280
caacctgatc ctggacgagc tgtggcacac caacgacaac cagatcgcta tcttcaaccg 2340
gctgaagctg gtgcccaaga aggtggacct gtcccagcag aaagagatcc ccaccaccct 2400
ggtggacgac ttcatcctga gccccgtcgt gaagagaagc ttcatccaga gcatcaaagt 2460
gatcaacgcc atcatcaaga agtacggcct gcccaacgac atcattatcg agctggcccg 2520
cgagaagaac tccaaggacg cccagaaaat gatcaacgag atgcagaagc ggaaccggca 2580
gaccaacgag cggatcgagg aaatcatccg gaccaccggc aaagagaacg ccaagtacct 2640
gatcgagaag atcaagctgc acgacatgca ggaaggcaag tgcctgtaca gcctggaagc 2700
catccctctg gaagatctgc tgaacaaccc cttcaactat gaggtggacc acatcatccc 2760
cagaagcgtg tccttcgaca acagcttcaa caacaaggtg ctcgtgaagc aggaagaaaa 2820
cagcaagaag ggcaaccgga ccccattcca gtacctgagc agcagcgaca gcaagatcag 2880
ctacgaaacc ttcaagaagc acatcctgaa tctggccaag ggcaagggca gaatcagcaa 2940
gaccaagaaa gagtatctgc tggaagaacg ggacatcaac aggttctccg tgcagaaaga 3000
cttcatcaac cggaacctgg tggataccag atacgccacc agaggcctga tgaacctgct 3060
gcggagctac ttcagagtga acaacctgga cgtgaaagtg aagtccatca atggcggctt 3120
caccagcttt ctgcggcgga agtggaagtt taagaaagag cggaacaagg ggtacaagca 3180
ccacgccgag gacgccctga tcattgccaa cgccgatttc atcttcaaag agtggaagaa 3240
actggacaag gccaaaaaag tgatggaaaa ccagatgttc gaggaaaagc aggccgagag 3300
catgcccgag atcgaaaccg agcaggagta caaagagatc ttcatcaccc cccaccagat 3360
caagcacatt aaggacttca aggactacaa gtacagccac cgggtggaca agaagcctaa 3420
tagagagctg attaacgaca ccctgtactc cacccggaag gacgacaagg gcaacaccct 3480
gatcgtgaac aatctgaacg gcctgtacga caaggacaat gacaagctga aaaagctgat 3540
caacaagagc cccgaaaagc tgctgatgta ccaccacgac ccccagacct accagaaact 3600
gaagctgatt atggaacagt acggcgacga gaagaatccc ctgtacaagt actacgagga 3660
aaccgggaac tacctgacca agtactccaa aaaggacaac ggccccgtga tcaagaagat 3720
taagtattac ggcaacaaac tgaacgccca tctggacatc accgacgact accccaacag 3780
cagaaacaag gtcgtgaagc tgtccctgaa gccctacaga ttcgacgtgt acctggacaa 3840
tggcgtgtac aagttcgtga ccgtgaagaa tctggatgtg atcaaaaaag aaaactacta 3900
cgaagtgaat agcaagtgct atgaggaagc taagaagctg aagaagatca gcaaccaggc 3960
cgagtttatc gcctccttct acaacaacga tctgatcaag atcaacggcg agctgtatag 4020
agtgatcggc gtgaacaacg acctgctgaa ccggatcgaa gtgaacatga tcgacatcac 4080
ctaccgcgag tacctggaaa acatgaacga caagaggccc cccaggatca ttaagacaat 4140
cgcctccaag acccagagca ttaagaagta cagcacagac attctgggca acctgtatga 4200
agtgaaatct aagaagcacc ctcagatcat caaaaagggc aaaaggcctg ctgccaccaa 4260
aaaggccggc caggcaaaaa agaaaaagta atgactagtg cctcgactgt gccttctagt 4320
tgccagccat ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact 4380
cccactgtcc tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat 4440
tctattctgg ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc 4500
aggcatgctg gggactcgag tagataagta gcatggcggg ttaatcatta actacaagga 4560
acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca ctgaggccgg 4620
gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc 4680
gcgcagcctt aattaaccta attcactggc cgtcgtttta caacgtcgtg actgggaaaa 4740
ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca gctggcgtaa 4800
tagcgaagag gcccgcaccg atcgcccttc ccaacagttg cgcagcctga atggcgaatg 4860
ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac 4920
cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt cctttctcgc 4980
cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag ggttccgatt 5040
tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt cacgtagtgg 5100
gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt tctttaatag 5160
tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt cttttgattt 5220
ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt aacaaaaatt 5280
taacgcgaat tttaacaaaa tattaacgct tacaatttag gtggcacttt tcggggaaat 5340
gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg 5400
agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa 5460
catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac 5520
ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac 5580
atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt 5640
ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc 5700
gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca 5760
ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc 5820
ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag 5880
gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa 5940
ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg 6000
gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa 6060
ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg 6120
gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt 6180
gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt 6240
caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag 6300
cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat 6360
ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct 6420
taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct 6480
tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca 6540
gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc 6600
agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg ccaccacttc 6660
aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct 6720
gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag 6780
gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc 6840
tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct tcccgaaggg 6900
agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag 6960
cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt 7020
gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac 7080
gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg 7140
ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc 7200
cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcccaata 7260
cgcaaaccgc ctctccccgc gcgttggccg attcattaat gcagctggca cgacaggttt 7320
cccgactgga aagcgggcag tgagcgcaac gcaattaatg tgagttagct cactcattag 7380
gcaccccagg ctttacactt tatgcttccg gctcgtatgt tgtgtggaat tgtgagcgga 7440
taacaatttc acacaggaaa cagctatgac catgattacg ccagatttaa ttaaggcctt 7500
aattagg 7507
<210> 5
<211> 4686
<212> DNA
<213> 人工序列
<220>
<223> 载体基因组U6.sgR3.PCSK9.ABP2.HLP.hSaCas9(pX601+3NLS)bGH
<220>
<221> LTR
<222> (1)..(168)
<223> AAV ITR
<220>
<221> 终止子
<222> (193)..(199)
<223> U6终止子
<220>
<221> misc_特征
<222> (199)..(275)
<223> gRNA支架
<220>
<221> misc_特征
<222> (276)..(295)
<223> PCSK9 sgRNA
<220>
<221> 启动子
<222> (297)..(545)
<223> U6启动子
<220>
<221> 增强子
<222> (557)..(656)
<223> α mic/bik增强子
<220>
<221> 增强子
<222> (663)..(762)
<223> α mic/bik增强子
<220>
<221> 启动子
<222> (777)..(1027)
<223> HLP
<220>
<221> CDS
<222> (1034)..(4288)
<223> SaCas9 (px601+3NLS)
<220>
<221> misc_特征
<222> (1040)..(1084)
<223> SV40 NLS
<220>
<221> 引物_结合
<222> (1227)..(1246)
<223> Sa2-序列1
<220>
<221> 引物_结合
<222> (1714)..(1733)
<223> Sa2-序列2
<220>
<221> 引物_结合
<222> (2237)..(2256)
<223> Sa2-序列3
<220>
<221> 引物_结合
<222> (2747)..(2767)
<223> Sa2-序列4
<220>
<221> 引物_结合
<222> (3197)..(3216)
<223> Sa2-序列5
<220>
<221> misc_特征
<222> (4241)..(4288)
<223> NLS
<220>
<221> LTR
<222> (4253)..(4686)
<223> AAV ITR
<220>
<221> 聚A_信号
<222> (4300)..(4502)
<223> bGH聚A
<400> 5
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta aggctatttc 180
tagctctaaa acaaaaaaat ctcgccaaca agttgacgag ataaacacgg cattttgcct 240
tgttttagta gattctgttt ccagagtact aaaacgggac tttggggacc aacttcggtg 300
tttcgtcctt tccacaagat atataaagcc aagaaatcga aatactttca agttacggta 360
agcatatgat agtccatttt aaaacataat tttaaaactg caaactaccc aagaaattat 420
tactttctac gtcacgtatt ttgtactaat atctttgtgt ttacagtcaa attaattcca 480
attatctctc taacagcctt gtatcgtata tgcaaatatg aaggaatcat gggaaatagg 540
ccctccttaa gctagcaggt taatttttaa aaagcagtca aaagtccaag tggcccttgg 600
cagcatttac tctctctgtt tgctctggtt aataatctca ggagcacaaa cattccagat 660
ccaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 720
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccgg cgcgcctgtt 780
tgctgcttgc aatgtttgcc cattttaggg tggacacagg acgctgtggt ttctgagcca 840
gggggcgact cagatcccag ccagtggact tagcccctgt ttgctcctcc gataactggg 900
gtgaccttgg ttaatattca ccagcagcct cccccgttgc ccctctggat ccactgctta 960
aatacggacg aggacagggc cctgtctcct cagcttcagg caccaccact gacctgggac 1020
agtgaatgcc acc atg gcc cca aag aag aag cgg aag gtc ggt atc cac 1069
Met Ala Pro Lys Lys Lys Arg Lys Val Gly Ile His
1 5 10
gga gtc cca gca gcc aag cgg aac tac atc ctg ggc ctg gac atc ggc 1117
Gly Val Pro Ala Ala Lys Arg Asn Tyr Ile Leu Gly Leu Asp Ile Gly
15 20 25
atc acc agc gtg ggc tac ggc atc atc gac tac gag aca cgg gac gtg 1165
Ile Thr Ser Val Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val
30 35 40
atc gat gcc ggc gtg cgg ctg ttc aaa gag gcc aac gtg gaa aac aac 1213
Ile Asp Ala Gly Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn
45 50 55 60
gag ggc agg cgg agc aag aga ggc gcc aga agg ctg aag cgg cgg agg 1261
Glu Gly Arg Arg Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg
65 70 75
cgg cat aga atc cag aga gtg aag aag ctg ctg ttc gac tac aac ctg 1309
Arg His Arg Ile Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu
80 85 90
ctg acc gac cac agc gag ctg agc ggc atc aac ccc tac gag gcc aga 1357
Leu Thr Asp His Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg
95 100 105
gtg aag ggc ctg agc cag aag ctg agc gag gaa gag ttc tct gcc gcc 1405
Val Lys Gly Leu Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala
110 115 120
ctg ctg cac ctg gcc aag aga aga ggc gtg cac aac gtg aac gag gtg 1453
Leu Leu His Leu Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val
125 130 135 140
gaa gag gac acc ggc aac gag ctg tcc acc aaa gag cag atc agc cgg 1501
Glu Glu Asp Thr Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg
145 150 155
aac agc aag gcc ctg gaa gag aaa tac gtg gcc gaa ctg cag ctg gaa 1549
Asn Ser Lys Ala Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu
160 165 170
cgg ctg aag aaa gac ggc gaa gtg cgg ggc agc atc aac aga ttc aag 1597
Arg Leu Lys Lys Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys
175 180 185
acc agc gac tac gtg aaa gaa gcc aaa cag ctg ctg aag gtg cag aag 1645
Thr Ser Asp Tyr Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys
190 195 200
gcc tac cac cag ctg gac cag agc ttc atc gac acc tac atc gac ctg 1693
Ala Tyr His Gln Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu
205 210 215 220
ctg gaa acc cgg cgg acc tac tat gag gga cct ggc gag ggc agc ccc 1741
Leu Glu Thr Arg Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro
225 230 235
ttc ggc tgg aag gac atc aaa gaa tgg tac gag atg ctg atg ggc cac 1789
Phe Gly Trp Lys Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His
240 245 250
tgc acc tac ttc ccc gag gaa ctg cgg agc gtg aag tac gcc tac aac 1837
Cys Thr Tyr Phe Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn
255 260 265
gcc gac ctg tac aac gcc ctg aac gac ctg aac aat ctc gtg atc acc 1885
Ala Asp Leu Tyr Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr
270 275 280
agg gac gag aac gag aag ctg gaa tat tac gag aag ttc cag atc atc 1933
Arg Asp Glu Asn Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile
285 290 295 300
gag aac gtg ttc aag cag aag aag aag ccc acc ctg aag cag atc gcc 1981
Glu Asn Val Phe Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala
305 310 315
aaa gaa atc ctc gtg aac gaa gag gat att aag ggc tac aga gtg acc 2029
Lys Glu Ile Leu Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr
320 325 330
agc acc ggc aag ccc gag ttc acc aac ctg aag gtg tac cac gac atc 2077
Ser Thr Gly Lys Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile
335 340 345
aag gac att acc gcc cgg aaa gag att att gag aac gcc gag ctg ctg 2125
Lys Asp Ile Thr Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu
350 355 360
gat cag att gcc aag atc ctg acc atc tac cag agc agc gag gac atc 2173
Asp Gln Ile Ala Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile
365 370 375 380
cag gaa gaa ctg acc aat ctg aac tcc gag ctg acc cag gaa gag atc 2221
Gln Glu Glu Leu Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile
385 390 395
gag cag atc tct aat ctg aag ggc tat acc ggc acc cac aac ctg agc 2269
Glu Gln Ile Ser Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser
400 405 410
ctg aag gcc atc aac ctg atc ctg gac gag ctg tgg cac acc aac gac 2317
Leu Lys Ala Ile Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp
415 420 425
aac cag atc gct atc ttc aac cgg ctg aag ctg gtg ccc aag aag gtg 2365
Asn Gln Ile Ala Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val
430 435 440
gac ctg tcc cag cag aaa gag atc ccc acc acc ctg gtg gac gac ttc 2413
Asp Leu Ser Gln Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe
445 450 455 460
atc ctg agc ccc gtc gtg aag aga agc ttc atc cag agc atc aaa gtg 2461
Ile Leu Ser Pro Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val
465 470 475
atc aac gcc atc atc aag aag tac ggc ctg ccc aac gac atc att atc 2509
Ile Asn Ala Ile Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile
480 485 490
gag ctg gcc cgc gag aag aac tcc aag gac gcc cag aaa atg atc aac 2557
Glu Leu Ala Arg Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn
495 500 505
gag atg cag aag cgg aac cgg cag acc aac gag cgg atc gag gaa atc 2605
Glu Met Gln Lys Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile
510 515 520
atc cgg acc acc ggc aaa gag aac gcc aag tac ctg atc gag aag atc 2653
Ile Arg Thr Thr Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile
525 530 535 540
aag ctg cac gac atg cag gaa ggc aag tgc ctg tac agc ctg gaa gcc 2701
Lys Leu His Asp Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala
545 550 555
atc cct ctg gaa gat ctg ctg aac aac ccc ttc aac tat gag gtg gac 2749
Ile Pro Leu Glu Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp
560 565 570
cac atc atc ccc aga agc gtg tcc ttc gac aac agc ttc aac aac aag 2797
His Ile Ile Pro Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys
575 580 585
gtg ctc gtg aag cag gaa gaa aac agc aag aag ggc aac cgg acc cca 2845
Val Leu Val Lys Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro
590 595 600
ttc cag tac ctg agc agc agc gac agc aag atc agc tac gaa acc ttc 2893
Phe Gln Tyr Leu Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe
605 610 615 620
aag aag cac atc ctg aat ctg gcc aag ggc aag ggc aga atc agc aag 2941
Lys Lys His Ile Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys
625 630 635
acc aag aaa gag tat ctg ctg gaa gaa cgg gac atc aac agg ttc tcc 2989
Thr Lys Lys Glu Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser
640 645 650
gtg cag aaa gac ttc atc aac cgg aac ctg gtg gat acc aga tac gcc 3037
Val Gln Lys Asp Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala
655 660 665
acc aga ggc ctg atg aac ctg ctg cgg agc tac ttc aga gtg aac aac 3085
Thr Arg Gly Leu Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn
670 675 680
ctg gac gtg aaa gtg aag tcc atc aat ggc ggc ttc acc agc ttt ctg 3133
Leu Asp Val Lys Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu
685 690 695 700
cgg cgg aag tgg aag ttt aag aaa gag cgg aac aag ggg tac aag cac 3181
Arg Arg Lys Trp Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His
705 710 715
cac gcc gag gac gcc ctg atc att gcc aac gcc gat ttc atc ttc aaa 3229
His Ala Glu Asp Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys
720 725 730
gag tgg aag aaa ctg gac aag gcc aaa aaa gtg atg gaa aac cag atg 3277
Glu Trp Lys Lys Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met
735 740 745
ttc gag gaa aag cag gcc gag agc atg ccc gag atc gaa acc gag cag 3325
Phe Glu Glu Lys Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln
750 755 760
gag tac aaa gag atc ttc atc acc ccc cac cag atc aag cac att aag 3373
Glu Tyr Lys Glu Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys
765 770 775 780
gac ttc aag gac tac aag tac agc cac cgg gtg gac aag aag cct aat 3421
Asp Phe Lys Asp Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn
785 790 795
aga gag ctg att aac gac acc ctg tac tcc acc cgg aag gac gac aag 3469
Arg Glu Leu Ile Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys
800 805 810
ggc aac acc ctg atc gtg aac aat ctg aac ggc ctg tac gac aag gac 3517
Gly Asn Thr Leu Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp
815 820 825
aat gac aag ctg aaa aag ctg atc aac aag agc ccc gaa aag ctg ctg 3565
Asn Asp Lys Leu Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu
830 835 840
atg tac cac cac gac ccc cag acc tac cag aaa ctg aag ctg att atg 3613
Met Tyr His His Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met
845 850 855 860
gaa cag tac ggc gac gag aag aat ccc ctg tac aag tac tac gag gaa 3661
Glu Gln Tyr Gly Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu
865 870 875
acc ggg aac tac ctg acc aag tac tcc aaa aag gac aac ggc ccc gtg 3709
Thr Gly Asn Tyr Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val
880 885 890
atc aag aag att aag tat tac ggc aac aaa ctg aac gcc cat ctg gac 3757
Ile Lys Lys Ile Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp
895 900 905
atc acc gac gac tac ccc aac agc aga aac aag gtc gtg aag ctg tcc 3805
Ile Thr Asp Asp Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser
910 915 920
ctg aag ccc tac aga ttc gac gtg tac ctg gac aat ggc gtg tac aag 3853
Leu Lys Pro Tyr Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys
925 930 935 940
ttc gtg acc gtg aag aat ctg gat gtg atc aaa aaa gaa aac tac tac 3901
Phe Val Thr Val Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr
945 950 955
gaa gtg aat agc aag tgc tat gag gaa gct aag aag ctg aag aag atc 3949
Glu Val Asn Ser Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile
960 965 970
agc aac cag gcc gag ttt atc gcc tcc ttc tac aac aac gat ctg atc 3997
Ser Asn Gln Ala Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile
975 980 985
aag atc aac ggc gag ctg tat aga gtg atc ggc gtg aac aac gac ctg 4045
Lys Ile Asn Gly Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu
990 995 1000
ctg aac cgg atc gaa gtg aac atg atc gac atc acc tac cgc gag 4090
Leu Asn Arg Ile Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu
1005 1010 1015
tac ctg gaa aac atg aac gac aag agg ccc ccc agg atc att aag 4135
Tyr Leu Glu Asn Met Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys
1020 1025 1030
aca atc gcc tcc aag acc cag agc att aag aag tac agc aca gac 4180
Thr Ile Ala Ser Lys Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp
1035 1040 1045
att ctg ggc aac ctg tat gaa gtg aaa tct aag aag cac cct cag 4225
Ile Leu Gly Asn Leu Tyr Glu Val Lys Ser Lys Lys His Pro Gln
1050 1055 1060
atc atc aaa aag ggc aaa agg cct gct gcc acc aaa aag gcc ggc 4270
Ile Ile Lys Lys Gly Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly
1065 1070 1075
cag gca aaa aag aaa aag taatgactag tgcctcgact gtgccttcta 4318
Gln Ala Lys Lys Lys Lys
1080 1085
gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca 4378
ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg agtaggtgtc 4438
attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg gaagacaata 4498
gcaggcatgc tggggactcg agtagataag tagcatggcg ggttaatcat taactacaag 4558
gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc 4618
gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga 4678
gcgcgcag 4686
<210> 6
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 6
Met Ala Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly Val Pro Ala
1 5 10 15
Ala Lys Arg Asn Tyr Ile Leu Gly Leu Asp Ile Gly Ile Thr Ser Val
20 25 30
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
35 40 45
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
50 55 60
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
65 70 75 80
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
85 90 95
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
100 105 110
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
115 120 125
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
130 135 140
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
145 150 155 160
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
165 170 175
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
180 185 190
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
195 200 205
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
210 215 220
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
225 230 235 240
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
245 250 255
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
260 265 270
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
275 280 285
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
290 295 300
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
305 310 315 320
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
325 330 335
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
340 345 350
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
355 360 365
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
370 375 380
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
385 390 395 400
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
405 410 415
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
420 425 430
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
435 440 445
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
450 455 460
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
465 470 475 480
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
485 490 495
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
500 505 510
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
515 520 525
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
530 535 540
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
545 550 555 560
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
565 570 575
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
580 585 590
Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
595 600 605
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
610 615 620
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
625 630 635 640
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
645 650 655
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
660 665 670
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
675 680 685
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
690 695 700
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
705 710 715 720
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
725 730 735
Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys
740 745 750
Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu
755 760 765
Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp
770 775 780
Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Glu Leu Ile
785 790 795 800
Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu
805 810 815
Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu
820 825 830
Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His
835 840 845
Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly
850 855 860
Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr
865 870 875 880
Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile
885 890 895
Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp
900 905 910
Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr
915 920 925
Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val
930 935 940
Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser
945 950 955 960
Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala
965 970 975
Glu Phe Ile Ala Ser Phe Tyr Asn Asn Asp Leu Ile Lys Ile Asn Gly
980 985 990
Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile
995 1000 1005
Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn
1010 1015 1020
Met Asn Asp Lys Arg Pro Pro Arg Ile Ile Lys Thr Ile Ala Ser
1025 1030 1035
Lys Thr Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn
1040 1045 1050
Leu Tyr Glu Val Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys
1055 1060 1065
Gly Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys
1070 1075 1080
Lys Lys
1085
<210> 7
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 核酸序列SaCas9 (pX601+3NLS)
<400> 7
atggccccaa agaagaagcg gaaggtcggt atccacggag tcccagcagc caagcggaac 60
tacatcctgg gcctggacat cggcatcacc agcgtgggct acggcatcat cgactacgag 120
acacgggacg tgatcgatgc cggcgtgcgg ctgttcaaag aggccaacgt ggaaaacaac 180
gagggcaggc ggagcaagag aggcgccaga aggctgaagc ggcggaggcg gcatagaatc 240
cagagagtga agaagctgct gttcgactac aacctgctga ccgaccacag cgagctgagc 300
ggcatcaacc cctacgaggc cagagtgaag ggcctgagcc agaagctgag cgaggaagag 360
ttctctgccg ccctgctgca cctggccaag agaagaggcg tgcacaacgt gaacgaggtg 420
gaagaggaca ccggcaacga gctgtccacc aaagagcaga tcagccggaa cagcaaggcc 480
ctggaagaga aatacgtggc cgaactgcag ctggaacggc tgaagaaaga cggcgaagtg 540
cggggcagca tcaacagatt caagaccagc gactacgtga aagaagccaa acagctgctg 600
aaggtgcaga aggcctacca ccagctggac cagagcttca tcgacaccta catcgacctg 660
ctggaaaccc ggcggaccta ctatgaggga cctggcgagg gcagcccctt cggctggaag 720
gacatcaaag aatggtacga gatgctgatg ggccactgca cctacttccc cgaggaactg 780
cggagcgtga agtacgccta caacgccgac ctgtacaacg ccctgaacga cctgaacaat 840
ctcgtgatca ccagggacga gaacgagaag ctggaatatt acgagaagtt ccagatcatc 900
gagaacgtgt tcaagcagaa gaagaagccc accctgaagc agatcgccaa agaaatcctc 960
gtgaacgaag aggatattaa gggctacaga gtgaccagca ccggcaagcc cgagttcacc 1020
aacctgaagg tgtaccacga catcaaggac attaccgccc ggaaagagat tattgagaac 1080
gccgagctgc tggatcagat tgccaagatc ctgaccatct accagagcag cgaggacatc 1140
caggaagaac tgaccaatct gaactccgag ctgacccagg aagagatcga gcagatctct 1200
aatctgaagg gctataccgg cacccacaac ctgagcctga aggccatcaa cctgatcctg 1260
gacgagctgt ggcacaccaa cgacaaccag atcgctatct tcaaccggct gaagctggtg 1320
cccaagaagg tggacctgtc ccagcagaaa gagatcccca ccaccctggt ggacgacttc 1380
atcctgagcc ccgtcgtgaa gagaagcttc atccagagca tcaaagtgat caacgccatc 1440
atcaagaagt acggcctgcc caacgacatc attatcgagc tggcccgcga gaagaactcc 1500
aaggacgccc agaaaatgat caacgagatg cagaagcgga accggcagac caacgagcgg 1560
atcgaggaaa tcatccggac caccggcaaa gagaacgcca agtacctgat cgagaagatc 1620
aagctgcacg acatgcagga aggcaagtgc ctgtacagcc tggaagccat ccctctggaa 1680
gatctgctga acaacccctt caactatgag gtggaccaca tcatccccag aagcgtgtcc 1740
ttcgacaaca gcttcaacaa caaggtgctc gtgaagcagg aagaaaacag caagaagggc 1800
aaccggaccc cattccagta cctgagcagc agcgacagca agatcagcta cgaaaccttc 1860
aagaagcaca tcctgaatct ggccaagggc aagggcagaa tcagcaagac caagaaagag 1920
tatctgctgg aagaacggga catcaacagg ttctccgtgc agaaagactt catcaaccgg 1980
aacctggtgg ataccagata cgccaccaga ggcctgatga acctgctgcg gagctacttc 2040
agagtgaaca acctggacgt gaaagtgaag tccatcaatg gcggcttcac cagctttctg 2100
cggcggaagt ggaagtttaa gaaagagcgg aacaaggggt acaagcacca cgccgaggac 2160
gccctgatca ttgccaacgc cgatttcatc ttcaaagagt ggaagaaact ggacaaggcc 2220
aaaaaagtga tggaaaacca gatgttcgag gaaaagcagg ccgagagcat gcccgagatc 2280
gaaaccgagc aggagtacaa agagatcttc atcacccccc accagatcaa gcacattaag 2340
gacttcaagg actacaagta cagccaccgg gtggacaaga agcctaatag agagctgatt 2400
aacgacaccc tgtactccac ccggaaggac gacaagggca acaccctgat cgtgaacaat 2460
ctgaacggcc tgtacgacaa ggacaatgac aagctgaaaa agctgatcaa caagagcccc 2520
gaaaagctgc tgatgtacca ccacgacccc cagacctacc agaaactgaa gctgattatg 2580
gaacagtacg gcgacgagaa gaatcccctg tacaagtact acgaggaaac cgggaactac 2640
ctgaccaagt actccaaaaa ggacaacggc cccgtgatca agaagattaa gtattacggc 2700
aacaaactga acgcccatct ggacatcacc gacgactacc ccaacagcag aaacaaggtc 2760
gtgaagctgt ccctgaagcc ctacagattc gacgtgtacc tggacaatgg cgtgtacaag 2820
ttcgtgaccg tgaagaatct ggatgtgatc aaaaaagaaa actactacga agtgaatagc 2880
aagtgctatg aggaagctaa gaagctgaag aagatcagca accaggccga gtttatcgcc 2940
tccttctaca acaacgatct gatcaagatc aacggcgagc tgtatagagt gatcggcgtg 3000
aacaacgacc tgctgaaccg gatcgaagtg aacatgatcg acatcaccta ccgcgagtac 3060
ctggaaaaca tgaacgacaa gaggcccccc aggatcatta agacaatcgc ctccaagacc 3120
cagagcatta agaagtacag cacagacatt ctgggcaacc tgtatgaagt gaaatctaag 3180
aagcaccctc agatcatcaa aaagggcaaa aggcctgctg ccaccaaaaa ggccggccag 3240
gcaaaaaaga aaaag 3255
<210> 8
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> PCSK9 sgRNA
<400> 8
aagttggtcc ccaaagtccc 20
<210> 9
<211> 77
<212> DNA
<213> 人工序列
<220>
<223> sgRNA支架
<400> 9
atctcgccaa caagttgacg agataaacac ggcattttgc cttgttttag tagattctgt 60
ttccagagta ctaaaac 77
<210> 10
<211> 249
<212> DNA
<213> 人工序列
<220>
<223> U6启动子
<400> 10
ggtgtttcgt cctttccaca agatatataa agccaagaaa tcgaaatact ttcaagttac 60
ggtaagcata tgatagtcca ttttaaaaca taattttaaa actgcaaact acccaagaaa 120
ttattacttt ctacgtcacg tattttgtac taatatcttt gtgtttacag tcaaattaat 180
tccaattatc tctctaacag ccttgtatcg tatatgcaaa tatgaaggaa tcatgggaaa 240
taggccctc 249
<210> 11
<211> 176
<212> DNA
<213> 人工序列
<220>
<223> TBG-S1启动子
<400> 11
actcaaagtt caaaccttat cattttttgc tttgttcctc ttggccttgg ttttgtacat 60
cagctttgaa aataccatcc cagggttaat gctggggtta atttataact aagagtgctc 120
tagttttgca atacaggaca tgctataaaa atggaaagat gttgctttct gagaga 176
<210> 12
<211> 251
<212> DNA
<213> 人工序列
<220>
<223> HLP启动子
<400> 12
tgtttgctgc ttgcaatgtt tgcccatttt agggtggaca caggacgctg tggtttctga 60
gccagggggc gactcagatc ccagccagtg gacttagccc ctgtttgctc ctccgataac 120
tggggtgacc ttggttaata ttcaccagca gcctcccccg ttgcccctct ggatccactg 180
cttaaatacg gacgaggaca gggccctgtc tcctcagctt caggcaccac cactgacctg 240
ggacagtgaa t 251
<210> 13
<211> 417
<212> DNA
<213> 人工序列
<220>
<223> rhPCSK9基因组序列-外显子7核酸序列
<220>
<221> misc_特征
<222> (214)..(397)
<223> 外显子7
<220>
<221> misc_特征
<222> (256)..(261)
<223> PAM (SaCas9)
<220>
<221> misc_RNA
<222> (262)..(281)
<223> sgRNA-SaCas9
<220>
<221> misc_特征
<222> (293)..(314)
<223> PCS 7-8靶向序列
<220>
<221> misc_特征
<222> (305)..(306)
<223> 大范围核酸酶切割位点
<400> 13
cctggctatg gtagggacag aggggagcac cagggcgggg caggggtgcc agagttctgc 60
ctggggagtc agattttcct taggagggga catttgaatg ggacccaaac aggtgtatag 120
cagttgttca gcccagctgg caaggcctca gtttgcttct gcaacccctc tcttgggctc 180
ctttctgtgc cacctacctc ctcacctttc caggtcatca cagttggggc caccaatgcc 240
caggaccagc cggtgaccct ggggactttg gggaccaact ttggccgctg tgtggacctc 300
tttgccccag gggaggacat cattggtgcc tccagcgact gcagcacctg ctttgtgtca 360
cggagtggga catcgcaggc tgctgcccac gtggctggta agtcaccacc ccactgc 417
<210> 14
<211> 8924
<212> DNA
<213> 人工序列
<220>
<223> 生产质粒TBG.hOTCco2.G4SVPA.LB
<220>
<221> 重复_区域
<222> (1)..(105)
<223> ITR
<220>
<221> 启动子
<222> (164)..(880)
<223> TBG启动子
<220>
<221> 增强子
<222> (183)..(282)
<223> 增强子
<220>
<221> TATA_信号
<222> (847)..(850)
<223> TATA信号
<220>
<221> misc_特征
<222> (972)..(2039)
<223> hOTCco2
<220>
<221> 聚A_信号
<222> (2042)..(2178)
<223> G4SVPA
<220>
<221> 重复_区域
<222> (2207)..(2374)
<223> ITR
<220>
<221> misc_特征
<222> (3898)..(5700)
<223> tmp1
<220>
<221> misc_特征
<222> (6866)..(7726)
<223> Amp-R
<220>
<221> misc_特征
<222> (7897)..(8485)
<223> 起源
<400> 14
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtgtagcc atgctctagg 120
aagatcaatt caattcacgc gtggtaccta gaactatagc tagaattcgc ccttaagcta 180
gcaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 240
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccag gttaattttt 300
aaaaagcagt caaaagtcca agtggccctt ggcagcattt actctctctg tttgctctgg 360
ttaataatct caggagcaca aacattccag atccggcgcg ccagggctgg aagctacctt 420
tgacatcatt tcctctgcga atgcatgtat aatttctaca gaacctatta gaaaggatca 480
cccagcctct gcttttgtac aactttccct taaaaaactg ccaattccac tgctgtttgg 540
cccaatagtg agaacttttt cctgctgcct cttggtgctt ttgcctatgg cccctattct 600
gcctgctgaa gacactcttg ccagcatgga cttaaacccc tccagctctg acaatcctct 660
ttctcttttg ttttacatga agggtctggc agccaaagca atcactcaaa gttcaaacct 720
tatcattttt tgctttgttc ctcttggcct tggttttgta catcagcttt gaaaatacca 780
tcccagggtt aatgctgggg ttaatttata actaagagtg ctctagtttt gcaatacagg 840
acatgctata aaaatggaaa gatgttgctt tctgagagac agctttattg cggtagttta 900
tcacagttaa attgctaacg cagtcagtgc ttctgacaca acagtctcga acttaagctg 960
cattagccac catgctgttc aacctgcgga tcctgctgaa caacgccgcc ttccggaacg 1020
gacacaactt catggtgcgg aacttccggt gcggacagcc actgcagaac aaggtgcagc 1080
tgaagggacg ggacctgctg accctgaaga acttcaccgg agaggagatc aagtacatgc 1140
tgtggctgag cgccgatctg aagttccgga tcaagcagaa gggagagtac ctgccactgc 1200
tgcagggaaa gagcctggga atgatcttcg agaagcggag cacccggacc cggctgagca 1260
ccgagaccgg attcgccctg ctgggaggac acccatgctt cctgaccacc caggacatcc 1320
acctgggagt gaatgagagc ctgaccgaca ccgcccgggt gctgagcagc atggccgacg 1380
ccgtgctggc ccgggtgtac aagcagagcg acctggatac cctggccaag gaggccagca 1440
tcccaatcat caacggactg agcgacctgt accacccaat ccagatcctg gccgattacc 1500
tgaccctgca ggagcactac agcagcctga agggactgac cctgagctgg atcggagacg 1560
gaaacaacat cctgcacagc atcatgatga gcgccgccaa gttcggaatg cacctgcagg 1620
ccgccacccc aaagggatac gagccagatg ccagcgtgac caagctggcc gagcagtacg 1680
ccaaggagaa cggaaccaag ctgctgctga ccaacgaccc actggaggcc gcccacggag 1740
gaaacgtgct gatcaccgat acctggatca gcatgggaca ggaggaggag aagaagaagc 1800
ggctgcaggc cttccaggga taccaggtga ccatgaagac cgccaaggtg gccgccagcg 1860
attggacctt cctgcactgc ctgccacgga agccagagga ggtggacgac gaggtgttct 1920
acagcccacg gagcctggtg ttcccagagg ccgagaaccg gaagtggacc atcatggccg 1980
tgatggtgag cctgctgacc gattacagcc cacagctgca gaagccaaag ttctgataag 2040
cggccgctat ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca 2100
ataaacaagt taacaacaac aattgcattc attttatgtt tcaggttcag ggggaggtgt 2160
gggaggtttt ttaggcatcg ataaggatct tcctagagca tggctacgta gataagtagc 2220
atggcgggtt aatcattaac tacaaggaac ccctagtgat ggagttggcc actccctctc 2280
tgcgcgctcg ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg 2340
cccgggcggc ctcagtgagc gagcgagcgc gcagccttaa ttaacctaat tcactggccg 2400
tcgttttaca acgtcgtgac tgggaaaacc ctggcgttac ccaacttaat cgccttgcag 2460
cacatccccc tttcgccagc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc 2520
aacagttgcg cagcctgaat ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg 2580
cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc 2640
ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg ctttccccgt caagctctaa 2700
atcgggggct ccctttaggg ttccgattta gtgctttacg gcacctcgac cccaaaaaac 2760
ttgattaggg tgatggttca cgtgagttac gtgcgaggtc ttccctgcag tgtgggattt 2820
acgctgattc aggaatgggt tgttccctgg gatatggttc taacgcggga ggagcttgta 2880
atcctgagga agtgtatgca cgtgtgcctg tgttgtgcca acattgatat catgacgagc 2940
atgatgatcc atggttacga gtcctgggct ctccactgtc attgttccag tcccggttcc 3000
ctgcagtgta tagccggcgg gcaggttttg gccagctggt ttaggatggt ggtggatggc 3060
gccatgttta atcagaggtt tatatggtac cgggaggtgg tgaattacaa catgccaaaa 3120
gaggtaatgt ttatgtccag cgtgtttatg aggggtcgcc acttaatcta cctgcgcttg 3180
tggtatgatg gccacgtggg ttctgtggtc cccgccatga gctttggata cagcgccttg 3240
cactgtggga ttttgaacaa tattgtggtg ctgtgctgca gttactgtgc tgatttaagt 3300
gagatcaggg tgcgctgctg tgcccggagg acaaggcgcc ttatgctgcg ggcggtgcga 3360
atcatcgctg aggagaccac tgccatgttg tattcctgca ggacggagcg gcggcggcag 3420
cagtttattc gcgcgctgct gcagcaccac cgccctatcc tgatgcacga ttatgactct 3480
acccccatgt aggcgtggac ttctccttcg ccgcccgtta agcaaccgca agttggacag 3540
cagcctgtgg ctcagcagct ggacagcgac atgaacttaa gtgagctgcc cggggagttt 3600
attaatatca ctgatgagcg tttggctcga caggaaaccg tgtggaatat aacacctaag 3660
aatatgtctg ttacccatga tatgatgctt tttaaggcca gccggggaga aaggactgtg 3720
tactctgtgt gttgggaggg aggtggcagg ttgaatacta gggttctgtg agtttgatta 3780
aggtacggtg atctgtataa gctatgtggt ggtggggcta tactactgaa tgaaaaatga 3840
cttgaaattt tctgcaattg aaaaataaac acgttgaaac ataacacaaa cgattcttta 3900
ttcttgggca atgtatgaaa aagtgtaaga ggatgtggca aatatttcat taatgtagtt 3960
gtggccagac cagtcccatg aaaatgacat agagtatgca cttggagttg tgtctcctgt 4020
ttcctgtgta ccgtttagtg taatggttag tgttacaggt ttagttttgt ctccgtttaa 4080
gtaaacttga ctgacaatgt tacttttggc agttttaccg tgagattttg gataagctga 4140
taggttaggc ataaatccaa cagcgtttgt ataggctgtg ccttcagtaa gatctccatt 4200
tctaaagttc caatattctg ggtccaggaa ggaattgttt agtagcactc cattttcgtc 4260
aaatcttata ataagatgag cactttgaac tgttccagat attggagcca aactgccttt 4320
aacagccaaa actgaaactg tagcaagtat ttgactgcca cattttgtta agaccaaagt 4380
gagtttagca tctttctctg catttagtct acagttagga gatggagctg gtgtggtcca 4440
caaagttagc ttatcattat ttttgtttcc tactgtaatg gcacctgtgc tgtcaaaact 4500
aaggccagtt cctagtttag gaaccatagc cttgtttgaa tcaaattcta ggccatggcc 4560
aatttttgtt ttgaggggat ttgtgtttgg tgcattaggt gaaccaaatt caagcccatc 4620
tcctgcatta atggctatgg ctgtagcgtc aaacatcaac cccttggcag tgcttaggtt 4680
aacctcaagc tttttggaat tgtttgaagc tgtaaacaag taaaggcctt tgttgtagtt 4740
aatatccaag ttgtgggctg agtttataaa aagagggccc tgtcctagtc ttagatttag 4800
ttggttttga gcatcaaacg gataactaac atcaagtata aggcgtctgt tttgagaatc 4860
aatccttagt cctcctgcta cattaagttg catattgcct tgtgaatcaa aacccaaggc 4920
tccagtaact ttagtttgca aggaagtatt attaatagtc acacctggac cagttgctac 4980
ggtcaaagtg tttaggtcgt ctgttacatg caaaggagcc ccgtacttta gtcctagttt 5040
tccattttgt gtataaatgg gctctttcaa gtcaatgccc aagctaccag tggcagtagt 5100
tagagggggt gaggcagtga tagtaagggt actgctatcg gtggtggtga gggggcctga 5160
tgtttgcagg gctagctttc cttctgacac tgtgaggggt ccttgggtgg caatgctaag 5220
tttggagtcg tgcacggtta gcggggcctg tgattgcatg gtgagtgtgt tgcccgcgac 5280
cattagaggt gcggcggcag ccacagttag ggcttctgag gtaactgtga ggggtgcaga 5340
tatttccagg tttatgtttg acttggtttt tttgagaggt gggctcacag tggttacatt 5400
ttgggaggta aggttgccgg cctcgtccag agagaggccg ttgcccattt tgagcgcaag 5460
catgccattg gaggtaacta gaggttcgga taggcgcaaa gagagtaccc cagggggact 5520
ctcttgaaac ccattggggg atacaaaggg aggagtaaga aaaggcacag ttggaggacc 5580
ggtttccgtg tcatatggat acacggggtt gaaggtatct tcagacggtc ttgcgcgctt 5640
catctgcaac aacatgaaga tagtgggtgc ggatggacag gaacaggagg aaactgacat 5700
tccatttaga ttgtggagaa agtttgcagc caggaggaag ctgcaatacc agagctggga 5760
ggagggcaag gaggtgctgc tgaataaact ggacagaaat ttgctaactg attttaagta 5820
agtgatgctt tattattttt ttttattagt taaagggaat aagatccccg ggtactctag 5880
ttaattaact agaggatctt gatgtaatcc aaggttagga cagttgcaaa tcacagtgag 5940
aacacagggt cccctgtccc gctcaactag cagggggcgc tgggtaaact cccgaatcag 6000
gctacgggca agctctccct gggcggtaag ccggacgccg tgcgccgggc cctcgatatg 6060
atcctcgggc aattcaaagt agcaaaactc accggagtcg cgggcaaagc acttgtggcg 6120
gcgacagtgg accaggtgtt tcaggcgcag ttgctctgcc tctccactta acattcagtc 6180
gtagccgtcc gccgagtcct ttaccgcgtc aaagttagga ataaattgat ccggatagtg 6240
gccgggaggt cccgagaagg ggttaaagta gaccgatggc acaaactcct caataaattg 6300
cagagttcca atgcctccag agcgcggctc agaggacgag gtctgcagag ttaggattgc 6360
ctgacgaggc gtgaatgaag gacggccggc gccgccgatc tgaaatgtcc cgtccggacg 6420
gagaccaagc gaggagctca ccgactcgtc gttgagctga atacctcgcc ctctgattgt 6480
caggtgagtt ataccctgcc cgggcgaccg cacgtgggcc atcgccctga tagacggttt 6540
ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 6600
caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg 6660
cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 6720
taacgcttac aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt 6780
atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct 6840
tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc 6900
cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa 6960
agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg 7020
taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt 7080
tctgctatgt ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg 7140
catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac 7200
ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc 7260
ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa 7320
catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc 7380
aaacgacgag cgtgacacca cgatgcctgt agcaatggca acaacgttgc gcaaactatt 7440
aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga tggaggcgga 7500
taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta ttgctgataa 7560
atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc cagatggtaa 7620
gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg atgaacgaaa 7680
tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt cagaccaagt 7740
ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa ggatctaggt 7800
gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg 7860
agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt 7920
aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca 7980
agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac 8040
tgttcttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac 8100
atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct 8160
taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg 8220
gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga gatacctaca 8280
gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt 8340
aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcctggta 8400
tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc 8460
gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc 8520
cttttgctgg ccttttgctc acatgttctt tcctgcgtta tcccctgatt ctgtggataa 8580
ccgtattacc gcctttgagt gagctgatac cgctcgccgc agccgaacga ccgagcgcag 8640
cgagtcagtg agcgaggaag cggaagagcg cccaatacgc aaaccgcctc tccccgcgcg 8700
ttggccgatt cattaatgca gctggcacga caggtttccc gactggaaag cgggcagtga 8760
gcgcaacgca attaatgtga gttagctcac tcattaggca ccccaggctt tacactttat 8820
gcttccggct cgtatgttgt gtggaattgt gagcggataa caatttcaca caggaaacag 8880
ctatgaccat gattacgcca gatttaatta aggccttaat tagg 8924
<210> 15
<211> 2374
<212> DNA
<213> 人工序列
<220>
<223> 载体基因组TBG.hOTCco2.G4SVPA.LB
<220>
<221> 重复_区域
<222> (1)..(105)
<223> ITR
<220>
<221> 启动子
<222> (164)..(880)
<223> TBG启动子
<220>
<221> 增强子
<222> (183)..(282)
<223> 增强子
<220>
<221> TATA_信号
<222> (847)..(850)
<223> TATA
<220>
<221> CDS
<222> (972)..(2039)
<223> hOTCco2
<220>
<221> 聚A_信号
<222> (2042)..(2178)
<223> G4SVPA
<220>
<221> 重复_区域
<222> (2207)..(2374)
<223> ITR
<400> 15
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtgtagcc atgctctagg 120
aagatcaatt caattcacgc gtggtaccta gaactatagc tagaattcgc ccttaagcta 180
gcaggttaat ttttaaaaag cagtcaaaag tccaagtggc ccttggcagc atttactctc 240
tctgtttgct ctggttaata atctcaggag cacaaacatt ccagatccag gttaattttt 300
aaaaagcagt caaaagtcca agtggccctt ggcagcattt actctctctg tttgctctgg 360
ttaataatct caggagcaca aacattccag atccggcgcg ccagggctgg aagctacctt 420
tgacatcatt tcctctgcga atgcatgtat aatttctaca gaacctatta gaaaggatca 480
cccagcctct gcttttgtac aactttccct taaaaaactg ccaattccac tgctgtttgg 540
cccaatagtg agaacttttt cctgctgcct cttggtgctt ttgcctatgg cccctattct 600
gcctgctgaa gacactcttg ccagcatgga cttaaacccc tccagctctg acaatcctct 660
ttctcttttg ttttacatga agggtctggc agccaaagca atcactcaaa gttcaaacct 720
tatcattttt tgctttgttc ctcttggcct tggttttgta catcagcttt gaaaatacca 780
tcccagggtt aatgctgggg ttaatttata actaagagtg ctctagtttt gcaatacagg 840
acatgctata aaaatggaaa gatgttgctt tctgagagac agctttattg cggtagttta 900
tcacagttaa attgctaacg cagtcagtgc ttctgacaca acagtctcga acttaagctg 960
cattagccac c atg ctg ttc aac ctg cgg atc ctg ctg aac aac gcc gcc 1010
Met Leu Phe Asn Leu Arg Ile Leu Leu Asn Asn Ala Ala
1 5 10
ttc cgg aac gga cac aac ttc atg gtg cgg aac ttc cgg tgc gga cag 1058
Phe Arg Asn Gly His Asn Phe Met Val Arg Asn Phe Arg Cys Gly Gln
15 20 25
cca ctg cag aac aag gtg cag ctg aag gga cgg gac ctg ctg acc ctg 1106
Pro Leu Gln Asn Lys Val Gln Leu Lys Gly Arg Asp Leu Leu Thr Leu
30 35 40 45
aag aac ttc acc gga gag gag atc aag tac atg ctg tgg ctg agc gcc 1154
Lys Asn Phe Thr Gly Glu Glu Ile Lys Tyr Met Leu Trp Leu Ser Ala
50 55 60
gat ctg aag ttc cgg atc aag cag aag gga gag tac ctg cca ctg ctg 1202
Asp Leu Lys Phe Arg Ile Lys Gln Lys Gly Glu Tyr Leu Pro Leu Leu
65 70 75
cag gga aag agc ctg gga atg atc ttc gag aag cgg agc acc cgg acc 1250
Gln Gly Lys Ser Leu Gly Met Ile Phe Glu Lys Arg Ser Thr Arg Thr
80 85 90
cgg ctg agc acc gag acc gga ttc gcc ctg ctg gga gga cac cca tgc 1298
Arg Leu Ser Thr Glu Thr Gly Phe Ala Leu Leu Gly Gly His Pro Cys
95 100 105
ttc ctg acc acc cag gac atc cac ctg gga gtg aat gag agc ctg acc 1346
Phe Leu Thr Thr Gln Asp Ile His Leu Gly Val Asn Glu Ser Leu Thr
110 115 120 125
gac acc gcc cgg gtg ctg agc agc atg gcc gac gcc gtg ctg gcc cgg 1394
Asp Thr Ala Arg Val Leu Ser Ser Met Ala Asp Ala Val Leu Ala Arg
130 135 140
gtg tac aag cag agc gac ctg gat acc ctg gcc aag gag gcc agc atc 1442
Val Tyr Lys Gln Ser Asp Leu Asp Thr Leu Ala Lys Glu Ala Ser Ile
145 150 155
cca atc atc aac gga ctg agc gac ctg tac cac cca atc cag atc ctg 1490
Pro Ile Ile Asn Gly Leu Ser Asp Leu Tyr His Pro Ile Gln Ile Leu
160 165 170
gcc gat tac ctg acc ctg cag gag cac tac agc agc ctg aag gga ctg 1538
Ala Asp Tyr Leu Thr Leu Gln Glu His Tyr Ser Ser Leu Lys Gly Leu
175 180 185
acc ctg agc tgg atc gga gac gga aac aac atc ctg cac agc atc atg 1586
Thr Leu Ser Trp Ile Gly Asp Gly Asn Asn Ile Leu His Ser Ile Met
190 195 200 205
atg agc gcc gcc aag ttc gga atg cac ctg cag gcc gcc acc cca aag 1634
Met Ser Ala Ala Lys Phe Gly Met His Leu Gln Ala Ala Thr Pro Lys
210 215 220
gga tac gag cca gat gcc agc gtg acc aag ctg gcc gag cag tac gcc 1682
Gly Tyr Glu Pro Asp Ala Ser Val Thr Lys Leu Ala Glu Gln Tyr Ala
225 230 235
aag gag aac gga acc aag ctg ctg ctg acc aac gac cca ctg gag gcc 1730
Lys Glu Asn Gly Thr Lys Leu Leu Leu Thr Asn Asp Pro Leu Glu Ala
240 245 250
gcc cac gga gga aac gtg ctg atc acc gat acc tgg atc agc atg gga 1778
Ala His Gly Gly Asn Val Leu Ile Thr Asp Thr Trp Ile Ser Met Gly
255 260 265
cag gag gag gag aag aag aag cgg ctg cag gcc ttc cag gga tac cag 1826
Gln Glu Glu Glu Lys Lys Lys Arg Leu Gln Ala Phe Gln Gly Tyr Gln
270 275 280 285
gtg acc atg aag acc gcc aag gtg gcc gcc agc gat tgg acc ttc ctg 1874
Val Thr Met Lys Thr Ala Lys Val Ala Ala Ser Asp Trp Thr Phe Leu
290 295 300
cac tgc ctg cca cgg aag cca gag gag gtg gac gac gag gtg ttc tac 1922
His Cys Leu Pro Arg Lys Pro Glu Glu Val Asp Asp Glu Val Phe Tyr
305 310 315
agc cca cgg agc ctg gtg ttc cca gag gcc gag aac cgg aag tgg acc 1970
Ser Pro Arg Ser Leu Val Phe Pro Glu Ala Glu Asn Arg Lys Trp Thr
320 325 330
atc atg gcc gtg atg gtg agc ctg ctg acc gat tac agc cca cag ctg 2018
Ile Met Ala Val Met Val Ser Leu Leu Thr Asp Tyr Ser Pro Gln Leu
335 340 345
cag aag cca aag ttc tga taa gcggccgcta tttgtgaaat ttgtgatgct 2069
Gln Lys Pro Lys Phe
350
attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa caattgcatt 2129
cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaggcatc gataaggatc 2189
ttcctagagc atggctacgt agataagtag catggcgggt taatcattaa ctacaaggaa 2249
cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac tgaggccggg 2309
cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg cctcagtgag cgagcgagcg 2369
cgcag 2374
<210> 16
<211> 354
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 16
Met Leu Phe Asn Leu Arg Ile Leu Leu Asn Asn Ala Ala Phe Arg Asn
1 5 10 15
Gly His Asn Phe Met Val Arg Asn Phe Arg Cys Gly Gln Pro Leu Gln
20 25 30
Asn Lys Val Gln Leu Lys Gly Arg Asp Leu Leu Thr Leu Lys Asn Phe
35 40 45
Thr Gly Glu Glu Ile Lys Tyr Met Leu Trp Leu Ser Ala Asp Leu Lys
50 55 60
Phe Arg Ile Lys Gln Lys Gly Glu Tyr Leu Pro Leu Leu Gln Gly Lys
65 70 75 80
Ser Leu Gly Met Ile Phe Glu Lys Arg Ser Thr Arg Thr Arg Leu Ser
85 90 95
Thr Glu Thr Gly Phe Ala Leu Leu Gly Gly His Pro Cys Phe Leu Thr
100 105 110
Thr Gln Asp Ile His Leu Gly Val Asn Glu Ser Leu Thr Asp Thr Ala
115 120 125
Arg Val Leu Ser Ser Met Ala Asp Ala Val Leu Ala Arg Val Tyr Lys
130 135 140
Gln Ser Asp Leu Asp Thr Leu Ala Lys Glu Ala Ser Ile Pro Ile Ile
145 150 155 160
Asn Gly Leu Ser Asp Leu Tyr His Pro Ile Gln Ile Leu Ala Asp Tyr
165 170 175
Leu Thr Leu Gln Glu His Tyr Ser Ser Leu Lys Gly Leu Thr Leu Ser
180 185 190
Trp Ile Gly Asp Gly Asn Asn Ile Leu His Ser Ile Met Met Ser Ala
195 200 205
Ala Lys Phe Gly Met His Leu Gln Ala Ala Thr Pro Lys Gly Tyr Glu
210 215 220
Pro Asp Ala Ser Val Thr Lys Leu Ala Glu Gln Tyr Ala Lys Glu Asn
225 230 235 240
Gly Thr Lys Leu Leu Leu Thr Asn Asp Pro Leu Glu Ala Ala His Gly
245 250 255
Gly Asn Val Leu Ile Thr Asp Thr Trp Ile Ser Met Gly Gln Glu Glu
260 265 270
Glu Lys Lys Lys Arg Leu Gln Ala Phe Gln Gly Tyr Gln Val Thr Met
275 280 285
Lys Thr Ala Lys Val Ala Ala Ser Asp Trp Thr Phe Leu His Cys Leu
290 295 300
Pro Arg Lys Pro Glu Glu Val Asp Asp Glu Val Phe Tyr Ser Pro Arg
305 310 315 320
Ser Leu Val Phe Pro Glu Ala Glu Asn Arg Lys Trp Thr Ile Met Ala
325 330 335
Val Met Val Ser Leu Leu Thr Asp Tyr Ser Pro Gln Leu Gln Lys Pro
340 345 350
Lys Phe
<210> 17
<211> 1068
<212> DNA
<213> 人工序列
<220>
<223> 工程化的核酸序列hOTCco2
<400> 17
atgctgttca acctgcggat cctgctgaac aacgccgcct tccggaacgg acacaacttc 60
atggtgcgga acttccggtg cggacagcca ctgcagaaca aggtgcagct gaagggacgg 120
gacctgctga ccctgaagaa cttcaccgga gaggagatca agtacatgct gtggctgagc 180
gccgatctga agttccggat caagcagaag ggagagtacc tgccactgct gcagggaaag 240
agcctgggaa tgatcttcga gaagcggagc acccggaccc ggctgagcac cgagaccgga 300
ttcgccctgc tgggaggaca cccatgcttc ctgaccaccc aggacatcca cctgggagtg 360
aatgagagcc tgaccgacac cgcccgggtg ctgagcagca tggccgacgc cgtgctggcc 420
cgggtgtaca agcagagcga cctggatacc ctggccaagg aggccagcat cccaatcatc 480
aacggactga gcgacctgta ccacccaatc cagatcctgg ccgattacct gaccctgcag 540
gagcactaca gcagcctgaa gggactgacc ctgagctgga tcggagacgg aaacaacatc 600
ctgcacagca tcatgatgag cgccgccaag ttcggaatgc acctgcaggc cgccacccca 660
aagggatacg agccagatgc cagcgtgacc aagctggccg agcagtacgc caaggagaac 720
ggaaccaagc tgctgctgac caacgaccca ctggaggccg cccacggagg aaacgtgctg 780
atcaccgata cctggatcag catgggacag gaggaggaga agaagaagcg gctgcaggcc 840
ttccagggat accaggtgac catgaagacc gccaaggtgg ccgccagcga ttggaccttc 900
ctgcactgcc tgccacggaa gccagaggag gtggacgacg aggtgttcta cagcccacgg 960
agcctggtgt tcccagaggc cgagaaccgg aagtggacca tcatggccgt gatggtgagc 1020
ctgctgaccg attacagccc acagctgcag aagccaaagt tctgataa 1068
<210> 18
<211> 4687
<212> DNA
<213> 人工序列
<220>
<223> 生产质粒TBG-S1-F113.PCS7-8L.197.bGH
<220>
<221> 重复_区域
<222> (1)..(168)
<223> ITR
<220>
<221> 启动子
<222> (206)..(318)
<223> TBG S1启动子
<220>
<221> misc_特征
<222> (330)..(1424)
<223> PCS7-8L
<220>
<221> 聚A_信号
<222> (1435)..(1649)
<223> bGH聚A信号
<220>
<221> 重复_区域
<222> (1699)..(1866)
<223> ITR
<220>
<221> misc_特征
<222> (2629)..(3486)
<223> Amp-R
<220>
<221> misc_特征
<222> (3660)..(4248)
<223> 起源
<400> 18
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180
aggaagatcg gaattcgccc ttaagctttg aaaataccat cccagggtta atgctggggt 240
taatttataa ctaagagtgc tctagttttg caatacagga catgctataa aaatggaaag 300
atgttgcttt ctgagagaca gcggccgcca tggcaccgaa gaagaagcgc aaggtgcata 360
tgaatacaaa atataataaa gagttcttac tctacttagc agggtttgta gacggtgacg 420
gttccatctt tgccaggatc aagcctagtc aacgtagtaa gttcaagcac aagctgcatc 480
tcgttttcgc tgtctatcag aagacacagc gccgttggtt cctcgacaag ctggtggacg 540
agatcggtgt gggttacgtg ctggactctg gcagcgtctc cttttactcg ctgtccgaga 600
tcaagccttt gcataatttt ttaacacaac tacaaccttt tctaaaacta aaacaaaaac 660
aagcaaattt agttttaaaa attattgaac aacttccgtc agcaaaagaa tccccggaca 720
aattcttaga agtttgtaca tgggtggatc aaattgcagc tctgaatgat tcgaagacgc 780
gtaaaacaac ttctgaaacc gttcgtgctg tgctagacag tttaccagga tccgtgggag 840
gtctatcgcc atctcaggca tccagcgccg catcctcggc ttcctcaagc ccgggttcag 900
ggatctccga agcactcaga gctggagcag gttccggcac tggatacaac aaggaattcc 960
tgctctacct ggcgggcttc gtcgacgggg acggctccat ctatgcccgt atcaagccgg 1020
ttcagcgggc taagttcaag cacgagctgg ttctcgggtt cgatgtcact cagaagacac 1080
agcgccgttg gttcctcgac aagctggtgg acgagatcgg tgtgggttac gtgtatgaca 1140
agggcagcgt ctccgcgtac cgtctgtccc agatcaagcc tctgcacaac ttcctgaccc 1200
agctccagcc cttcctgaag ctcaagcaga agcaggccaa cctcgtgctg aagatcatcg 1260
agcagctgcc ctccgccaag gaatccccgg acaagttcct ggaggtgtgc acctgggtgg 1320
accagatcgc cgctctgaac gactccaaga cccgcaagac cacttccgaa accgtccgcg 1380
ccgttctaga cagtctctcc gagaagaaga agtcgtcccc ctaaggtacg atctgcctcg 1440
actgtgcctt ctagttgcca gccatctgtt gtttgcccct cccccgtgcc ttccttgacc 1500
ctggaaggtg ccactcccac tgtcctttcc taataaaatg aggaaattgc atcgcattgt 1560
ctgagtaggt gtcattctat tctggggggt ggggtggggc aggacagcaa gggggaggat 1620
tgggaagaca atagcaggca tgctggggac tcgagttaag ggcgaattcc cgataaggat 1680
cttcctagag catggctacg tagataagta gcatggcggg ttaatcatta actacaagga 1740
acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca ctgaggccgg 1800
gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc 1860
gcgcagcctt aattaaccta attcactggc cgtcgtttta caacgtcgtg actgggaaaa 1920
ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca gctggcgtaa 1980
tagcgaagag gcccgcaccg atcgcccttc ccaacagttg cgcagcctga atggcgaatg 2040
ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac 2100
cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt cctttctcgc 2160
cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag ggttccgatt 2220
tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt cacgtagtgg 2280
gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt tctttaatag 2340
tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt cttttgattt 2400
ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt aacaaaaatt 2460
taacgcgaat tttaacaaaa tattaacgct tacaatttag gtggcacttt tcggggaaat 2520
gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg 2580
agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa 2640
catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac 2700
ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac 2760
atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt 2820
ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc 2880
gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca 2940
ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc 3000
ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag 3060
gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa 3120
ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg 3180
gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa 3240
ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg 3300
gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt 3360
gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt 3420
caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag 3480
cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat 3540
ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct 3600
taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct 3660
tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca 3720
gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc 3780
agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg ccaccacttc 3840
aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct 3900
gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag 3960
gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc 4020
tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct tcccgaaggg 4080
agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag 4140
cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt 4200
gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac 4260
gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg 4320
ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc 4380
cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcccaata 4440
cgcaaaccgc ctctccccgc gcgttggccg attcattaat gcagctggca cgacaggttt 4500
cccgactgga aagcgggcag tgagcgcaac gcaattaatg tgagttagct cactcattag 4560
gcaccccagg ctttacactt tatgcttccg gctcgtatgt tgtgtggaat tgtgagcgga 4620
taacaatttc acacaggaaa cagctatgac catgattacg ccagatttaa ttaaggcctt 4680
aattagg 4687
<210> 19
<211> 1866
<212> DNA
<213> 人工序列
<220>
<223> 载体基因组TBG-S1-F113.PCS7-8L.197.bGH
<220>
<221> 重复_区域
<222> (1)..(168)
<223> ITR
<220>
<221> 启动子
<222> (206)..(318)
<223> TBG S1
<220>
<221> CDS
<222> (330)..(1424)
<223> PCS7-8L
<220>
<221> 聚A_信号
<222> (1435)..(1649)
<223> bGH聚A
<220>
<221> 重复_区域
<222> (1691)..(1736)
<223> ITR
<400> 19
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180
aggaagatcg gaattcgccc ttaagctttg aaaataccat cccagggtta atgctggggt 240
taatttataa ctaagagtgc tctagttttg caatacagga catgctataa aaatggaaag 300
atgttgcttt ctgagagaca gcggccgcc atg gca ccg aag aag aag cgc aag 353
Met Ala Pro Lys Lys Lys Arg Lys
1 5
gtg cat atg aat aca aaa tat aat aaa gag ttc tta ctc tac tta gca 401
Val His Met Asn Thr Lys Tyr Asn Lys Glu Phe Leu Leu Tyr Leu Ala
10 15 20
ggg ttt gta gac ggt gac ggt tcc atc ttt gcc agg atc aag cct agt 449
Gly Phe Val Asp Gly Asp Gly Ser Ile Phe Ala Arg Ile Lys Pro Ser
25 30 35 40
caa cgt agt aag ttc aag cac aag ctg cat ctc gtt ttc gct gtc tat 497
Gln Arg Ser Lys Phe Lys His Lys Leu His Leu Val Phe Ala Val Tyr
45 50 55
cag aag aca cag cgc cgt tgg ttc ctc gac aag ctg gtg gac gag atc 545
Gln Lys Thr Gln Arg Arg Trp Phe Leu Asp Lys Leu Val Asp Glu Ile
60 65 70
ggt gtg ggt tac gtg ctg gac tct ggc agc gtc tcc ttt tac tcg ctg 593
Gly Val Gly Tyr Val Leu Asp Ser Gly Ser Val Ser Phe Tyr Ser Leu
75 80 85
tcc gag atc aag cct ttg cat aat ttt tta aca caa cta caa cct ttt 641
Ser Glu Ile Lys Pro Leu His Asn Phe Leu Thr Gln Leu Gln Pro Phe
90 95 100
cta aaa cta aaa caa aaa caa gca aat tta gtt tta aaa att att gaa 689
Leu Lys Leu Lys Gln Lys Gln Ala Asn Leu Val Leu Lys Ile Ile Glu
105 110 115 120
caa ctt ccg tca gca aaa gaa tcc ccg gac aaa ttc tta gaa gtt tgt 737
Gln Leu Pro Ser Ala Lys Glu Ser Pro Asp Lys Phe Leu Glu Val Cys
125 130 135
aca tgg gtg gat caa att gca gct ctg aat gat tcg aag acg cgt aaa 785
Thr Trp Val Asp Gln Ile Ala Ala Leu Asn Asp Ser Lys Thr Arg Lys
140 145 150
aca act tct gaa acc gtt cgt gct gtg cta gac agt tta cca gga tcc 833
Thr Thr Ser Glu Thr Val Arg Ala Val Leu Asp Ser Leu Pro Gly Ser
155 160 165
gtg gga ggt cta tcg cca tct cag gca tcc agc gcc gca tcc tcg gct 881
Val Gly Gly Leu Ser Pro Ser Gln Ala Ser Ser Ala Ala Ser Ser Ala
170 175 180
tcc tca agc ccg ggt tca ggg atc tcc gaa gca ctc aga gct gga gca 929
Ser Ser Ser Pro Gly Ser Gly Ile Ser Glu Ala Leu Arg Ala Gly Ala
185 190 195 200
ggt tcc ggc act gga tac aac aag gaa ttc ctg ctc tac ctg gcg ggc 977
Gly Ser Gly Thr Gly Tyr Asn Lys Glu Phe Leu Leu Tyr Leu Ala Gly
205 210 215
ttc gtc gac ggg gac ggc tcc atc tat gcc cgt atc aag ccg gtt cag 1025
Phe Val Asp Gly Asp Gly Ser Ile Tyr Ala Arg Ile Lys Pro Val Gln
220 225 230
cgg gct aag ttc aag cac gag ctg gtt ctc ggg ttc gat gtc act cag 1073
Arg Ala Lys Phe Lys His Glu Leu Val Leu Gly Phe Asp Val Thr Gln
235 240 245
aag aca cag cgc cgt tgg ttc ctc gac aag ctg gtg gac gag atc ggt 1121
Lys Thr Gln Arg Arg Trp Phe Leu Asp Lys Leu Val Asp Glu Ile Gly
250 255 260
gtg ggt tac gtg tat gac aag ggc agc gtc tcc gcg tac cgt ctg tcc 1169
Val Gly Tyr Val Tyr Asp Lys Gly Ser Val Ser Ala Tyr Arg Leu Ser
265 270 275 280
cag atc aag cct ctg cac aac ttc ctg acc cag ctc cag ccc ttc ctg 1217
Gln Ile Lys Pro Leu His Asn Phe Leu Thr Gln Leu Gln Pro Phe Leu
285 290 295
aag ctc aag cag aag cag gcc aac ctc gtg ctg aag atc atc gag cag 1265
Lys Leu Lys Gln Lys Gln Ala Asn Leu Val Leu Lys Ile Ile Glu Gln
300 305 310
ctg ccc tcc gcc aag gaa tcc ccg gac aag ttc ctg gag gtg tgc acc 1313
Leu Pro Ser Ala Lys Glu Ser Pro Asp Lys Phe Leu Glu Val Cys Thr
315 320 325
tgg gtg gac cag atc gcc gct ctg aac gac tcc aag acc cgc aag acc 1361
Trp Val Asp Gln Ile Ala Ala Leu Asn Asp Ser Lys Thr Arg Lys Thr
330 335 340
act tcc gaa acc gtc cgc gcc gtt cta gac agt ctc tcc gag aag aag 1409
Thr Ser Glu Thr Val Arg Ala Val Leu Asp Ser Leu Ser Glu Lys Lys
345 350 355 360
aag tcg tcc ccc taa ggtacgatct gcctcgactg tgccttctag ttgccagcca 1464
Lys Ser Ser Pro
tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac tcccactgtc 1524
ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca ttctattctg 1584
gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag caggcatgct 1644
ggggactcga gttaagggcg aattcccgat aaggatcttc ctagagcatg gctacgtaga 1704
taagtagcat ggcgggttaa tcattaacta caaggaaccc ctagtgatgg agttggccac 1764
tccctctctg cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc 1824
gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc ag 1866
<210> 20
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 20
Met Ala Pro Lys Lys Lys Arg Lys Val His Met Asn Thr Lys Tyr Asn
1 5 10 15
Lys Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp Gly Ser
20 25 30
Ile Phe Ala Arg Ile Lys Pro Ser Gln Arg Ser Lys Phe Lys His Lys
35 40 45
Leu His Leu Val Phe Ala Val Tyr Gln Lys Thr Gln Arg Arg Trp Phe
50 55 60
Leu Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Leu Asp Ser
65 70 75 80
Gly Ser Val Ser Phe Tyr Ser Leu Ser Glu Ile Lys Pro Leu His Asn
85 90 95
Phe Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys Gln Ala
100 105 110
Asn Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys Glu Ser
115 120 125
Pro Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile Ala Ala
130 135 140
Leu Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val Arg Ala
145 150 155 160
Val Leu Asp Ser Leu Pro Gly Ser Val Gly Gly Leu Ser Pro Ser Gln
165 170 175
Ala Ser Ser Ala Ala Ser Ser Ala Ser Ser Ser Pro Gly Ser Gly Ile
180 185 190
Ser Glu Ala Leu Arg Ala Gly Ala Gly Ser Gly Thr Gly Tyr Asn Lys
195 200 205
Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp Gly Ser Ile
210 215 220
Tyr Ala Arg Ile Lys Pro Val Gln Arg Ala Lys Phe Lys His Glu Leu
225 230 235 240
Val Leu Gly Phe Asp Val Thr Gln Lys Thr Gln Arg Arg Trp Phe Leu
245 250 255
Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Tyr Asp Lys Gly
260 265 270
Ser Val Ser Ala Tyr Arg Leu Ser Gln Ile Lys Pro Leu His Asn Phe
275 280 285
Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys Gln Ala Asn
290 295 300
Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys Glu Ser Pro
305 310 315 320
Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile Ala Ala Leu
325 330 335
Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val Arg Ala Val
340 345 350
Leu Asp Ser Leu Ser Glu Lys Lys Lys Ser Ser Pro
355 360
<210> 21
<211> 1095
<212> DNA
<213> 人工序列
<220>
<223> 核酸序列PCS7-8L
<400> 21
atggcaccga agaagaagcg caaggtgcat atgaatacaa aatataataa agagttctta 60
ctctacttag cagggtttgt agacggtgac ggttccatct ttgccaggat caagcctagt 120
caacgtagta agttcaagca caagctgcat ctcgttttcg ctgtctatca gaagacacag 180
cgccgttggt tcctcgacaa gctggtggac gagatcggtg tgggttacgt gctggactct 240
ggcagcgtct ccttttactc gctgtccgag atcaagcctt tgcataattt tttaacacaa 300
ctacaacctt ttctaaaact aaaacaaaaa caagcaaatt tagttttaaa aattattgaa 360
caacttccgt cagcaaaaga atccccggac aaattcttag aagtttgtac atgggtggat 420
caaattgcag ctctgaatga ttcgaagacg cgtaaaacaa cttctgaaac cgttcgtgct 480
gtgctagaca gtttaccagg atccgtggga ggtctatcgc catctcaggc atccagcgcc 540
gcatcctcgg cttcctcaag cccgggttca gggatctccg aagcactcag agctggagca 600
ggttccggca ctggatacaa caaggaattc ctgctctacc tggcgggctt cgtcgacggg 660
gacggctcca tctatgcccg tatcaagccg gttcagcggg ctaagttcaa gcacgagctg 720
gttctcgggt tcgatgtcac tcagaagaca cagcgccgtt ggttcctcga caagctggtg 780
gacgagatcg gtgtgggtta cgtgtatgac aagggcagcg tctccgcgta ccgtctgtcc 840
cagatcaagc ctctgcacaa cttcctgacc cagctccagc ccttcctgaa gctcaagcag 900
aagcaggcca acctcgtgct gaagatcatc gagcagctgc cctccgccaa ggaatccccg 960
gacaagttcc tggaggtgtg cacctgggtg gaccagatcg ccgctctgaa cgactccaag 1020
acccgcaaga ccacttccga aaccgtccgc gccgttctag acagtctctc cgagaagaag 1080
aagtcgtccc cctaa 1095
<210> 22
<211> 2079
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (1)..(2079)
<223> PCSK9 CDS
<400> 22
atg ggc acc gtc agc tcc agg cgg tcc tgg tgg ccg ctg cca ctg ctg 48
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
ctg ctg ctg ctg ctg ctc ctg ggt ccc gcg ggc gcc cgt gcg cag gag 96
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
gac gag gac ggc gac tac gag gag ctg gtg cta gcc ttg cgt tcc gag 144
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
gag gac ggc ctg gcc gaa gca ccc gag cac gga acc aca gcc acc ttc 192
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
cac cgc tgc gcc aag gat ccg tgg agg ttg cct ggc acc tac gtg gtg 240
His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val
65 70 75 80
gtg ctg aag gag gag acc cac ctc tcg cag tca gag cgc act gcc cgc 288
Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg
85 90 95
cgc ctg cag gcc cag gct gcc cgc cgg gga tac ctc acc aag atc ctg 336
Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu
100 105 110
cat gtc ttc cat ggc ctt ctt cct ggc ttc ctg gtg aag atg agt ggc 384
His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly
115 120 125
gac ctg ctg gag ctg gcc ttg aag ttg ccc cat gtc gac tac atc gag 432
Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu
130 135 140
gag gac tcc tct gtc ttt gcc cag agc atc ccg tgg aac ctg gag cgg 480
Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg
145 150 155 160
att acc cct cca cgg tac cgg gcg gat gaa tac cag ccc ccc gac gga 528
Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly
165 170 175
ggc agc ctg gtg gag gtg tat ctc cta gac acc agc ata cag agt gac 576
Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp
180 185 190
cac cgg gaa atc gag ggc agg gtc atg gtc acc gac ttc gag aat gtg 624
His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val
195 200 205
ccc gag gag gac ggg acc cgc ttc cac aga cag gcc agc aag tgt gac 672
Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp
210 215 220
agt cat ggc acc cac ctg gca ggg gtg gtc agc ggc cgg gat gcc ggc 720
Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly
225 230 235 240
gtg gcc aag ggt gcc agc atg cgc agc ctg cgc gtg ctc aac tgc caa 768
Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln
245 250 255
ggg aag ggc acg gtt agc ggc acc ctc ata ggc ctg gag ttt att cgg 816
Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg
260 265 270
aaa agc cag ctg gtc cag cct gtg ggg cca ctg gtg gtg ctg ctg ccc 864
Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro
275 280 285
ctg gcg ggt ggg tac agc cgc gtc ctc aac gcc gcc tgc cag cgc ctg 912
Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu
290 295 300
gcg agg gct ggg gtc gtg ctg gtc acc gct gcc ggc aac ttc cgg gac 960
Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp
305 310 315 320
gat gcc tgc ctc tac tcc cca gcc tca gct ccc gag gtc atc aca gtt 1008
Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val
325 330 335
ggg gcc acc aat gcc caa gac cag ccg gtg acc ctg ggg act ttg ggg 1056
Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly
340 345 350
acc aac ttt ggc cgc tgt gtg gac ctc ttt gcc cca ggg gag gac atc 1104
Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile
355 360 365
att ggt gcc tcc agc gac tgc agc acc tgc ttt gtg tca cag agt ggg 1152
Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly
370 375 380
aca tca cag gct gct gcc cac gtg gct ggc att gca gcc atg atg ctg 1200
Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu
385 390 395 400
tct gcc gag ccg gag ctc acc ctg gcc gag ttg agg cag aga ctg atc 1248
Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile
405 410 415
cac ttc tct gcc aaa gat gtc atc aat gag gcc tgg ttc cct gag gac 1296
His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp
420 425 430
cag cgg gta ctg acc ccc aac ctg gtg gcc gcc ctg ccc ccc agc acc 1344
Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr
435 440 445
cat ggg gca ggt tgg cag ctg ttt tgc agg act gta tgg tca gca cac 1392
His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His
450 455 460
tcg ggg cct aca cgg atg gcc aca gcc gtc gcc cgc tgc gcc cca gat 1440
Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp
465 470 475 480
gag gag ctg ctg agc tgc tcc agt ttc tcc agg agt ggg aag cgg cgg 1488
Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg
485 490 495
ggc gag cgc atg gag gcc caa ggg ggc aag ctg gtc tgc cgg gcc cac 1536
Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His
500 505 510
aac gct ttt ggg ggt gag ggt gtc tac gcc att gcc agg tgc tgc ctg 1584
Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu
515 520 525
cta ccc cag gcc aac tgc agc gtc cac aca gct cca cca gct gag gcc 1632
Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala
530 535 540
agc atg ggg acc cgt gtc cac tgc cac caa cag ggc cac gtc ctc aca 1680
Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr
545 550 555 560
ggc tgc agc tcc cac tgg gag gtg gag gac ctt ggc acc cac aag ccg 1728
Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro
565 570 575
cct gtg ctg agg cca cga ggt cag ccc aac cag tgc gtg ggc cac agg 1776
Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg
580 585 590
gag gcc agc atc cac gct tcc tgc tgc cat gcc cca ggt ctg gaa tgc 1824
Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys
595 600 605
aaa gtc aag gag cat gga atc ccg gcc cct cag gag cag gtg acc gtg 1872
Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val
610 615 620
gcc tgc gag gag ggc tgg acc ctg act ggc tgc agt gcc ctc cct ggg 1920
Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly
625 630 635 640
acc tcc cac gtc ctg ggg gcc tac gcc gta gac aac acg tgt gta gtc 1968
Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val
645 650 655
agg agc cgg gac gtc agc act aca ggc agc acc agc gaa ggg gcc gtg 2016
Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val
660 665 670
aca gcc gtt gcc atc tgc tgc cgg agc cgg cac ctg gcg cag gcc tcc 2064
Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser
675 680 685
cag gag ctc cag tga 2079
Gln Glu Leu Gln
690
<210> 23
<211> 692
<212> PRT
<213> 智人
<400> 23
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val
65 70 75 80
Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg
85 90 95
Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu
100 105 110
His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly
115 120 125
Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu
130 135 140
Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg
145 150 155 160
Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly
165 170 175
Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp
180 185 190
His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val
195 200 205
Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp
210 215 220
Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly
225 230 235 240
Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln
245 250 255
Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg
260 265 270
Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro
275 280 285
Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu
290 295 300
Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp
305 310 315 320
Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val
325 330 335
Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly
340 345 350
Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile
355 360 365
Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly
370 375 380
Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu
385 390 395 400
Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile
405 410 415
His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp
420 425 430
Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr
435 440 445
His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His
450 455 460
Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp
465 470 475 480
Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg
485 490 495
Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His
500 505 510
Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu
515 520 525
Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala
530 535 540
Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr
545 550 555 560
Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro
565 570 575
Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg
580 585 590
Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys
595 600 605
Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val
610 615 620
Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly
625 630 635 640
Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val
645 650 655
Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val
660 665 670
Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser
675 680 685
Gln Glu Leu Gln
690
<210> 24
<211> 132
<212> DNA
<213> 智人
<400> 24
tgggctcctt tctctgccac ccacctcctc acctttccag gtcatcacag ttggggccac 60
caatgcccaa gaccagccgg tgaccctggg gactttgggg accaactttg gccgctgtgt 120
ggacctcttt gc 132
<210> 25
<211> 137
<212> DNA
<213> 智人
<400> 25
ttgccccagg ggaggacatc attggtgcct ccagcgactg cagcacctgc tttgtgtcac 60
agagtgggac atcacaggct gctgcccacg tggctggtaa gtcaccaccc cactgcctcg 120
gccaccgtga tgctaac 137
<210> 26
<211> 500
<212> DNA
<213> 智人
<400> 26
acctaggtcc ccccggccta tcaaggcttc cctggcggcc gaatttaaag gcatcaagca 60
aacaaagccc aacacatctc tgccttgtcc tctcagtttc cccccgtggc acttagaacc 120
acttgataca ccgaatagtt tccggtctat ctcccccact aggatgtaaa ctccacaggg 180
gcattgggaa tgctgcctgg ctatggtagg gacagagggg agcaccaggg cggggcaggg 240
gtgccagagt tctgcctggg cagtcagatt ttccttagga ggggacattt gagtgggacc 300
caaacaggtg tatagcagtt gtccagccca gctggcaagg cctgagtctg cctctgcaac 360
ccctctcttg ggctcctttc tctgccaccc acctcctcac ctttccaggt catcacagtt 420
ggggccacca atgcccagga ccagccggtg accctgggga ctttggggac caactttggc 480
cgctgtgtgg acctctttgc 500
<210> 27
<211> 500
<212> DNA
<213> 智人
<400> 27
ttgccccagg ggaggacatc attggtgcct ccagcgactg cagcacctgc tttgtgtcac 60
agagtgggac atcacaggct gctgcccacg tggctggtaa gtcaccaccc cactgcctcg 120
gccaccgtga tgctaacagc ccctttggca gtcagggtct gtgccgggac ctccagtgcc 180
aggctctgtg cagggggacc agagatgaag taggcctgat ggtgccttca aggacactca 240
gtctgatgag ggaggcgagt gcacagaggg aacacgaggt cagggctgta ttagagggag 300
cccagaggag gcacctgccc agcccgaggg tcagagaagg catcttggag gagggacatt 360
tgatcgggag cttgatggat gaataggagt ttacctggcc gataagacag caactaccaa 420
ggcttagagg tgtgagagga ggctgtctta cctcactgag taaggactgc aggcggctta 480
ccttcgagaa gagagcttag 500
<210> 28
<211> 516
<212> DNA
<213> 恒河猴
<400> 28
aagcatacct gacagcggta acccagatcc tccctggcct cggaggcttc cctggcagcc 60
caatttaaag gcatcaagca aacaaagccc aacacatctc tgccttgccc tctcagtctc 120
cccccgtggc acttagagcc acctgataca ccgagtagtt tcctatctcc ctcactagaa 180
tgtaaactcc acaggggcat tgggaatgct gcctggctat ggtagggaca gaggggagca 240
ccagggcggg gcaggggtgc cagagttctg cctggggagt cagattttcc ttaggagggg 300
acatttgaat gggacccaaa caggtgtata gcagttgttc agcccagctg gcaaggcctc 360
agtttgcttc tgcaacccct ctcttgggct cctttctgtg ccacctacct cctcaccttt 420
ccaggtcatc acagttgggg ccaccaatgc ccaggaccag ccggtgaccc tggggacttt 480
ggggaccaac tttggccgct gtgtggacct ctttgc 516
<210> 29
<211> 510
<212> DNA
<213> 恒河猴
<400> 29
ttgccccagg ggaggacatc attggtgcct ccagcgactg cagcacctgc tttgtgtcac 60
ggagtgggac atcgcaggct gctgcccacg tggctggtaa gtcaccaccc cactgccttg 120
gccaccgtga tgctaacagc cctttggcgg tcagggtctg tgccaggacc tccagtgcca 180
ggctctgtgc agggggacca gagatgagac aggcctgatg gtgccttcat ggacactcag 240
tctgatgagg gagacgagtg cacagtggga acacgaggtt agggctgtat tagagggagc 300
ccagaggagg cacctgccca gcccgagggt cagagaaggc ttcttggaca agggacattt 360
gatctggagc ttgatggatg aataggagtc cacctggccg ataagacagc aactaccaag 420
gcttagaggt gtgacggaag gctgtcttac ctcactgtgt gagggactgc aggcggctta 480
ccttctagaa gagagcttgg tgtctctggt 510
<210> 30
<211> 1062
<212> DNA
<213> 智人
<220>
<221> misc_特征
<222> (1)..(1062)
<223> hOTC的CDS
<400> 30
atgctgttta atctgaggat cctgttaaac aatgcagctt ttagaaatgg tcacaacttc 60
atggttcgaa attttcggtg tggacaacca ctacaaaata aagtgcagct gaagggccgt 120
gaccttctca ctctaaaaaa ctttaccgga gaagaaatta aatatatgct atggctatca 180
gcagatctga aatttaggat aaaacagaaa ggagagtatt tgcctttatt gcaagggaag 240
tccttaggca tgatttttga gaaaagaagt actcgaacaa gattgtctac agaaacaggc 300
tttgcacttc tgggaggaca tccttgtttt cttaccacac aagatattca tttgggtgtg 360
aatgaaagtc tcacggacac ggcccgtgta ttgtctagca tggcagatgc agtattggct 420
cgagtgtata aacaatcaga tttggacacc ctggctaaag aagcatccat cccaattatc 480
aatgggctgt cagatttgta ccatcctatc cagatcctgg ctgattacct cacgctccag 540
gaacactata gctctctgaa aggtcttacc ctcagctgga tcggggatgg gaacaatatc 600
ctgcactcca tcatgatgag cgcagcgaaa ttcggaatgc accttcaggc agctactcca 660
aagggttatg agccggatgc tagtgtaacc aagttggcag agcagtatgc caaagagaat 720
ggtaccaagc tgttgctgac aaatgatcca ttggaagcag cgcatggagg caatgtatta 780
attacagaca cttggataag catgggacaa gaagaggaga agaaaaagcg gctccaggct 840
ttccaaggtt accaggttac aatgaagact gctaaagttg ctgcctctga ctggacattt 900
ttacactgct tgcccagaaa gccagaagaa gtggatgatg aagtctttta ttctcctcga 960
tcactagtgt tcccagaggc agaaaacaga aagtggacaa tcatggctgt catggtgtcc 1020
ctgctgacag attactcacc tcagctccag aagcctaaat tt 1062
<210> 31
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CRE基序
<400> 31
Leu Ala Gly Leu Ile Asp Ala Asp Gly
1 5
<210> 32
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> CRE识别序列
<400> 32
caaaacgtcg tgagacagtt tg 22
<210> 33
<211> 2214
<212> DNA
<213> 腺相关病毒rh79
<220>
<221> CDS
<222> (1)..(2214)
<400> 33
atg gct gct gac ggt tat ctt cca gat tgg ctc gag gac aac ctc tct 48
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
gag ggc att cgc gag tgg tgg gac ctg aaa cct gga gcc ccc aag ccc 96
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
aag gcc aac cag cag aag cag gac gac ggc cgg ggt ctg gtg ctt cct 144
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
ggc tac aag tac ctc gga ccc ttc aac gga ctc gac aag ggg gag ccc 192
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
gtc aac gag gcg gac gcc gcg gcc ctc gag cac gac aag gcc tac gac 240
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
cag cag ctc aaa gcg ggt gac aat ccg tac ctg cgg tat aac cac gcc 288
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
gac gcc gag ttt cag gag cgt ctg caa gaa gat acg tct ttt ggg ggc 336
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
aac ctc ggg cga gca gtc ttc cag gcc aag aag cgg gtt ctc gaa cct 384
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
ctc ggt ctg gtt gag gaa gct gct aag acg gct cct gga aag aag aga 432
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
ccg gta gaa ccg tca cct cag cga tcc ccc gac tcc tcc acg ggc atc 480
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
ggc aaa aaa ggc cag cag ccc gcg aga aag aga ctg aac ttt ggg cag 528
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
act ggc gac tca gag tca gtc ccc gac cct caa cca atc gga gaa cca 576
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
cca gca ggc ccc tct ggt ctg gga tct ggt aca atg gct gca ggc ggt 624
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
ggc gct cca atg gca gac aat aac gaa ggc gcc gac gga gtg ggt agt 672
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
tcc tca gga aat tgg cat tgc gat tcc aca tgg ctg ggc gac aga gtc 720
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
atc acc acc agc acc cga acc tgg gcc ctg ccc acc tac aac aac cac 768
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
ctc tac aag caa atc tcc aat ggg aca tcg gga gga agc acc aac gac 816
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
aac acc tac ttc ggc tac agc acc ccc tgg ggg tat ttt gac ttc aac 864
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
aga ttc cac tgt cac ttc tca cca cgt gac tgg cag aga ctc atc aac 912
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
aac aac tgg gga ttc cgg ccc aag aga ctc agc ttc aag ctc ttc aac 960
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
atc cag gtt aag gag gtc acg cag aat gaa ggc acc aag acc atc gcc 1008
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
aat aac ctt acc agc acg att cag gta ttt acg gac tcg gaa tac cag 1056
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
ctg ccg tac gtc ctc ggc tcc gcg cac cag ggc tgc ctg cct ccg ttc 1104
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
ccg gcg gat gtc ttc atg att ccc cag tac ggc tac ctg aca ctg aac 1152
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
aac gga agt caa gcc gta ggc cgt tcc tca ttc tac tgc ctg gaa tat 1200
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
ttt cca tct caa atg ctg cgg act gga aac aac ttt gaa ttt agc tac 1248
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
acc ttt gag gac gtg ccc ttc cac agc agc tac gca cac agc cag agc 1296
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
ctg gac cgg ctg atg aac cct ctc atc gac cag tac ctg tat tac cta 1344
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
tcc aga act cag tcc aca gga gga act caa ggt aca cag caa ttg tta 1392
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
ttt tct caa gcc ggg cct gca aat atg tcg gct cag gcc aag aac tgg 1440
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
cta cct gga cct tgc tac cgg cag cag cga gtc tcc acg aca ctg tcg 1488
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
caa aac aac aac agc aac ttt gct tgg act ggt gcc acg aaa tat cat 1536
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
ctg aac gga aga gac tct ttg gtg aat ccc ggt gtt gct atg gca acg 1584
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
cat aag gac gac gag gaa cgt ttc ttt cca tcg agc gga gtc ctg atg 1632
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
ttt gga aaa cag ggt gct gga aga gac aat gtg gac tat agc agc gtt 1680
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
atg cta acc agc gag gaa gaa atc aag acc act aac cct gta gcc act 1728
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
gaa caa tac ggc gtg gtg gct gat aac ttg cag caa acc aat aca gga 1776
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
cct atc gtg gga aat gtc aac agc caa gga gcc tta cct ggc atg gtc 1824
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
tgg cag aac cga gac gtg tac ctg cag ggt ccc att tgg gcc aag att 1872
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
cct cac acg gac ggc aac ttt cac ccg tct cct ctg atg ggc ggc ttt 1920
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
gga ctg aaa cac ccg cct cct caa atc ctg atc aag aac act ccc gtt 1968
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
cct gcg gat cct cca acg acg ttc agc cag gcg aaa ttg gct tcc ttc 2016
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
atc acg cag tat agt acc ggc cag gtc agc gtg gag atc gag tgg gag 2064
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
ctg cag aag gag aac agc aag cgc tgg aac cca gaa att cag tat act 2112
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
tcc aac tac tac aaa tct aca aat gtg gac ttt gct gtc aat acc gag 2160
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
ggt aca tat tca gag cct cgc ccc att gga act cgt tac ctc acc cgt 2208
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
aat ctg 2214
Asn Leu
<210> 34
<211> 738
<212> PRT
<213> 腺相关病毒rh79
<400> 34
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 Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu 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 Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val 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 Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 35
<211> 2214
<212> DNA
<213> 腺相关病毒8
<220>
<221> CDS
<222> (1)..(2214)
<400> 35
atg gct gcc gat ggt tat ctt cca gat tgg ctc gag gac aac ctc tct 48
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
gag ggc att cgc gag tgg tgg gcg ctg aaa cct gga gcc ccg aag ccc 96
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
aaa gcc aac cag caa aag cag gac gac ggc cgg ggt ctg gtg ctt cct 144
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
ggc tac aag tac ctc gga ccc ttc aac gga ctc gac aag ggg gag ccc 192
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
gtc aac gcg gcg gac gca gcg gcc ctc gag cac gac aag gcc tac gac 240
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
cag cag ctg cag gcg ggt gac aat ccg tac ctg cgg tat aac cac gcc 288
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
gac gcc gag ttt cag gag cgt ctg caa gaa gat acg tct ttt ggg ggc 336
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
aac ctc ggg cga gca gtc ttc cag gcc aag aag cgg gtt ctc gaa cct 384
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
ctc ggt ctg gtt gag gaa ggc gct aag acg gct cct gga aag aag aga 432
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
ccg gta gag cca tca ccc cag cgt tct cca gac tcc tct acg ggc atc 480
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
ggc aag aaa ggc caa cag ccc gcc aga aaa aga ctc aat ttt ggt cag 528
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
act ggc gac tca gag tca gtt cca gac cct caa cct ctc gga gaa cct 576
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
cca gca gcg ccc tct ggt gtg gga cct aat aca atg gct gca ggc ggt 624
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
ggc gca cca atg gca gac aat aac gaa ggc gcc gac gga gtg ggt agt 672
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
tcc tcg gga aat tgg cat tgc gat tcc aca tgg ctg ggc gac aga gtc 720
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
atc acc acc agc acc cga acc tgg gcc ctg ccc acc tac aac aac cac 768
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
ctc tac aag caa atc tcc aac ggg aca tcg gga gga gcc acc aac gac 816
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
aac acc tac ttc ggc tac agc acc ccc tgg ggg tat ttt gac ttt aac 864
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
aga ttc cac tgc cac ttt tca cca cgt gac tgg cag cga ctc atc aac 912
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
aac aac tgg gga ttc cgg ccc aag aga ctc agc ttc aag ctc ttc aac 960
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
atc cag gtc aag gag gtc acg cag aat gaa ggc acc aag acc atc gcc 1008
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
aat aac ctc acc agc acc atc cag gtg ttt acg gac tcg gag tac cag 1056
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
ctg ccg tac gtt ctc ggc tct gcc cac cag ggc tgc ctg cct ccg ttc 1104
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
ccg gcg gac gtg ttc atg att ccc cag tac ggc tac cta aca ctc aac 1152
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
aac ggt agt cag gcc gtg gga cgc tcc tcc ttc tac tgc ctg gaa tac 1200
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
ttt cct tcg cag atg ctg aga acc ggc aac aac ttc cag ttt act tac 1248
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
acc ttc gag gac gtg cct ttc cac agc agc tac gcc cac agc cag agc 1296
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
ttg gac cgg ctg atg aat cct ctg att gac cag tac ctg tac tac ttg 1344
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
tct cgg act caa aca aca gga ggc acg gca aat acg cag act ctg ggc 1392
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
ttc agc caa ggt ggg cct aat aca atg gcc aat cag gca aag aac tgg 1440
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
ctg cca gga ccc tgt tac cgc caa caa cgc gtc tca acg aca acc ggg 1488
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
caa aac aac aat agc aac ttt gcc tgg act gct ggg acc aaa tac cat 1536
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
ctg aat gga aga aat tca ttg gct aat cct ggc atc gct atg gca aca 1584
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
cac aaa gac gac gag gag cgt ttt ttt ccc agt aac ggg atc ctg att 1632
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
ttt ggc aaa caa aat gct gcc aga gac aat gcg gat tac agc gat gtc 1680
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
atg ctc acc agc gag gaa gaa atc aaa acc act aac cct gtg gct aca 1728
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
gag gaa tac ggt atc gtg gca gat aac ttg cag cag caa aac acg gct 1776
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
cct caa att gga act gtc aac agc cag ggg gcc tta ccc ggt atg gtc 1824
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
tgg cag aac cgg gac gtg tac ctg cag ggt ccc atc tgg gcc aag att 1872
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
cct cac acg gac ggc aac ttc cac ccg tct ccg ctg atg ggc ggc ttt 1920
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
ggc ctg aaa cat cct ccg cct cag atc ctg atc aag aac acg cct gta 1968
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
cct gcg gat cct ccg acc acc ttc aac cag tca aag ctg aac tct ttc 2016
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
atc acg caa tac agc acc gga cag gtc agc gtg gaa att gaa tgg gag 2064
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
ctg cag aag gaa aac agc aag cgc tgg aac ccc gag atc cag tac acc 2112
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
tcc aac tac tac aaa tct aca agt gtg gac ttt gct gtt aat aca gaa 2160
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
ggc gtg tac tct gaa ccc cgc ccc att ggc acc cgt tac ctc acc cgt 2208
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
aat ctg 2214
Asn Leu
<210> 36
<211> 738
<212> PRT
<213> 腺相关病毒8
<400> 36
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 Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe 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 Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 37
<211> 2214
<212> DNA
<213> 腺相关病毒hu37
<220>
<221> CDS
<222> (1)..(2214)
<400> 37
atg gct gct gac ggt tat ctt cca gat tgg ctc gag gac aac ctc tct 48
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
gag ggc att cgc gag tgg tgg gac ctg aaa cct gga gcc ccc aag ccc 96
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
aag gcc aac cag cag aag cag gac gac ggc cgg ggt ctg gtg ctt cct 144
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
ggc tac aag tac ctc gga ccc ttc aac gga ctc gac aag ggg gag ccc 192
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
gtc aac gcg gcg gac gca gcg gcc ctc gag cac gac aag gcc tac gac 240
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
cag cag ctc aaa gcg ggt gac aat ccg tac ctg cgg tat aac cac gcc 288
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
gac gcc gag ttt cag gag cgt ctg caa gaa gat acg tct ttt ggg ggc 336
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
aac ctc ggg cga gca gtc ttc cag gcc aag aag cgg gtt ctc gaa cct 384
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
ctc ggt ctg gtt gag gaa gct gct aag acg gct cct gga aag aag aga 432
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
ccg gta gaa ccg tca cct cag cgt tcc ccc gac tcc tcc acg ggc atc 480
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
ggc aag aaa ggc cag cag ccc gct aaa aag aga ctg aac ttt ggt cag 528
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
act ggc gac tca gag tca gtc ccc gac cct caa cca atc gga gaa cca 576
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
cca gca ggc ccc tct ggt ctg gga tct ggt aca atg gct gca ggc ggt 624
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
ggc gct cca atg gca gac aat aac gaa ggc gcc gac gga gtg ggt agt 672
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
tcc tca gga aat tgg cat tgc gat tcc aca tgg ctg ggc gac aga gtc 720
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
atc acc acc agc acc cga acc tgg gcc ctg ccc acc tac aac aac cac 768
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
ctc tac aag caa ata tcc aat ggg aca tcg gga gga agc acc aac gac 816
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
aac acc tac ttc ggc tac agc acc ccc tgg ggg tat ttt gac ttc aac 864
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
aga ttc cac tgc cac ttc tca cca cgt gac tgg cag cga ctc atc aac 912
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
aac aac tgg gga ttc cgg cca aaa aga ctc agc ttc aag ctc ttc aac 960
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
atc cag gtc aag gag gtc acg cag aat gaa ggc acc aag acc atc gcc 1008
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
aat aac ctt acc agc acg att cag gta ttt acg gac tcg gaa tac cag 1056
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
ctg ccg tac gtc ctc ggc tcc gcg cac cag ggc tgc ctg cct ccg ttc 1104
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
ccg gcg gac gtc ttc atg att ccc cag tac ggc tac ctt aca ctg aac 1152
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
aat gga agt caa gcc gta ggc cgt tcc tcc ttc tac tgc ctg gaa tat 1200
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
ttt cca tct caa atg ctg cga act gga aac aat ttt gaa ttc agc tac 1248
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
acc ttc gag gac gtg cct ttc cac agc agc tac gca cac agc cag agc 1296
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
ttg gac cga ctg atg aat cct ctc atc gac cag tac ctg tac tac tta 1344
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
tcc aga act cag tcc aca gga gga act caa ggt acc cag caa ttg tta 1392
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
ttt tct caa gct ggg cct gca aac atg tcg gct cag gct aag aac tgg 1440
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
cta cct gga cct tgc tac cgg cag cag cga gtc tct acg aca ctg tcg 1488
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
caa aac aac aac agc aac ttt gct tgg act ggt gcc acc aaa tat cac 1536
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
ctg aac gga aga gac tct ttg gta aat ccc ggt gtc gcc atg gca acc 1584
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
cac aag gac gac gag gaa cgc ttc ttc ccg tcg agt gga gtc ctg atg 1632
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
ttc gga aaa cag ggt gct gga aga gac aat gtg gac tac agc agc gtt 1680
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
atg cta acc agc gaa gaa gaa att aaa acc act aac ccc gta gcc aca 1728
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
gaa caa tac ggt gtg gtg gct gac aac ttg cag caa acc aat aca ggg 1776
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
cct att gtg gga aat gtc aac agc caa gga gcc tta cct ggc atg gtc 1824
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
tgg cag aac cga gac gtg tac ctg cag ggt ccc atc tgg gcc aag att 1872
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
cct cac acg gac ggc aac ttc cac cct tca ccg cta atg gga gga ttt 1920
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
gga ctg aag cac cca cct cct cag atc ctg atc aag aac acg ccg gta 1968
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
cct gcg gat cct cca aca acg ttc agc cag gcg aaa ttg gct tcc ttc 2016
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
att acg cag tac agc acc gga cag gtc agc gtg gaa atc gag tgg gag 2064
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
ctg cag aag gag aac agc aaa cgc tgg aac cca gag att cag tac act 2112
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
tca aac tac tac aaa tct aca aat gtg gac ttt gct gtc aat aca gag 2160
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
gga act tat tct gag cct cgc ccc att ggt act cgt tac ctc acc cgt 2208
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
aat ctg 2214
Asn Leu
<210> 38
<211> 738
<212> PRT
<213> 腺相关病毒hu37
<400> 38
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 Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe 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 Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val 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 Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Thr Asn Thr Gly
580 585 590
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 39
<211> 2217
<212> DNA
<213> 腺相关病毒rh.90
<220>
<221> CDS
<222> (1)..(2217)
<400> 39
atg gct gcc gat ggt tat ctt cca gat tgg ctc gag gac aac ctc tct 48
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
gag ggc att cgc gag tgg tgg gac ctg aaa cct gga gcc cca aaa ccc 96
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
aaa gcc aac cag caa aag cag gac gac ggc cgg ggt ctg gtg ctt cct 144
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
ggc tac aag tac ctc gga ccc ttc aac gga ctc gac aag ggg gag ccc 192
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
gtc aac gcg gcg gac gca gcg gcc ctc gag cac gac aag gcc tac gac 240
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
cag cag ctg cag gcg ggt gat aat ccg tac ctg cgg tat aac cac gcc 288
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
gac gcc gag ttt cag gag cgt ctg caa gaa gat acg tca ttt ggg ggc 336
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
aac ctc ggg cga gca gtc ttc cag gcc aag aag cgg gtt ctc gaa cct 384
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
ctc ggt ctg gtt gag gaa ggc gct aag acg gct cct gga aag aag aga 432
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
ccg gta gag cca tca cca cag cgt tcc ccc gac tcc tcc acg ggc atc 480
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
ggc aag aaa ggc cag cag ccc gcc aga aag aga ctc aat ttc ggt cag 528
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
act ggc gac tca gag tca gtc ccc gac cct caa cct ctc gga gaa cct 576
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
cca gca gcg ccc tct agt gtg gga tct ggt aca atg gct gca ggc ggt 624
Pro Ala Ala Pro Ser Ser Val Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
ggc gca cca atg gca gac aat aac gaa ggt gcc gac gga gtg ggt agt 672
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
tcc tcg gga aat tgg cat tgc gat tcc aca tgg ctg ggc gac aga gtc 720
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
atc acc acc agc acc cga acc tgg gcc ctg ccc acc tac aac aac cac 768
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
ctc tac aag caa atc tcc aac ggg acc tcg gga ggc agc acc aac gac 816
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
aac acc tac ttc ggc tac agc acc ccc tgg ggg tat ttt gac ttt aac 864
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
aga ttc cac tgc cac ttc tca cca cgt gac tgg cag cga ctt atc aac 912
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
aac aac tgg gga ttc cgg ccc aag aga ctc agc ttc aag ctc ttc aac 960
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
atc cag gtc aag gag gtc acg caa aat gaa ggc acc aag acc atc gcc 1008
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
aat aac ctc acc agc acc atc cag gtg ttt acg gac tcg gaa tac cag 1056
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
ctg cca tac gtc ctc ggc tct gcc cac cag ggc tgc ctg cct ccg ttc 1104
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
ccg gcg gac gtc ttc atg att cct cag tat ggc tac ctg acg ctg aac 1152
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
aac gga agt cag gcc gtg ggc cgt tcc tcc ttc tac tgc ctg gag tac 1200
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
ttt ccc tct cag atg cta aga acg ggc aac aac ttc tcc ttc agc tat 1248
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Ser Phe Ser Tyr
405 410 415
acc ttc gag gac gtg cct ttc cac agc agc tac gcg cac agc cag agc 1296
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
ctg gac cgg ctg atg aat ccc ctc att gac cag tac ctg tac tac ctg 1344
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
tcg cgg aca caa tcc aca gga ggc aca gcg gga act cag cag ttg ctg 1392
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
ttt tct cag gcc ggg cct aac aac atg tct gct cag gcc aaa aac tgg 1440
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
cta ccc gga cct tgt tat cgg cag caa cgt gtt tcc acg aca ctg tcg 1488
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
caa aac aac aac agc aac ttt gcc tgg acc ggt gcc acc aaa tac cac 1536
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
ctg aac gga aga gac tct ctg gta aat ccg ggt gtc gcc atg gca acc 1584
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
aac aag gac gac gag gac cgc ttc ttc cca tcc agc ggc atc ctc atg 1632
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
ttt ggc aag cag ggg gct gga aaa gac aac gtg gac tat agc aac gtg 1680
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn Val
545 550 555 560
atg cta acc agc gag gaa gaa atc aag acc act aac cct gtg gcc aca 1728
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
gaa cag tat ggt gtg gtg gcg gat aac ctg cag cag caa aac aca gct 1776
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
cct att gtg ggg gcc gtc aac agc caa gga gcc tta cct ggc atg gtt 1824
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
tgg cag aac cgg gac gtg tac ctg cag ggt ccc atc tgg gcc aag att 1872
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
cct cac acg gat ggt aac ttt cac ccg tct cct ctc atg ggc ggc ttt 1920
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
gga ctt aaa cat ccg cct cct cag atc ctg atc aag aac act ccc gtt 1968
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
cct gcg gat cct cca acg gcg ttc aac cag gcc aag ctg aac tct ttc 2016
Pro Ala Asp Pro Pro Thr Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe
660 665 670
atc acg cag tac agc acc gga caa gtc agc gtg gag atc gag tgg gag 2064
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
ctg cag aag gag aac agc aag cgc tgg aac cca gag att cag tat acc 2112
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
tcc aac tac tac aaa tct aca aat gtg gac ttt gct gtt aat act gag 2160
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
ggt gtt tac tct gag cct cgc ccc att ggc acc cgt tac ctc acc cgt 2208
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
aat ctg taa 2217
Asn Leu
<210> 40
<211> 738
<212> PRT
<213> 腺相关病毒rh.90
<400> 40
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 Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe 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 Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Ser Val Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Ser Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
Asn Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Ile Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Asn Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Ala Phe Asn Gln Ala Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 41
<211> 434
<212> DNA
<213> 智人
<220>
<221> misc_特征
<222> (1)..(434)
<223> TBG启动子
<400> 41
tgtataattt ctacagaacc tattagaaag gatcacccag cctctgcttt tgtacaactt 60
tcccttaaaa aactgccaat tccactgctg tttggcccaa tagtgagaac tttttcctgc 120
tgcctcttgg tgcttttgcc tatggcccct attctgcctg ctgaagacac tcttgccagc 180
atggacttaa acccctccag ctctgacaat cctctttctc ttttgtttta catgaagggt 240
ctggcagcca aagcaatcac tcaaagttca aaccttatca ttttttgctt tgttcctctt 300
ggccttggtt ttgtacatca gctttgaaaa taccatccca gggttaatgc tggggttaat 360
ttataactaa gagtgctcta gttttgcaat acaggacatg ctataaaaat ggaaagatgt 420
tgctttctga gaga 434
<210> 42
<211> 3181
<212> DNA
<213> 人工序列
<220>
<223> 构建的序列
<220>
<221> 重复_区域
<222> (1)..(130)
<223> 5' ITR
<220>
<221> 启动子
<222> (211)..(907)
<223> 具有增强子的TBG
<220>
<221> 启动子
<222> (211)..(310)
<223> α mic/bik增强子
<220>
<221> 启动子
<222> (317)..(419)
<223> α mic/bik增强子
<220>
<221> 启动子
<222> (474)..(907)
<223> TBG启动子
<220>
<221> 内含子
<222> (939)..(1071)
<220>
<221> CDS
<222> (1089)..(2183)
<223> ARCUS
<220>
<221> misc_特征
<222> (2022)..(2743)
<223> WPRE
<220>
<221> 聚A_信号
<222> (2750)..(2964)
<223> BGH聚A
<220>
<221> 重复_区域
<222> (3052)..(3181)
<223> 3' ITR
<400> 42
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180
aggaagatcg gaattcgccc ttaagctagc aggttaattt ttaaaaagca gtcaaaagtc 240
caagtggccc ttggcagcat ttactctctc tgtttgctct ggttaataat ctcaggagca 300
caaacattcc agatccaggt taatttttaa aaagcagtca aaagtccaag tggcccttgg 360
cagcatttac tctctctgtt tgctctggtt aataatctca ggagcacaaa cattccagat 420
ccggcgcgcc agggctggaa gctacctttg acatcatttc ctctgcgaat gcatgtataa 480
tttctacaga acctattaga aaggatcacc cagcctctgc ttttgtacaa ctttccctta 540
aaaaactgcc aattccactg ctgtttggcc caatagtgag aactttttcc tgctgcctct 600
tggtgctttt gcctatggcc cctattctgc ctgctgaaga cactcttgcc agcatggact 660
taaacccctc cagctctgac aatcctcttt ctcttttgtt ttacatgaag ggtctggcag 720
ccaaagcaat cactcaaagt tcaaacctta tcattttttg ctttgttcct cttggccttg 780
gttttgtaca tcagctttga aaataccatc ccagggttaa tgctggggtt aatttataac 840
taagagtgct ctagttttgc aatacaggac atgctataaa aatggaaaga tgttgctttc 900
tgagagactg cagaagttgg tcgtgaggca ctgggcaggt aagtatcaag gttacaagac 960
aggtttaagg agaccaatag aaactgggct tgtcgagaca gagaagactc ttgcgtttct 1020
gataggcacc tattggtctt actgacatcc actttgcctt tctctccaca ggtgtccagg 1080
cggccgcc atg gca ccg aag aag aag cgc aag gtg cat atg aat aca aaa 1130
Met Ala Pro Lys Lys Lys Arg Lys Val His Met Asn Thr Lys
1 5 10
tat aat aaa gag ttc tta ctc tac tta gca ggg ttt gta gac ggt gac 1178
Tyr Asn Lys Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp
15 20 25 30
ggt tcc atc ttt gcc agg atc aag cct agt caa cgt agt aag ttc aag 1226
Gly Ser Ile Phe Ala Arg Ile Lys Pro Ser Gln Arg Ser Lys Phe Lys
35 40 45
cac aag ctg cat ctc gtt ttc gct gtc tat cag aag aca cag cgc cgt 1274
His Lys Leu His Leu Val Phe Ala Val Tyr Gln Lys Thr Gln Arg Arg
50 55 60
tgg ttc ctc gac aag ctg gtg gac gag atc ggt gtg ggt tac gtg ctg 1322
Trp Phe Leu Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Leu
65 70 75
gac tct ggc agc gtc tcc ttt tac tcg ctg tcc gag atc aag cct ttg 1370
Asp Ser Gly Ser Val Ser Phe Tyr Ser Leu Ser Glu Ile Lys Pro Leu
80 85 90
cat aat ttt tta aca caa cta caa cct ttt cta aaa cta aaa caa aaa 1418
His Asn Phe Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys
95 100 105 110
caa gca aat tta gtt tta aaa att att gaa caa ctt ccg tca gca aaa 1466
Gln Ala Asn Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys
115 120 125
gaa tcc ccg gac aaa ttc tta gaa gtt tgt aca tgg gtg gat caa att 1514
Glu Ser Pro Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile
130 135 140
gca gct ctg aat gat tcg aag acg cgt aaa aca act tct gaa acc gtt 1562
Ala Ala Leu Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val
145 150 155
cgt gct gtg cta gac agt tta cca gga tcc gtg gga ggt cta tcg cca 1610
Arg Ala Val Leu Asp Ser Leu Pro Gly Ser Val Gly Gly Leu Ser Pro
160 165 170
tct cag gca tcc agc gcc gca tcc tcg gct tcc tca agc ccg ggt tca 1658
Ser Gln Ala Ser Ser Ala Ala Ser Ser Ala Ser Ser Ser Pro Gly Ser
175 180 185 190
ggg atc tcc gaa gca ctc aga gct gga gca ggt tcc ggc act gga tac 1706
Gly Ile Ser Glu Ala Leu Arg Ala Gly Ala Gly Ser Gly Thr Gly Tyr
195 200 205
aac aag gaa ttc ctg ctc tac ctg gcg ggc ttc gtc gac ggg gac ggc 1754
Asn Lys Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp Gly
210 215 220
tcc atc tat gcc cgt atc aag ccg gtt cag cgg gct aag ttc aag cac 1802
Ser Ile Tyr Ala Arg Ile Lys Pro Val Gln Arg Ala Lys Phe Lys His
225 230 235
gag ctg gtt ctc ggg ttc gat gtc act cag aag aca cag cgc cgt tgg 1850
Glu Leu Val Leu Gly Phe Asp Val Thr Gln Lys Thr Gln Arg Arg Trp
240 245 250
ttc ctc gac aag ctg gtg gac gag atc ggt gtg ggt tac gtg tat gac 1898
Phe Leu Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Tyr Asp
255 260 265 270
aag ggc agc gtc tcc gcg tac cgt ctg tcc cag atc aag cct ctg cac 1946
Lys Gly Ser Val Ser Ala Tyr Arg Leu Ser Gln Ile Lys Pro Leu His
275 280 285
aac ttc ctg acc cag ctc cag ccc ttc ctg aag ctc aag cag aag cag 1994
Asn Phe Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys Gln
290 295 300
gcc aac ctc gtg ctg aag atc atc gag cag ctg ccc tcc gcc aag gaa 2042
Ala Asn Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys Glu
305 310 315
tcc ccg gac aag ttc ctg gag gtg tgc acc tgg gtg gac cag atc gcc 2090
Ser Pro Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile Ala
320 325 330
gct ctg aac gac tcc aag acc cgc aag acc act tcc gaa acc gtc cgc 2138
Ala Leu Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val Arg
335 340 345 350
gcc gtt cta gac agt ctc tcc gag aag aag aag tcg tcc ccc taa 2183
Ala Val Leu Asp Ser Leu Ser Glu Lys Lys Lys Ser Ser Pro
355 360
ggtaccagcg gccgatccaa tcaacctctg gattacaaaa tttgtgaaag attgactggt 2243
attcttaact atgttgctcc ttttacgcta tgtggatacg ctgctttaat gcctttgtat 2303
catgctattg cttcccgtat ggctttcatt ttctcctcct tgtataaatc ctggttgctg 2363
tctctttatg aggagttgtg gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt 2423
gctgacgcaa cccccactgg ttggggcatt gccaccacct gtcagctcct ttccgggact 2483
ttcgctttcc ccctccctat tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc 2543
tggacagggg ctcggctgtt gggcactgac aattccgtgg tgttgtcggg gaaatcatcg 2603
tcctttcctt ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc 2663
tacgtccctt cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg 2723
cggcctcttc cgcgtcttcg agatctgcct cgactgtgcc ttctagttgc cagccatctg 2783
ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 2843
cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 2903
gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 2963
actcgagtta agggcgaatt cccgataagg atcttcctag agcatggcta cgtagataag 3023
tagcatggcg ggttaatcat taactacaag gaacccctag tgatggagtt ggccactccc 3083
tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc 3143
tttgcccggg cggcctcagt gagcgagcga gcgcgcag 3181
<210> 43
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 43
Met Ala Pro Lys Lys Lys Arg Lys Val His Met Asn Thr Lys Tyr Asn
1 5 10 15
Lys Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp Gly Ser
20 25 30
Ile Phe Ala Arg Ile Lys Pro Ser Gln Arg Ser Lys Phe Lys His Lys
35 40 45
Leu His Leu Val Phe Ala Val Tyr Gln Lys Thr Gln Arg Arg Trp Phe
50 55 60
Leu Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Leu Asp Ser
65 70 75 80
Gly Ser Val Ser Phe Tyr Ser Leu Ser Glu Ile Lys Pro Leu His Asn
85 90 95
Phe Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys Gln Ala
100 105 110
Asn Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys Glu Ser
115 120 125
Pro Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile Ala Ala
130 135 140
Leu Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val Arg Ala
145 150 155 160
Val Leu Asp Ser Leu Pro Gly Ser Val Gly Gly Leu Ser Pro Ser Gln
165 170 175
Ala Ser Ser Ala Ala Ser Ser Ala Ser Ser Ser Pro Gly Ser Gly Ile
180 185 190
Ser Glu Ala Leu Arg Ala Gly Ala Gly Ser Gly Thr Gly Tyr Asn Lys
195 200 205
Glu Phe Leu Leu Tyr Leu Ala Gly Phe Val Asp Gly Asp Gly Ser Ile
210 215 220
Tyr Ala Arg Ile Lys Pro Val Gln Arg Ala Lys Phe Lys His Glu Leu
225 230 235 240
Val Leu Gly Phe Asp Val Thr Gln Lys Thr Gln Arg Arg Trp Phe Leu
245 250 255
Asp Lys Leu Val Asp Glu Ile Gly Val Gly Tyr Val Tyr Asp Lys Gly
260 265 270
Ser Val Ser Ala Tyr Arg Leu Ser Gln Ile Lys Pro Leu His Asn Phe
275 280 285
Leu Thr Gln Leu Gln Pro Phe Leu Lys Leu Lys Gln Lys Gln Ala Asn
290 295 300
Leu Val Leu Lys Ile Ile Glu Gln Leu Pro Ser Ala Lys Glu Ser Pro
305 310 315 320
Asp Lys Phe Leu Glu Val Cys Thr Trp Val Asp Gln Ile Ala Ala Leu
325 330 335
Asn Asp Ser Lys Thr Arg Lys Thr Thr Ser Glu Thr Val Arg Ala Val
340 345 350
Leu Asp Ser Leu Ser Glu Lys Lys Lys Ser Ser Pro
355 360
<210> 44
<211> 184
<212> DNA
<213> 智人
<220>
<221> misc_特征
<222> (80)..(101)
<223> ARCUS靶向序列
<400> 44
gtcatcacag ttggggccac caatgcccaa gaccagccgg tgaccctggg gactttgggg 60
accaactttg gccgctgtgt ggacctcttt gccccagggg aggacatcat tggtgcctcc 120
agcgactgca gcacctgctt tgtgtcacag agtgggacat cacaggctgc tgcccacgtg 180
gctg 184
<210> 45
<211> 184
<212> DNA
<213> 恒河猴
<400> 45
gtcatcacag ttggggccac caatgcccag gaccagccgg tgaccctggg gactttgggg 60
accaactttg gccgctgtgt ggacctcttt gccccagggg aggacatcat tggtgcctcc 120
agcgactgca gcacctgctt tgtgtcacgg agtgggacat cgcaggctgc tgcccacgtg 180
gctg 184
<210> 46
<211> 184
<212> DNA
<213> 小家鼠
<400> 46
gtcatcacag tcggggccac gaatgcccag gaccagccag ttaccttggg gactttgggg 60
actaattttg gacgctgtgt ggatctcttt gcccccggga aggacatcat cggagcgtcc 120
agtgactgca gcacatgctt catgtcacag agtgggacct cacaggctgc tgcccacgtg 180
gccg 184
<210> 47
<211> 1179
<212> DNA
<213> 智人
<400> 47
atggcctctc acaagctgct ggtgaccccc cccaaggccc tgctcaagcc cctctccatc 60
cccaaccagc tcctgctggg gcctggtcct tccaacctgc ctcctcgcat catggcagcc 120
ggggggctgc agatgatcgg gtccatgagc aaggatatgt accagatcat ggacgagatc 180
aaggaaggca tccagtacgt gttccagacc aggaacccac tcacactggt catctctggc 240
tcgggacact gtgccctgga ggccgccctg gtcaatgtgc tggagcctgg ggactccttc 300
ctggttgggg ccaatggcat ttgggggcag cgagccgtgg acatcgggga gcgcatagga 360
gcccgagtgc acccgatgac caaggaccct ggaggccact acacactgca ggaggtggag 420
gagggcctgg cccagcacaa gccagtgctg ctgttcttaa cccacgggga gtcgtccacc 480
ggcgtgctgc agccccttga tggcttcggg gaactctgcc acaggtacaa gtgcctgctc 540
ctggtggatt cggtggcatc cctgggcggg accccccttt acatggaccg gcaaggcatc 600
gacatcctgt actcgggctc ccagaaggcc ctgaacgccc ctccagggac ctcgctcatc 660
tccttcagtg acaaggccaa aaagaagatg tactcccgca agacgaagcc cttctccttc 720
tacctggaca tcaagtggct ggccaacttc tggggctgtg acgaccagcc caggatgtac 780
catcacacaa tccccgtcat cagcctgtac agcctgagag agagcctggc cctcattgcg 840
gaacagggcc tggagaacag ctggcgccag caccgcgagg ccgcggcgta tctgcatggg 900
cgcctgcagg cactggggct gcagctcttc gtgaaggacc cggcgctccg gcttcccaca 960
gtcaccactg tggctgtacc cgctggctat gactggagag acatcgtcag ctacgtcata 1020
gaccacttcg acattgagat catgggtggc cttgggccct ccacggggaa ggtgctgcgg 1080
atcggcctgc tgggctgcaa tgccacccgc gagaatgtgg accgcgtgac ggaggccctg 1140
agggcggccc tgcagcactg ccccaagaag aagctgtga 1179
<210> 48
<211> 392
<212> PRT
<213> 智人
<400> 48
Met Ala Ser His Lys Leu Leu Val Thr Pro Pro Lys Ala Leu Leu Lys
1 5 10 15
Pro Leu Ser Ile Pro Asn Gln Leu Leu Leu Gly Pro Gly Pro Ser Asn
20 25 30
Leu Pro Pro Arg Ile Met Ala Ala Gly Gly Leu Gln Met Ile Gly Ser
35 40 45
Met Ser Lys Asp Met Tyr Gln Ile Met Asp Glu Ile Lys Glu Gly Ile
50 55 60
Gln Tyr Val Phe Gln Thr Arg Asn Pro Leu Thr Leu Val Ile Ser Gly
65 70 75 80
Ser Gly His Cys Ala Leu Glu Ala Ala Leu Val Asn Val Leu Glu Pro
85 90 95
Gly Asp Ser Phe Leu Val Gly Ala Asn Gly Ile Trp Gly Gln Arg Ala
100 105 110
Val Asp Ile Gly Glu Arg Ile Gly Ala Arg Val His Pro Met Thr Lys
115 120 125
Asp Pro Gly Gly His Tyr Thr Leu Gln Glu Val Glu Glu Gly Leu Ala
130 135 140
Gln His Lys Pro Val Leu Leu Phe Leu Thr His Gly Glu Ser Ser Thr
145 150 155 160
Gly Val Leu Gln Pro Leu Asp Gly Phe Gly Glu Leu Cys His Arg Tyr
165 170 175
Lys Cys Leu Leu Leu Val Asp Ser Val Ala Ser Leu Gly Gly Thr Pro
180 185 190
Leu Tyr Met Asp Arg Gln Gly Ile Asp Ile Leu Tyr Ser Gly Ser Gln
195 200 205
Lys Ala Leu Asn Ala Pro Pro Gly Thr Ser Leu Ile Ser Phe Ser Asp
210 215 220
Lys Ala Lys Lys Lys Met Tyr Ser Arg Lys Thr Lys Pro Phe Ser Phe
225 230 235 240
Tyr Leu Asp Ile Lys Trp Leu Ala Asn Phe Trp Gly Cys Asp Asp Gln
245 250 255
Pro Arg Met Tyr His His Thr Ile Pro Val Ile Ser Leu Tyr Ser Leu
260 265 270
Arg Glu Ser Leu Ala Leu Ile Ala Glu Gln Gly Leu Glu Asn Ser Trp
275 280 285
Arg Gln His Arg Glu Ala Ala Ala Tyr Leu His Gly Arg Leu Gln Ala
290 295 300
Leu Gly Leu Gln Leu Phe Val Lys Asp Pro Ala Leu Arg Leu Pro Thr
305 310 315 320
Val Thr Thr Val Ala Val Pro Ala Gly Tyr Asp Trp Arg Asp Ile Val
325 330 335
Ser Tyr Val Ile Asp His Phe Asp Ile Glu Ile Met Gly Gly Leu Gly
340 345 350
Pro Ser Thr Gly Lys Val Leu Arg Ile Gly Leu Leu Gly Cys Asn Ala
355 360 365
Thr Arg Glu Asn Val Asp Arg Val Thr Glu Ala Leu Arg Ala Ala Leu
370 375 380
Gln His Cys Pro Lys Lys Lys Leu
385 390
<210> 49
<211> 1113
<212> DNA
<213> 智人
<400> 49
atgctccccc ggctaatttg tatcaatgat tatgaacaac atgctaaatc agtacttcca 60
aagtctatat atgactatta caggtctggg gcaaatgatg aagaaacttt ggctgataat 120
attgcagcat tttccagatg gaagctgtat ccaaggatgc tccggaatgt tgctgaaaca 180
gatctgtcga cttctgtttt aggacagagg gtcagcatgc caatatgtgt gggggctacg 240
gccatgcagc gcatggctca tgtggacggc gagcttgcca ctgtgagagc ctgtcagtcc 300
ctgggaacgg gcatgatgtt gagttcctgg gccacctcct caattgaaga agtggcggaa 360
gctggtcctg aggcacttcg ttggctgcaa ctgtatatct acaaggaccg agaagtcacc 420
aagaagctag tgcggcaggc agagaagatg ggctacaagg ccatatttgt gacagtggac 480
acaccttacc tgggcaaccg tctggatgat gtgcgtaaca gattcaaact gccgccacaa 540
ctcaggatga aaaattttga aaccagtact ttatcatttt ctcctgagga aaattttgga 600
gacgacagtg gacttgctgc atatgtggct aaagcaatag acccatctat cagctgggaa 660
gatatcaaat ggctgagaag actgacatca ttgccaattg ttgcaaaggg cattttgaga 720
ggtgatgatg ccagggaggc tgttaaacat ggcttgaatg ggatcttggt gtcgaatcat 780
ggggctcgac aactcgatgg ggtgccagcc actattgatg ttctgccaga aattgtggag 840
gctgtggaag ggaaggtgga agtcttcctg gacgggggtg tgcggaaagg cactgatgtt 900
ctgaaagctc tggctcttgg cgccaaggct gtgtttgtgg ggagaccaat cgtttggggc 960
ttagctttcc agggggagaa aggtgttcaa gatgtcctcg agatactaaa ggaagaattc 1020
cggttggcca tggctctgag tgggtgccag aatgtgaaag tcatcgacaa gacattggtg 1080
aggaaaaatc ctttggccgt ttccaagatc tga 1113
<210> 50
<211> 370
<212> PRT
<213> 智人
<400> 50
Met Leu Pro Arg Leu Ile Cys Ile Asn Asp Tyr Glu Gln His Ala Lys
1 5 10 15
Ser Val Leu Pro Lys Ser Ile Tyr Asp Tyr Tyr Arg Ser Gly Ala Asn
20 25 30
Asp Glu Glu Thr Leu Ala Asp Asn Ile Ala Ala Phe Ser Arg Trp Lys
35 40 45
Leu Tyr Pro Arg Met Leu Arg Asn Val Ala Glu Thr Asp Leu Ser Thr
50 55 60
Ser Val Leu Gly Gln Arg Val Ser Met Pro Ile Cys Val Gly Ala Thr
65 70 75 80
Ala Met Gln Arg Met Ala His Val Asp Gly Glu Leu Ala Thr Val Arg
85 90 95
Ala Cys Gln Ser Leu Gly Thr Gly Met Met Leu Ser Ser Trp Ala Thr
100 105 110
Ser Ser Ile Glu Glu Val Ala Glu Ala Gly Pro Glu Ala Leu Arg Trp
115 120 125
Leu Gln Leu Tyr Ile Tyr Lys Asp Arg Glu Val Thr Lys Lys Leu Val
130 135 140
Arg Gln Ala Glu Lys Met Gly Tyr Lys Ala Ile Phe Val Thr Val Asp
145 150 155 160
Thr Pro Tyr Leu Gly Asn Arg Leu Asp Asp Val Arg Asn Arg Phe Lys
165 170 175
Leu Pro Pro Gln Leu Arg Met Lys Asn Phe Glu Thr Ser Thr Leu Ser
180 185 190
Phe Ser Pro Glu Glu Asn Phe Gly Asp Asp Ser Gly Leu Ala Ala Tyr
195 200 205
Val Ala Lys Ala Ile Asp Pro Ser Ile Ser Trp Glu Asp Ile Lys Trp
210 215 220
Leu Arg Arg Leu Thr Ser Leu Pro Ile Val Ala Lys Gly Ile Leu Arg
225 230 235 240
Gly Asp Asp Ala Arg Glu Ala Val Lys His Gly Leu Asn Gly Ile Leu
245 250 255
Val Ser Asn His Gly Ala Arg Gln Leu Asp Gly Val Pro Ala Thr Ile
260 265 270
Asp Val Leu Pro Glu Ile Val Glu Ala Val Glu Gly Lys Val Glu Val
275 280 285
Phe Leu Asp Gly Gly Val Arg Lys Gly Thr Asp Val Leu Lys Ala Leu
290 295 300
Ala Leu Gly Ala Lys Ala Val Phe Val Gly Arg Pro Ile Val Trp Gly
305 310 315 320
Leu Ala Phe Gln Gly Glu Lys Gly Val Gln Asp Val Leu Glu Ile Leu
325 330 335
Lys Glu Glu Phe Arg Leu Ala Met Ala Leu Ser Gly Cys Gln Asn Val
340 345 350
Lys Val Ile Asp Lys Thr Leu Val Arg Lys Asn Pro Leu Ala Val Ser
355 360 365
Lys Ile
370
<210> 51
<211> 1611
<212> DNA
<213> 智人
<400> 51
atggagtttt caagtccttc cagagaggaa tgtcccaagc ctttgagtag ggtaagcatc 60
atggctggca gcctcacagg attgcttcta cttcaggcag tgtcgtgggc atcaggtgcc 120
cgcccctgca tccctaaaag cttcggctac agctcggtgg tgtgtgtctg caatgccaca 180
tactgtgact cctttgaccc cccgaccttt cctgcccttg gtaccttcag ccgctatgag 240
agtacacgca gtgggcgacg gatggagctg agtatggggc ccatccaggc taatcacacg 300
ggcacaggcc tgctactgac cctgcagcca gaacagaagt tccagaaagt gaagggattt 360
ggaggggcca tgacagatgc tgctgctctc aacatccttg ccctgtcacc ccctgcccaa 420
aatttgctac ttaaatcgta cttctctgaa gaaggaatcg gatataacat catccgggta 480
cccatggcca gctgtgactt ctccatccgc acctacacct atgcagacac ccctgatgat 540
ttccagttgc acaacttcag cctcccagag gaagatacca agctcaagat acccctgatt 600
caccgagccc tgcagttggc ccagcgtccc gtttcactcc ttgccagccc ctggacatca 660
cccacttggc tcaagaccaa tggagcggtg aatgggaagg ggtcactcaa gggacagccc 720
ggagacatct accaccagac ctgggccaga tactttgtga agttcctgga tgcctatgct 780
gagcacaagt tacagttctg ggcagtgaca gctgaaaatg agccttctgc tgggctgttg 840
agtggatacc ccttccagtg cctgggcttc acccctgaac atcagcgaga cttcattgcc 900
cgtgacctag gtcctaccct cgccaacagt actcaccaca atgtccgcct actcatgctg 960
gatgaccaac gcttgctgct gccccactgg gcaaaggtgg tactgacaga cccagaagca 1020
gctaaatatg ttcatggcat tgctgtacat tggtacctgg actttctggc tccagccaaa 1080
gccaccctag gggagacaca ccgcctgttc cccaacacca tgctctttgc ctcagaggcc 1140
tgtgtgggct ccaagttctg ggagcagagt gtgcggctag gctcctggga tcgagggatg 1200
cagtacagcc acagcatcat cacgaacctc ctgtaccatg tggtcggctg gaccgactgg 1260
aaccttgccc tgaaccccga aggaggaccc aattgggtgc gtaactttgt cgacagtccc 1320
atcattgtag acatcaccaa ggacacgttt tacaaacagc ccatgttcta ccaccttggc 1380
cacttcagca agttcattcc tgagggctcc cagagagtgg ggctggttgc cagtcagaag 1440
aacgacctgg acgcagtggc actgatgcat cccgatggct ctgctgttgt ggtcgtgcta 1500
aaccgctcct ctaaggatgt gcctcttacc atcaaggatc ctgctgtggg cttcctggag 1560
acaatctcac ctggctactc cattcacacc tacctgtggc gtcgccagtg a 1611
<210> 52
<211> 536
<212> PRT
<213> 智人
<400> 52
Met Glu Phe Ser Ser Pro Ser Arg Glu Glu Cys Pro Lys Pro Leu Ser
1 5 10 15
Arg Val Ser Ile Met Ala Gly Ser Leu Thr Gly Leu Leu Leu Leu Gln
20 25 30
Ala Val Ser Trp Ala Ser Gly Ala Arg Pro Cys Ile Pro Lys Ser Phe
35 40 45
Gly Tyr Ser Ser Val Val Cys Val Cys Asn Ala Thr Tyr Cys Asp Ser
50 55 60
Phe Asp Pro Pro Thr Phe Pro Ala Leu Gly Thr Phe Ser Arg Tyr Glu
65 70 75 80
Ser Thr Arg Ser Gly Arg Arg Met Glu Leu Ser Met Gly Pro Ile Gln
85 90 95
Ala Asn His Thr Gly Thr Gly Leu Leu Leu Thr Leu Gln Pro Glu Gln
100 105 110
Lys Phe Gln Lys Val Lys Gly Phe Gly Gly Ala Met Thr Asp Ala Ala
115 120 125
Ala Leu Asn Ile Leu Ala Leu Ser Pro Pro Ala Gln Asn Leu Leu Leu
130 135 140
Lys Ser Tyr Phe Ser Glu Glu Gly Ile Gly Tyr Asn Ile Ile Arg Val
145 150 155 160
Pro Met Ala Ser Cys Asp Phe Ser Ile Arg Thr Tyr Thr Tyr Ala Asp
165 170 175
Thr Pro Asp Asp Phe Gln Leu His Asn Phe Ser Leu Pro Glu Glu Asp
180 185 190
Thr Lys Leu Lys Ile Pro Leu Ile His Arg Ala Leu Gln Leu Ala Gln
195 200 205
Arg Pro Val Ser Leu Leu Ala Ser Pro Trp Thr Ser Pro Thr Trp Leu
210 215 220
Lys Thr Asn Gly Ala Val Asn Gly Lys Gly Ser Leu Lys Gly Gln Pro
225 230 235 240
Gly Asp Ile Tyr His Gln Thr Trp Ala Arg Tyr Phe Val Lys Phe Leu
245 250 255
Asp Ala Tyr Ala Glu His Lys Leu Gln Phe Trp Ala Val Thr Ala Glu
260 265 270
Asn Glu Pro Ser Ala Gly Leu Leu Ser Gly Tyr Pro Phe Gln Cys Leu
275 280 285
Gly Phe Thr Pro Glu His Gln Arg Asp Phe Ile Ala Arg Asp Leu Gly
290 295 300
Pro Thr Leu Ala Asn Ser Thr His His Asn Val Arg Leu Leu Met Leu
305 310 315 320
Asp Asp Gln Arg Leu Leu Leu Pro His Trp Ala Lys Val Val Leu Thr
325 330 335
Asp Pro Glu Ala Ala Lys Tyr Val His Gly Ile Ala Val His Trp Tyr
340 345 350
Leu Asp Phe Leu Ala Pro Ala Lys Ala Thr Leu Gly Glu Thr His Arg
355 360 365
Leu Phe Pro Asn Thr Met Leu Phe Ala Ser Glu Ala Cys Val Gly Ser
370 375 380
Lys Phe Trp Glu Gln Ser Val Arg Leu Gly Ser Trp Asp Arg Gly Met
385 390 395 400
Gln Tyr Ser His Ser Ile Ile Thr Asn Leu Leu Tyr His Val Val Gly
405 410 415
Trp Thr Asp Trp Asn Leu Ala Leu Asn Pro Glu Gly Gly Pro Asn Trp
420 425 430
Val Arg Asn Phe Val Asp Ser Pro Ile Ile Val Asp Ile Thr Lys Asp
435 440 445
Thr Phe Tyr Lys Gln Pro Met Phe Tyr His Leu Gly His Phe Ser Lys
450 455 460
Phe Ile Pro Glu Gly Ser Gln Arg Val Gly Leu Val Ala Ser Gln Lys
465 470 475 480
Asn Asp Leu Asp Ala Val Ala Leu Met His Pro Asp Gly Ser Ala Val
485 490 495
Val Val Val Leu Asn Arg Ser Ser Lys Asp Val Pro Leu Thr Ile Lys
500 505 510
Asp Pro Ala Val Gly Phe Leu Glu Thr Ile Ser Pro Gly Tyr Ser Ile
515 520 525
His Thr Tyr Leu Trp Arg Arg Gln
530 535
<210> 53
<211> 7056
<212> DNA
<213> 智人
<400> 53
atgcaaatag agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc 60
accagaagat actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc 120
ggtgagctgc ctgtggacgc aagatttcct cctagagtgc caaaatcttt tccattcaac 180
acctcagtcg tgtacaaaaa gactctgttt gtagaattca cggatcacct tttcaacatc 240
gctaagccaa ggccaccctg gatgggtctg ctaggtccta ccatccaggc tgaggtttat 300
gatacagtgg tcattacact taagaacatg gcttcccatc ctgtcagtct tcatgctgtt 360
ggtgtatcct actggaaagc ttctgaggga gctgaatatg atgatcagac cagtcaaagg 420
gagaaagaag atgataaagt cttccctggt ggaagccata catatgtctg gcaggtcctg 480
aaagagaatg gtccaatggc ctctgaccca ctgtgcctta cctactcata tctttctcat 540
gtggacctgg taaaagactt gaattcaggc ctcattggag ccctactagt atgtagagaa 600
gggagtctgg ccaaggaaaa gacacagacc ttgcacaaat ttatactact ttttgctgta 660
tttgatgaag ggaaaagttg gcactcagaa acaaagaact ccttgatgca ggatagggat 720
gctgcatctg ctcgggcctg gcctaaaatg cacacagtca atggttatgt aaacaggtct 780
ctgccaggtc tgattggatg ccacaggaaa tcagtctatt ggcatgtgat tggaatgggc 840
accactcctg aagtgcactc aatattcctc gaaggtcaca catttcttgt gaggaaccat 900
cgccaggcgt ccttggaaat ctcgccaata actttcctta ctgctcaaac actcttgatg 960
gaccttggac agtttctact gttttgtcat atctcttccc accaacatga tggcatggaa 1020
gcttatgtca aagtagacag ctgtccagag gaaccccaac tacgaatgaa aaataatgaa 1080
gaagcggaag actatgatga tgatcttact gattctgaaa tggatgtggt caggtttgat 1140
gatgacaact ctccttcctt tatccaaatt cgctcagttg ccaagaagca tcctaaaact 1200
tgggtacatt acattgctgc tgaagaggag gactgggact atgctccctt agtcctcgcc 1260
cccgatgaca gaagttataa aagtcaatat ttgaacaatg gccctcagcg gattggtagg 1320
aagtacaaaa aagtccgatt tatggcatac acagatgaaa cctttaagac tcgtgaagct 1380
attcagcatg aatcaggaat cttgggacct ttactttatg gggaagttgg agacacactg 1440
ttgattatat ttaagaatca agcaagcaga ccatataaca tctaccctca cggaatcact 1500
gatgtccgtc ctttgtattc aaggagatta ccaaaaggtg taaaacattt gaaggatttt 1560
ccaattctgc caggagaaat attcaaatat aaatggacag tgactgtaga agatgggcca 1620
actaaatcag atcctcggtg cctgacccgc tattactcta gtttcgttaa tatggagaga 1680
gatctagctt caggactcat tggccctctc ctcatctgct acaaagaatc tgtagatcaa 1740
agaggaaacc agataatgtc agacaagagg aatgtcatcc tgttttctgt atttgatgag 1800
aaccgaagct ggtacctcac agagaatata caacgctttc tccccaatcc agctggagtg 1860
cagcttgagg atccagagtt ccaagcctcc aacatcatgc acagcatcaa tggctatgtt 1920
tttgatagtt tgcagttgtc agtttgtttg catgaggtgg catactggta cattctaagc 1980
attggagcac agactgactt cctttctgtc ttcttctctg gatatacctt caaacacaaa 2040
atggtctatg aagacacact caccctattc ccattctcag gagaaactgt cttcatgtcg 2100
atggaaaacc caggtctatg gattctgggg tgccacaact cagactttcg gaacagaggc 2160
atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta ttacgaggac 2220
agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga accaagaagc 2280
ttctcccaga attcaagaca ccctagcact aggcaaaagc aatttaatgc caccacaatt 2340
ccagaaaatg acatagagaa gactgaccct tggtttgcac acagaacacc tatgcctaaa 2400
atacaaaatg tctcctctag tgatttgttg atgctcttgc gacagagtcc tactccacat 2460
gggctatcct tatctgatct ccaagaagcc aaatatgaga ctttttctga tgatccatca 2520
cctggagcaa tagacagtaa taacagcctg tctgaaatga cacacttcag gccacagctc 2580
catcacagtg gggacatggt atttacccct gagtcaggcc tccaattaag attaaatgag 2640
aaactgggga caactgcagc aacagagttg aagaaacttg atttcaaagt ttctagtaca 2700
tcaaataatc tgatttcaac aattccatca gacaatttgg cagcaggtac tgataataca 2760
agttccttag gacccccaag tatgccagtt cattatgata gtcaattaga taccactcta 2820
tttggcaaaa agtcatctcc ccttactgag tctggtggac ctctgagctt gagtgaagaa 2880
aataatgatt caaagttgtt agaatcaggt ttaatgaata gccaagaaag ttcatgggga 2940
aaaaatgtat cgtcaacaga gagtggtagg ttatttaaag ggaaaagagc tcatggacct 3000
gctttgttga ctaaagataa tgccttattc aaagttagca tctctttgtt aaagacaaac 3060
aaaacttcca ataattcagc aactaataga aagactcaca ttgatggccc atcattatta 3120
attgagaata gtccatcagt ctggcaaaat atattagaaa gtgacactga gtttaaaaaa 3180
gtgacacctt tgattcatga cagaatgctt atggacaaaa atgctacagc tttgaggcta 3240
aatcatatgt caaataaaac tacttcatca aaaaacatgg aaatggtcca acagaaaaaa 3300
gagggcccca ttccaccaga tgcacaaaat ccagatatgt cgttctttaa gatgctattc 3360
ttgccagaat cagcaaggtg gatacaaagg actcatggaa agaactctct gaactctggg 3420
caaggcccca gtccaaagca attagtatcc ttaggaccag aaaaatctgt ggaaggtcag 3480
aatttcttgt ctgagaaaaa caaagtggta gtaggaaagg gtgaatttac aaaggacgta 3540
ggactcaaag agatggtttt tccaagcagc agaaacctat ttcttactaa cttggataat 3600
ttacatgaaa ataatacaca caatcaagaa aaaaaaattc aggaagaaat agaaaagaag 3660
gaaacattaa tccaagagaa tgtagttttg cctcagatac atacagtgac tggcactaag 3720
aatttcatga agaacctttt cttactgagc actaggcaaa atgtagaagg ttcatatgac 3780
ggggcatatg ctccagtact tcaagatttt aggtcattaa atgattcaac aaatagaaca 3840
aagaaacaca cagctcattt ctcaaaaaaa ggggaggaag aaaacttgga aggcttggga 3900
aatcaaacca agcaaattgt agagaaatat gcatgcacca caaggatatc tcctaataca 3960
agccagcaga attttgtcac gcaacgtagt aagagagctt tgaaacaatt cagactccca 4020
ctagaagaaa cagaacttga aaaaaggata attgtggatg acacctcaac ccagtggtcc 4080
aaaaacatga aacatttgac cccgagcacc ctcacacaga tagactacaa tgagaaggag 4140
aaaggggcca ttactcagtc tcccttatca gattgcctta cgaggagtca tagcatccct 4200
caagcaaata gatctccatt acccattgca aaggtatcat catttccatc tattagacct 4260
atatatctga ccagggtcct attccaagac aactcttctc atcttccagc agcatcttat 4320
agaaagaaag attctggggt ccaagaaagc agtcatttct tacaaggagc caaaaaaaat 4380
aacctttctt tagccattct aaccttggag atgactggtg atcaaagaga ggttggctcc 4440
ctggggacaa gtgccacaaa ttcagtcaca tacaagaaag ttgagaacac tgttctcccg 4500
aaaccagact tgcccaaaac atctggcaaa gttgaattgc ttccaaaagt tcacatttat 4560
cagaaggacc tattccctac ggaaactagc aatgggtctc ctggccatct ggatctcgtg 4620
gaagggagcc ttcttcaggg aacagaggga gcgattaagt ggaatgaagc aaacagacct 4680
ggaaaagttc cctttctgag agtagcaaca gaaagctctg caaagactcc ctccaagcta 4740
ttggatcctc ttgcttggga taaccactat ggtactcaga taccaaaaga agagtggaaa 4800
tcccaagaga agtcaccaga aaaaacagct tttaagaaaa aggataccat tttgtccctg 4860
aacgcttgtg aaagcaatca tgcaatagca gcaataaatg agggacaaaa taagcccgaa 4920
atagaagtca cctgggcaaa gcaaggtagg actgaaaggc tgtgctctca aaacccacca 4980
gtcttgaaac gccatcaacg ggaaataact cgtactactc ttcagtcaga tcaagaggaa 5040
attgactatg atgataccat atcagttgaa atgaagaagg aagattttga catttatgat 5100
gaggatgaaa atcagagccc ccgcagcttt caaaagaaaa cacgacacta ttttattgct 5160
gcagtggaga ggctctggga ttatgggatg agtagctccc cacatgttct aagaaacagg 5220
gctcagagtg gcagtgtccc tcagttcaag aaagttgttt tccaggaatt tactgatggc 5280
tcctttactc agcccttata ccgtggagaa ctaaatgaac atttgggact cctggggcca 5340
tatataagag cagaagttga agataatatc atggtaactt tcagaaatca ggcctctcgt 5400
ccctattcct tctattctag ccttatttct tatgaggaag atcagaggca aggagcagaa 5460
cctagaaaaa actttgtcaa gcctaatgaa accaaaactt acttttggaa agtgcaacat 5520
catatggcac ccactaaaga tgagtttgac tgcaaagcct gggcttattt ctctgatgtt 5580
gacctggaaa aagatgtgca ctcaggcctg attggacccc ttctggtctg ccacactaac 5640
acactgaacc ctgctcatgg gagacaagtg acagtacagg aatttgctct gtttttcacc 5700
atctttgatg agaccaaaag ctggtacttc actgaaaata tggaaagaaa ctgcagggct 5760
ccctgcaata tccagatgga agatcccact tttaaagaga attatcgctt ccatgcaatc 5820
aatggctaca taatggatac actacctggc ttagtaatgg ctcaggatca aaggattcga 5880
tggtatctgc tcagcatggg cagcaatgaa aacatccatt ctattcattt cagtggacat 5940
gtgttcactg tacgaaaaaa agaggagtat aaaatggcac tgtacaatct ctatccaggt 6000
gtttttgaga cagtggaaat gttaccatcc aaagctggaa tttggcgggt ggaatgcctt 6060
attggcgagc atctacatgc tgggatgagc acactttttc tggtgtacag caataagtgt 6120
cagactcccc tgggaatggc ttctggacac attagagatt ttcagattac agcttcagga 6180
caatatggac agtgggcccc aaagctggcc agacttcatt attccggatc aatcaatgcc 6240
tggagcacca aggagccctt ttcttggatc aaggtggatc tgttggcacc aatgattatt 6300
cacggcatca agacccaggg tgcccgtcag aagttctcca gcctctacat ctctcagttt 6360
atcatcatgt atagtcttga tgggaagaag tggcagactt atcgaggaaa ttccactgga 6420
accttaatgg tcttctttgg caatgtggat tcatctggga taaaacacaa tatttttaac 6480
cctccaatta ttgctcgata catccgtttg cacccaactc attatagcat tcgcagcact 6540
cttcgcatgg agttgatggg ctgtgattta aatagttgca gcatgccatt gggaatggag 6600
agtaaagcaa tatcagatgc acagattact gcttcatcct actttaccaa tatgtttgcc 6660
acctggtctc cttcaaaagc tcgacttcac ctccaaggga ggagtaatgc ctggagacct 6720
caggtgaata atccaaaaga gtggctgcaa gtggacttcc agaagacaat gaaagtcaca 6780
ggagtaacta ctcagggagt aaaatctctg cttaccagca tgtatgtgaa ggagttcctc 6840
atctccagca gtcaagatgg ccatcagtgg actctctttt ttcagaatgg caaagtaaag 6900
gtttttcagg gaaatcaaga ctccttcaca cctgtggtga actctctaga cccaccgtta 6960
ctgactcgct accttcgaat tcacccccag agttgggtgc accagattgc cctgaggatg 7020
gaggttctgg gctgcgaggc acaggacctc tactga 7056
<210> 54
<211> 2351
<212> PRT
<213> 智人
<400> 54
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Cys Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg
35 40 45
Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val
50 55 60
Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile
65 70 75 80
Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln
85 90 95
Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser
100 105 110
His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser
115 120 125
Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp
130 135 140
Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu
145 150 155 160
Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser
165 170 175
Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile
180 185 190
Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr
195 200 205
Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly
210 215 220
Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp
225 230 235 240
Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr
245 250 255
Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val
260 265 270
Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile
275 280 285
Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser
290 295 300
Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met
305 310 315 320
Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His
325 330 335
Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro
340 345 350
Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp
355 360 365
Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser
370 375 380
Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn
420 425 430
Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met
435 440 445
Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu
450 455 460
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
His Gly Ile Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys
500 505 510
Gly Val Lys His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe
515 520 525
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg
545 550 555 560
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val
580 585 590
Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu
595 600 605
Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp
610 615 620
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly
705 710 715 720
Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp
725 730 735
Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys
740 745 750
Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro
755 760 765
Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp
770 775 780
Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys
785 790 795 800
Ile Gln Asn Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser
805 810 815
Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr
820 825 830
Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn
835 840 845
Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly
850 855 860
Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu
865 870 875 880
Lys Leu Gly Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys
885 890 895
Val Ser Ser Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn
900 905 910
Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met
915 920 925
Pro Val His Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys
930 935 940
Ser Ser Pro Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu
945 950 955 960
Asn Asn Asp Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu
965 970 975
Ser Ser Trp Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe
980 985 990
Lys Gly Lys Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala
995 1000 1005
Leu Phe Lys Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser
1010 1015 1020
Asn Asn Ser Ala Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser
1025 1030 1035
Leu Leu Ile Glu Asn Ser Pro Ser Val Trp Gln Asn Ile Leu Glu
1040 1045 1050
Ser Asp Thr Glu Phe Lys Lys Val Thr Pro Leu Ile His Asp Arg
1055 1060 1065
Met Leu Met Asp Lys Asn Ala Thr Ala Leu Arg Leu Asn His Met
1070 1075 1080
Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln
1085 1090 1095
Lys Lys Glu Gly Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met
1100 1105 1110
Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile
1115 1120 1125
Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro
1130 1135 1140
Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu Lys Ser Val Glu
1145 1150 1155
Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val Val Val Gly Lys
1160 1165 1170
Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu Met Val Phe Pro
1175 1180 1185
Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu
1190 1195 1200
Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu
1205 1210 1215
Lys Lys Glu Thr Leu Ile Gln Glu Asn Val Val Leu Pro Gln Ile
1220 1225 1230
His Thr Val Thr Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu
1235 1240 1245
Leu Ser Thr Arg Gln Asn Val Glu Gly Ser Tyr Asp Gly Ala Tyr
1250 1255 1260
Ala Pro Val Leu Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn
1265 1270 1275
Arg Thr Lys Lys His Thr Ala His Phe Ser Lys Lys Gly Glu Glu
1280 1285 1290
Glu Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu
1295 1300 1305
Lys Tyr Ala Cys Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln
1310 1315 1320
Asn Phe Val Thr Gln Arg Ser Lys Arg Ala Leu Lys Gln Phe Arg
1325 1330 1335
Leu Pro Leu Glu Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp
1340 1345 1350
Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro
1355 1360 1365
Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala
1370 1375 1380
Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr Arg Ser His Ser
1385 1390 1395
Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys Val Ser
1400 1405 1410
Ser Phe Pro Ser Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu Phe
1415 1420 1425
Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys
1430 1435 1440
Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys
1445 1450 1455
Lys Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly
1460 1465 1470
Asp Gln Arg Glu Val Gly Ser Leu Gly Thr Ser Ala Thr Asn Ser
1475 1480 1485
Val Thr Tyr Lys Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp
1490 1495 1500
Leu Pro Lys Thr Ser Gly Lys Val Glu Leu Leu Pro Lys Val His
1505 1510 1515
Ile Tyr Gln Lys Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser
1520 1525 1530
Pro Gly His Leu Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr
1535 1540 1545
Glu Gly Ala Ile Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val
1550 1555 1560
Pro Phe Leu Arg Val Ala Thr Glu Ser Ser Ala Lys Thr Pro Ser
1565 1570 1575
Lys Leu Leu Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln
1580 1585 1590
Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys
1595 1600 1605
Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys
1610 1615 1620
Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys
1625 1630 1635
Pro Glu Ile Glu Val Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg
1640 1645 1650
Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg Glu
1655 1660 1665
Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln Glu Glu Ile Asp Tyr
1670 1675 1680
Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile
1685 1690 1695
Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys
1700 1705 1710
Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr
1715 1720 1725
Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser
1730 1735 1740
Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr
1745 1750 1755
Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
1760 1765 1770
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp
1775 1780 1785
Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser
1790 1795 1800
Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly
1805 1810 1815
Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr
1820 1825 1830
Tyr Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu
1835 1840 1845
Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu
1850 1855 1860
Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu Leu Val Cys His
1865 1870 1875
Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr Val Gln
1880 1885 1890
Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp
1895 1900 1905
Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn
1910 1915 1920
Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His
1925 1930 1935
Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met
1940 1945 1950
Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser
1955 1960 1965
Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr
1970 1975 1980
Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr
1985 1990 1995
Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro Ser Lys Ala Gly
2000 2005 2010
Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala Gly
2015 2020 2025
Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro
2030 2035 2040
Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala
2045 2050 2055
Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His
2060 2065 2070
Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser
2075 2080 2085
Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile
2090 2095 2100
Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser Leu Tyr Ile Ser
2105 2110 2115
Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr
2120 2125 2130
Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn
2135 2140 2145
Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile
2150 2155 2160
Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg
2165 2170 2175
Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys
2180 2185 2190
Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln
2195 2200 2205
Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser
2210 2215 2220
Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp
2225 2230 2235
Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe
2240 2245 2250
Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys
2255 2260 2265
Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser
2270 2275 2280
Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys
2285 2290 2295
Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val
2300 2305 2310
Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His
2315 2320 2325
Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu
2330 2335 2340
Gly Cys Glu Ala Gln Asp Leu Tyr
2345 2350
<210> 55
<211> 1386
<212> DNA
<213> 智人
<400> 55
atgcagcgcg tgaacatgat catggcagaa tcaccaggcc tcatcaccat ctgcctttta 60
ggatatctac tcagtgctga atgtacagtt tttcttgatc atgaaaacgc caacaaaatt 120
ctgaatcggc caaagaggta taattcaggt aaattggaag agtttgttca agggaacctt 180
gagagagaat gtatggaaga aaagtgtagt tttgaagaag cacgagaagt ttttgaaaac 240
actgaaagaa caactgaatt ttggaagcag tatgttgatg gagatcagtg tgagtccaat 300
ccatgtttaa atggcggcag ttgcaaggat gacattaatt cctatgaatg ttggtgtccc 360
tttggatttg aaggaaagaa ctgtgaatta gatgtaacat gtaacattaa gaatggcaga 420
tgcgagcagt tttgtaaaaa tagtgctgat aacaaggtgg tttgctcctg tactgaggga 480
tatcgacttg cagaaaacca gaagtcctgt gaaccagcag tgccatttcc atgtggaaga 540
gtttctgttt cacaaacttc taagctcacc cgtgctgaga ctgtttttcc tgatgtggac 600
tatgtaaatt ctactgaagc tgaaaccatt ttggataaca tcactcaaag cacccaatca 660
tttaatgact tcactcgggt tgttggtgga gaagatgcca aaccaggtca attcccttgg 720
caggttgttt tgaatggtaa agttgatgca ttctgtggag gctctatcgt taatgaaaaa 780
tggattgtaa ctgctgccca ctgtgttgaa actggtgtta aaattacagt tgtcgcaggt 840
gaacataata ttgaggagac agaacataca gagcaaaagc gaaatgtgat tcgaattatt 900
cctcaccaca actacaatgc agctattaat aagtacaacc atgacattgc ccttctggaa 960
ctggacgaac ccttagtgct aaacagctac gttacaccta tttgcattgc tgacaaggaa 1020
tacacgaaca tcttcctcaa atttggatct ggctatgtaa gtggctgggg aagagtcttc 1080
cacaaaggga gatcagcttt agttcttcag taccttagag ttccacttgt tgaccgagcc 1140
acatgtcttc gatctacaaa gttcaccatc tataacaaca tgttctgtgc tggcttccat 1200
gaaggaggta gagattcatg tcaaggagat agtgggggac cccatgttac tgaagtggaa 1260
gggaccagtt tcttaactgg aattattagc tggggtgaag agtgtgcaat gaaaggcaaa 1320
tatggaatat ataccaaggt atcccggtat gtcaactgga ttaaggaaaa aacaaagctc 1380
acttaa 1386
<210> 56
<211> 461
<212> PRT
<213> 智人
<400> 56
Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe
130 135 140
Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala
180 185 190
Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu
195 200 205
Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe
210 215 220
Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp
225 230 235 240
Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile
245 250 255
Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly
260 265 270
Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu
275 280 285
His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn
290 295 300
Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu
305 310 315 320
Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile
325 330 335
Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr
340 345 350
Val Ser Gly Trp Gly Arg Val Phe His Lys Gly Arg Ser Ala Leu Val
355 360 365
Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Arg
370 375 380
Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His
385 390 395 400
Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val
405 410 415
Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly
420 425 430
Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser
435 440 445
Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 57
<211> 1395
<212> DNA
<213> 智人
<400> 57
atggcctcgg agagtgggaa gctttggggt ggccggtttg tgggtgcagt ggaccccatc 60
atggagaagt tcaacgcgtc cattgcctac gaccggcacc tttgggaggt ggatgttcaa 120
ggcagcaaag cctacagcag gggcctggag aaggcagggc tcctcaccaa ggccgagatg 180
gaccagatac tccatggcct agacaaggtg gctgaggagt gggcccaggg caccttcaaa 240
ctgaactcca atgatgagga catccacaca gccaatgagc gccgcctgaa ggagctcatt 300
ggtgcaacgg cagggaagct gcacacggga cggagccgga atgaccaggt ggtcacagac 360
ctcaggctgt ggatgcggca gacctgctcc acgctctcgg gcctcctctg ggagctcatt 420
aggaccatgg tggatcgggc agaggcggaa cgtgatgttc tcttcccggg gtacacccat 480
ttgcagaggg cccagcccat ccgctggagc cactggattc tgagccacgc cgtggcactg 540
acccgagact ctgagcggct gctggaggtg cggaagcgga tcaatgtcct gcccctgggg 600
agtggggcca ttgcaggcaa tcccctgggt gtggaccgag agctgctccg agcagaactc 660
aactttgggg ccatcactct caacagcatg gatgccacta gtgagcggga ctttgtggcc 720
gagttcctgt tctgggcttc gctgtgcatg acccatctca gcaggatggc cgaggacctc 780
atcctctact gcaccaagga attcagcttc gtgcagctct cagatgccta cagcacggga 840
agcagcctga tgccccagaa gaaaaacccc gacagtttgg agctgatccg gagcaaggct 900
gggcgtgtgt ttgggcggtg tgccgggctc ctgatgaccc tcaagggact tcccagcacc 960
tacaacaaag acttacagga ggacaaggaa gctgtgtttg aagtgtcaga cactatgagt 1020
gccgtgctcc aggtggccac tggcgtcatc tctacgctgc agattcacca agagaacatg 1080
ggacaggctc tcagccccga catgctggcc actgaccttg cctattacct ggtccgcaaa 1140
gggatgccat tccgccaggc ccacgaggcc tccgggaaag ctgtgttcat ggccgagacc 1200
aagggggtcg ccctcaacca gctgtcactg caggagctgc agaccatcag ccccctgttc 1260
tcgggcgacg tgatctgcgt gtgggactac gggcacagtg tggagcagta tggtgccctg 1320
ggcggcactg cgcgctccag cgtcgactgg cagatccgcc aggtgcgggc gctactgcag 1380
gcacagcagg cctag 1395
<210> 58
<211> 464
<212> PRT
<213> 智人
<400> 58
Met Ala Ser Glu Ser Gly Lys Leu Trp Gly Gly Arg Phe Val Gly Ala
1 5 10 15
Val Asp Pro Ile Met Glu Lys Phe Asn Ala Ser Ile Ala Tyr Asp Arg
20 25 30
His Leu Trp Glu Val Asp Val Gln Gly Ser Lys Ala Tyr Ser Arg Gly
35 40 45
Leu Glu Lys Ala Gly Leu Leu Thr Lys Ala Glu Met Asp Gln Ile Leu
50 55 60
His Gly Leu Asp Lys Val Ala Glu Glu Trp Ala Gln Gly Thr Phe Lys
65 70 75 80
Leu Asn Ser Asn Asp Glu Asp Ile His Thr Ala Asn Glu Arg Arg Leu
85 90 95
Lys Glu Leu Ile Gly Ala Thr Ala Gly Lys Leu His Thr Gly Arg Ser
100 105 110
Arg Asn Asp Gln Val Val Thr Asp Leu Arg Leu Trp Met Arg Gln Thr
115 120 125
Cys Ser Thr Leu Ser Gly Leu Leu Trp Glu Leu Ile Arg Thr Met Val
130 135 140
Asp Arg Ala Glu Ala Glu Arg Asp Val Leu Phe Pro Gly Tyr Thr His
145 150 155 160
Leu Gln Arg Ala Gln Pro Ile Arg Trp Ser His Trp Ile Leu Ser His
165 170 175
Ala Val Ala Leu Thr Arg Asp Ser Glu Arg Leu Leu Glu Val Arg Lys
180 185 190
Arg Ile Asn Val Leu Pro Leu Gly Ser Gly Ala Ile Ala Gly Asn Pro
195 200 205
Leu Gly Val Asp Arg Glu Leu Leu Arg Ala Glu Leu Asn Phe Gly Ala
210 215 220
Ile Thr Leu Asn Ser Met Asp Ala Thr Ser Glu Arg Asp Phe Val Ala
225 230 235 240
Glu Phe Leu Phe Trp Ala Ser Leu Cys Met Thr His Leu Ser Arg Met
245 250 255
Ala Glu Asp Leu Ile Leu Tyr Cys Thr Lys Glu Phe Ser Phe Val Gln
260 265 270
Leu Ser Asp Ala Tyr Ser Thr Gly Ser Ser Leu Met Pro Gln Lys Lys
275 280 285
Asn Pro Asp Ser Leu Glu Leu Ile Arg Ser Lys Ala Gly Arg Val Phe
290 295 300
Gly Arg Cys Ala Gly Leu Leu Met Thr Leu Lys Gly Leu Pro Ser Thr
305 310 315 320
Tyr Asn Lys Asp Leu Gln Glu Asp Lys Glu Ala Val Phe Glu Val Ser
325 330 335
Asp Thr Met Ser Ala Val Leu Gln Val Ala Thr Gly Val Ile Ser Thr
340 345 350
Leu Gln Ile His Gln Glu Asn Met Gly Gln Ala Leu Ser Pro Asp Met
355 360 365
Leu Ala Thr Asp Leu Ala Tyr Tyr Leu Val Arg Lys Gly Met Pro Phe
370 375 380
Arg Gln Ala His Glu Ala Ser Gly Lys Ala Val Phe Met Ala Glu Thr
385 390 395 400
Lys Gly Val Ala Leu Asn Gln Leu Ser Leu Gln Glu Leu Gln Thr Ile
405 410 415
Ser Pro Leu Phe Ser Gly Asp Val Ile Cys Val Trp Asp Tyr Gly His
420 425 430
Ser Val Glu Gln Tyr Gly Ala Leu Gly Gly Thr Ala Arg Ser Ser Val
435 440 445
Asp Trp Gln Ile Arg Gln Val Arg Ala Leu Leu Gln Ala Gln Gln Ala
450 455 460
<210> 59
<211> 1074
<212> DNA
<213> 智人
<400> 59
atggaggaag gaatgaatgt tctccatgac tttgggatcc agtcaacaca ttacctccag 60
gtgaattacc aagactccca ggactggttc atcttggtgt ccgtgatcgc agacctcagg 120
aatgccttct acgtcctctt ccccatctgg ttccatcttc aggaagctgt gggcattaaa 180
ctcctttggg tagctgtgat tggagactgg ctcaacctcg tctttaagtg gattctcttt 240
ggacagcgtc catactggtg ggttttggat actgactact acagcaacac ttccgtgccc 300
ctgataaagc agttccctgt aacctgtgag actggaccag ggagcccctc tggccatgcc 360
atgggcacag caggtgtata ctacgtgatg gtcacatcta ctctttccat ctttcaggga 420
aagataaagc cgacctacag atttcggtgc ttgaatgtca ttttgtggtt gggattctgg 480
gctgtgcagc tgaatgtctg tctgtcacga atctaccttg ctgctcattt tcctcatcaa 540
gttgttgctg gagtcctgtc aggcattgct gttgcagaaa ctttcagcca catccacagc 600
atctataatg ccagcctcaa gaaatatttt ctcattacct tcttcctgtt cagcttcgcc 660
atcggatttt atctgctgct caagggactg ggtgtagacc tcctgtggac tctggagaaa 720
gcccagaggt ggtgcgagca gccagaatgg gtccacattg acaccacacc ctttgccagc 780
ctcctcaaga acctgggcac gctctttggc ctggggctgg ctctcaactc cagcatgtac 840
agggagagct gcaaggggaa actcagcaag tggctcccat tccgcctcag ctctattgta 900
gcctccctcg tcctcctgca cgtctttgac tccttgaaac ccccatccca agtcgagctg 960
gtcttctacg tcttgtcctt ctgcaagagt gcggtagtgc ccctggcatc cgtcagtgtc 1020
atcccctact gcctcgccca ggtcctgggc cagccgcaca agaagtcgtt gtaa 1074
<210> 60
<211> 359
<212> PRT
<213> 智人
<400> 60
Met Arg Met Glu Glu Gly Met Asn Val Leu His Asp Phe Gly Ile Gln
1 5 10 15
Ser Thr His Tyr Leu Gln Val Asn Tyr Gln Asp Ser Gln Asp Trp Phe
20 25 30
Ile Leu Val Ser Val Ile Ala Asp Leu Arg Asn Ala Phe Tyr Val Leu
35 40 45
Phe Pro Ile Trp Phe His Leu Gln Glu Ala Val Gly Ile Lys Leu Leu
50 55 60
Trp Val Ala Val Ile Gly Asp Trp Leu Asn Leu Val Phe Lys Trp Ile
65 70 75 80
Leu Phe Gly Gln Arg Pro Tyr Trp Trp Val Leu Asp Thr Asp Tyr Tyr
85 90 95
Ser Asn Thr Ser Val Pro Leu Ile Lys Gln Phe Pro Val Thr Cys Glu
100 105 110
Thr Gly Pro Gly Ser Pro Ser Gly His Ala Met Gly Thr Ala Gly Val
115 120 125
Tyr Tyr Val Met Val Thr Ser Thr Leu Ser Ile Phe Gln Gly Lys Ile
130 135 140
Lys Pro Thr Tyr Arg Phe Arg Cys Leu Asn Val Ile Leu Trp Leu Gly
145 150 155 160
Phe Trp Ala Val Gln Leu Asn Val Cys Leu Ser Arg Ile Tyr Leu Ala
165 170 175
Ala His Phe Pro His Gln Val Val Ala Gly Val Leu Ser Gly Ile Ala
180 185 190
Val Ala Glu Thr Phe Ser His Ile His Ser Ile Tyr Asn Ala Ser Leu
195 200 205
Lys Lys Tyr Phe Leu Ile Thr Phe Phe Leu Phe Ser Phe Ala Ile Gly
210 215 220
Phe Tyr Leu Leu Leu Lys Gly Leu Gly Val Asp Leu Leu Trp Thr Leu
225 230 235 240
Glu Lys Ala Gln Arg Trp Cys Glu Gln Pro Glu Trp Val His Ile Asp
245 250 255
Thr Thr Pro Phe Ala Ser Leu Leu Lys Asn Leu Gly Thr Leu Phe Gly
260 265 270
Leu Gly Leu Ala Leu Asn Ser Ser Met Tyr Arg Glu Ser Cys Lys Gly
275 280 285
Lys Leu Ser Lys Trp Leu Pro Phe Arg Leu Ser Ser Ile Val Ala Ser
290 295 300
Leu Val Leu Leu His Val Phe Asp Ser Leu Lys Pro Pro Ser Gln Val
305 310 315 320
Glu Leu Val Phe Tyr Val Leu Ser Phe Cys Lys Ser Ala Val Val Pro
325 330 335
Leu Ala Ser Val Ser Val Ile Pro Tyr Cys Leu Ala Gln Val Leu Gly
340 345 350
Gln Pro His Lys Lys Ser Leu
355
<210> 61
<211> 1503
<212> DNA
<213> 智人
<400> 61
atggcctcca ggctgaccct gctgaccctc ctgctgctgc tgctggctgg ggatagagcc 60
tcctcaaatc caaatgctac cagctccagc tcccaggatc cagagagttt gcaagacaga 120
ggcgaaggga aggtcgcaac aacagttatc tccaagatgc tattcgttga acccatcctg 180
gaggtttcca gcttgccgac aaccaactca acaaccaatt cagccaccaa aataacagct 240
aataccactg atgaacccac cacacaaccc accacagagc ccaccaccca acccaccatc 300
caacccaccc aaccaactac ccagctccca acagattctc ctacccagcc cactactggg 360
tccttctgcc caggacctgt tactctctgc tctgacttgg agagtcattc aacagaggcc 420
gtgttggggg atgctttggt agatttctcc ctgaagctct accacgcctt ctcagcaatg 480
aagaaggtgg agaccaacat ggccttttcc ccattcagca tcgccagcct ccttacccag 540
gtcctgctcg gggctgggga gaacaccaaa acaaacctgg agagcatcct ctcttacccc 600
aaggacttca cctgtgtcca ccaggccctg aagggcttca cgaccaaagg tgtcacctca 660
gtctctcaga tcttccacag cccagacctg gccataaggg acacctttgt gaatgcctct 720
cggaccctgt acagcagcag ccccagagtc ctaagcaaca acagtgacgc caacttggag 780
ctcatcaaca cctgggtggc caagaacacc aacaacaaga tcagccggct gctagacagt 840
ctgccctccg atacccgcct tgtcctcctc aatgctatct acctgagtgc caagtggaag 900
acaacatttg atcccaagaa aaccagaatg gaaccctttc acttcaaaaa ctcagttata 960
aaagtgccca tgatgaatag caagaagtac cctgtggccc atttcattga ccaaactttg 1020
aaagccaagg tggggcagct gcagctctcc cacaatctga gtttggtgat cctggtaccc 1080
cagaacctga aacatcgtct tgaagacatg gaacaggctc tcagcccttc tgttttcaag 1140
gccatcatgg agaaactgga gatgtccaag ttccagccca ctctcctaac actaccccgc 1200
atcaaagtga cgaccagcca ggatatgctc tcaatcatgg agaaattgga attcttcgat 1260
ttttcttatg accttaacct gtgtgggctg acagaggacc cagatcttca ggtttctgcg 1320
atgcagcacc agacagtgct ggaactgaca gagactgggg tggaggcggc tgcagcctcc 1380
gccatctctg tggcccgcac cctgctggtc tttgaagtgc agcagccctt cctcttcgtg 1440
ctctgggacc agcagcacaa gttccctgtc ttcatggggc gagtatatga ccccagggcc 1500
tga 1503
<210> 62
<211> 500
<212> PRT
<213> 智人
<400> 62
Met Ala Ser Arg Leu Thr Leu Leu Thr Leu Leu Leu Leu Leu Leu Ala
1 5 10 15
Gly Asp Arg Ala Ser Ser Asn Pro Asn Ala Thr Ser Ser Ser Ser Gln
20 25 30
Asp Pro Glu Ser Leu Gln Asp Arg Gly Glu Gly Lys Val Ala Thr Thr
35 40 45
Val Ile Ser Lys Met Leu Phe Val Glu Pro Ile Leu Glu Val Ser Ser
50 55 60
Leu Pro Thr Thr Asn Ser Thr Thr Asn Ser Ala Thr Lys Ile Thr Ala
65 70 75 80
Asn Thr Thr Asp Glu Pro Thr Thr Gln Pro Thr Thr Glu Pro Thr Thr
85 90 95
Gln Pro Thr Ile Gln Pro Thr Gln Pro Thr Thr Gln Leu Pro Thr Asp
100 105 110
Ser Pro Thr Gln Pro Thr Thr Gly Ser Phe Cys Pro Gly Pro Val Thr
115 120 125
Leu Cys Ser Asp Leu Glu Ser His Ser Thr Glu Ala Val Leu Gly Asp
130 135 140
Ala Leu Val Asp Phe Ser Leu Lys Leu Tyr His Ala Phe Ser Ala Met
145 150 155 160
Lys Lys Val Glu Thr Asn Met Ala Phe Ser Pro Phe Ser Ile Ala Ser
165 170 175
Leu Leu Thr Gln Val Leu Leu Gly Ala Gly Glu Asn Thr Lys Thr Asn
180 185 190
Leu Glu Ser Ile Leu Ser Tyr Pro Lys Asp Phe Thr Cys Val His Gln
195 200 205
Ala Leu Lys Gly Phe Thr Thr Lys Gly Val Thr Ser Val Ser Gln Ile
210 215 220
Phe His Ser Pro Asp Leu Ala Ile Arg Asp Thr Phe Val Asn Ala Ser
225 230 235 240
Arg Thr Leu Tyr Ser Ser Ser Pro Arg Val Leu Ser Asn Asn Ser Asp
245 250 255
Ala Asn Leu Glu Leu Ile Asn Thr Trp Val Ala Lys Asn Thr Asn Asn
260 265 270
Lys Ile Ser Arg Leu Leu Asp Ser Leu Pro Ser Asp Thr Arg Leu Val
275 280 285
Leu Leu Asn Ala Ile Tyr Leu Ser Ala Lys Trp Lys Thr Thr Phe Asp
290 295 300
Pro Lys Lys Thr Arg Met Glu Pro Phe His Phe Lys Asn Ser Val Ile
305 310 315 320
Lys Val Pro Met Met Asn Ser Lys Lys Tyr Pro Val Ala His Phe Ile
325 330 335
Asp Gln Thr Leu Lys Ala Lys Val Gly Gln Leu Gln Leu Ser His Asn
340 345 350
Leu Ser Leu Val Ile Leu Val Pro Gln Asn Leu Lys His Arg Leu Glu
355 360 365
Asp Met Glu Gln Ala Leu Ser Pro Ser Val Phe Lys Ala Ile Met Glu
370 375 380
Lys Leu Glu Met Ser Lys Phe Gln Pro Thr Leu Leu Thr Leu Pro Arg
385 390 395 400
Ile Lys Val Thr Thr Ser Gln Asp Met Leu Ser Ile Met Glu Lys Leu
405 410 415
Glu Phe Phe Asp Phe Ser Tyr Asp Leu Asn Leu Cys Gly Leu Thr Glu
420 425 430
Asp Pro Asp Leu Gln Val Ser Ala Met Gln His Gln Thr Val Leu Glu
435 440 445
Leu Thr Glu Thr Gly Val Glu Ala Ala Ala Ala Ser Ala Ile Ser Val
450 455 460
Ala Arg Thr Leu Leu Val Phe Glu Val Gln Gln Pro Phe Leu Phe Val
465 470 475 480
Leu Trp Asp Gln Gln His Lys Phe Pro Val Phe Met Gly Arg Val Tyr
485 490 495
Asp Pro Arg Ala
500
<210> 63
<211> 1140
<212> DNA
<213> 智人
<400> 63
atgtcgcgca gtggaaccga tcctcagcaa cgccagcagg cgtcagaggc ggacgccgca 60
gcagcaacct tccgggcaaa cgaccatcag catatccgct acaacccgct gcaggatgag 120
tgggtgctgg tgtcagctca ccgcatgaag cggccctggc agggtcaagt ggagccccag 180
cttctgaaga cagtgccccg ccatgaccct ctcaaccctc tgtgtcctgg ggccatccga 240
gccaacggag aggtgaatcc ccagtacgat agcaccttcc tgtttgacaa cgacttccca 300
gctctgcagc ctgatgcccc cagtccagga cccagtgatc atcccctttt ccaagcaaag 360
tctgctcgag gagtctgtaa ggtcatgtgc ttccacccct ggtcggatgt aacgctgcca 420
ctcatgtcgg tccctgagat ccgggctgtt gttgatgcat gggcctcagt cacagaggag 480
ctgggtgccc agtacccttg ggtgcagatc tttgaaaaca aaggtgccat gatgggctgt 540
tctaaccccc acccccactg ccaggtatgg gccagcagtt tcctgccaga tattgcccag 600
cgtgaggagc gatctcagca ggcctataag agtcagcatg gagagcccct gctaatggag 660
tacagccgcc aggagctact caggaaggaa cgtctggtcc taaccagtga gcactggtta 720
gtactggtcc ccttctgggc aacatggccc taccagacac tgctgctgcc ccgtcggcat 780
gtgcggcggc tacctgagct gacccctgct gagcgtgatg atctagcctc catcatgaag 840
aagctcttga ccaagtatga caacctcttt gagacgtcct ttccctactc catgggctgg 900
catggggctc ccacaggatc agaggctggg gccaactgga accattggca gctgcacgct 960
cattactacc ctccgctcct gcgctctgcc actgtccgga aattcatggt tggctacgaa 1020
atgcttgctc aggctcagag ggacctcacc cctgagcagg ctgcagagag actaagggca 1080
cttcctgagg ttcattacca cctggggcag aaggacaggg agacagcaac catcgcctga 1140
<210> 64
<211> 379
<212> PRT
<213> 智人
<400> 64
Met Ser Arg Ser Gly Thr Asp Pro Gln Gln Arg Gln Gln Ala Ser Glu
1 5 10 15
Ala Asp Ala Ala Ala Ala Thr Phe Arg Ala Asn Asp His Gln His Ile
20 25 30
Arg Tyr Asn Pro Leu Gln Asp Glu Trp Val Leu Val Ser Ala His Arg
35 40 45
Met Lys Arg Pro Trp Gln Gly Gln Val Glu Pro Gln Leu Leu Lys Thr
50 55 60
Val Pro Arg His Asp Pro Leu Asn Pro Leu Cys Pro Gly Ala Ile Arg
65 70 75 80
Ala Asn Gly Glu Val Asn Pro Gln Tyr Asp Ser Thr Phe Leu Phe Asp
85 90 95
Asn Asp Phe Pro Ala Leu Gln Pro Asp Ala Pro Ser Pro Gly Pro Ser
100 105 110
Asp His Pro Leu Phe Gln Ala Lys Ser Ala Arg Gly Val Cys Lys Val
115 120 125
Met Cys Phe His Pro Trp Ser Asp Val Thr Leu Pro Leu Met Ser Val
130 135 140
Pro Glu Ile Arg Ala Val Val Asp Ala Trp Ala Ser Val Thr Glu Glu
145 150 155 160
Leu Gly Ala Gln Tyr Pro Trp Val Gln Ile Phe Glu Asn Lys Gly Ala
165 170 175
Met Met Gly Cys Ser Asn Pro His Pro His Cys Gln Val Trp Ala Ser
180 185 190
Ser Phe Leu Pro Asp Ile Ala Gln Arg Glu Glu Arg Ser Gln Gln Ala
195 200 205
Tyr Lys Ser Gln His Gly Glu Pro Leu Leu Met Glu Tyr Ser Arg Gln
210 215 220
Glu Leu Leu Arg Lys Glu Arg Leu Val Leu Thr Ser Glu His Trp Leu
225 230 235 240
Val Leu Val Pro Phe Trp Ala Thr Trp Pro Tyr Gln Thr Leu Leu Leu
245 250 255
Pro Arg Arg His Val Arg Arg Leu Pro Glu Leu Thr Pro Ala Glu Arg
260 265 270
Asp Asp Leu Ala Ser Ile Met Lys Lys Leu Leu Thr Lys Tyr Asp Asn
275 280 285
Leu Phe Glu Thr Ser Phe Pro Tyr Ser Met Gly Trp His Gly Ala Pro
290 295 300
Thr Gly Ser Glu Ala Gly Ala Asn Trp Asn His Trp Gln Leu His Ala
305 310 315 320
His Tyr Tyr Pro Pro Leu Leu Arg Ser Ala Thr Val Arg Lys Phe Met
325 330 335
Val Gly Tyr Glu Met Leu Ala Gln Ala Gln Arg Asp Leu Thr Pro Glu
340 345 350
Gln Ala Ala Glu Arg Leu Arg Ala Leu Pro Glu Val His Tyr His Leu
355 360 365
Gly Gln Lys Asp Arg Glu Thr Ala Thr Ile Ala
370 375
<210> 65
<211> 1656
<212> DNA
<213> 智人
<400> 65
atgccttctg agacccccca ggcagaagtg gggcccacag gctgccccca ccgctcaggg 60
ccacactcgg cgaaggggag cctggagaag gggtccccag aggataagga agccaaggag 120
cccctgtgga tccggcccga tgctccgagc aggtgcacct ggcagctggg ccggcctgcc 180
tccgagtccc cacatcacca cactgccccg gcaaaatctc caaaaatctt gccagatatt 240
ctgaagaaaa tcggggacac ccctatggtc agaatcaaca agattgggaa gaagttcggc 300
ctgaagtgtg agctcttggc caagtgtgag ttcttcaacg cgggcgggag cgtgaaggac 360
cgcatcagcc tgcggatgat tgaggatgct gagcgcgacg ggacgctgaa gcccggggac 420
acgattatcg agccgacatc cgggaacacc gggatcgggc tggccctggc tgcggcagtg 480
aggggctatc gctgcatcat cgtgatgcca gagaagatga gctccgagaa ggtggacgtg 540
ctgcgggcac tgggggctga gattgtgagg acgcccacca atgccaggtt cgactccccg 600
gagtcacacg tgggggtggc ctggcggctg aagaacgaaa tccccaattc tcacatccta 660
gaccagtacc gcaacgccag caaccccctg gctcactacg acaccaccgc tgatgagatc 720
ctgcagcagt gtgatgggaa gctggacatg ctggtggctt cagtgggcac gggcggcacc 780
atcacgggca ttgccaggaa gctgaaggag aagtgtcctg gatgcaggat cattggggtg 840
gatcccgaag ggtccatcct cgcagagccg gaggagctga accagacgga gcagacaacc 900
tacgaggtgg aagggatcgg ctacgacttc atccccacgg tgctggacag gacggtggtg 960
gacaagtggt tcaagagcaa cgatgaggag gcgttcacct ttgcccgcat gctgatcgcg 1020
caagaggggc tgctgtgcgg tggcagtgct ggcagcacgg tggcggtggc cgtgaaggcc 1080
gcgcaggagc tgcaggaggg ccagcgctgc gtggtcattc tgcccgactc agtgcggaac 1140
tacatgacca agttcctgag cgacaggtgg atgctgcaga agggctttct gaaggaggag 1200
gacctcacgg agaagaagcc ctggtggtgg cacctccgtg ttcaggagct gggcctgtca 1260
gccccgctga ccgtgctccc gaccatcacc tgtgggcaca ccatcgagat cctccgggag 1320
aagggcttcg accaggcgcc cgtggtggat gaggcggggg taatcctggg aatggtgacg 1380
cttgggaaca tgctctcgtc cctgcttgcc gggaaggtgc agccgtcaga ccaagttggc 1440
aaagtcatct acaagcagtt caaacagatc cgcctcacgg acacgctggg caggctctcg 1500
cacatcctgg agatggacca cttcgccctg gtggtgcacg agcagatcca gtaccacagc 1560
accgggaagt ccagtcagcg gcagatggtg ttcggggtgg tcaccgccat tgacttgctg 1620
aacttcgtgg ccgcccagga gcgggaccag aagtga 1656
<210> 66
<211> 551
<212> PRT
<213> 智人
<400> 66
Met Pro Ser Glu Thr Pro Gln Ala Glu Val Gly Pro Thr Gly Cys Pro
1 5 10 15
His Arg Ser Gly Pro His Ser Ala Lys Gly Ser Leu Glu Lys Gly Ser
20 25 30
Pro Glu Asp Lys Glu Ala Lys Glu Pro Leu Trp Ile Arg Pro Asp Ala
35 40 45
Pro Ser Arg Cys Thr Trp Gln Leu Gly Arg Pro Ala Ser Glu Ser Pro
50 55 60
His His His Thr Ala Pro Ala Lys Ser Pro Lys Ile Leu Pro Asp Ile
65 70 75 80
Leu Lys Lys Ile Gly Asp Thr Pro Met Val Arg Ile Asn Lys Ile Gly
85 90 95
Lys Lys Phe Gly Leu Lys Cys Glu Leu Leu Ala Lys Cys Glu Phe Phe
100 105 110
Asn Ala Gly Gly Ser Val Lys Asp Arg Ile Ser Leu Arg Met Ile Glu
115 120 125
Asp Ala Glu Arg Asp Gly Thr Leu Lys Pro Gly Asp Thr Ile Ile Glu
130 135 140
Pro Thr Ser Gly Asn Thr Gly Ile Gly Leu Ala Leu Ala Ala Ala Val
145 150 155 160
Arg Gly Tyr Arg Cys Ile Ile Val Met Pro Glu Lys Met Ser Ser Glu
165 170 175
Lys Val Asp Val Leu Arg Ala Leu Gly Ala Glu Ile Val Arg Thr Pro
180 185 190
Thr Asn Ala Arg Phe Asp Ser Pro Glu Ser His Val Gly Val Ala Trp
195 200 205
Arg Leu Lys Asn Glu Ile Pro Asn Ser His Ile Leu Asp Gln Tyr Arg
210 215 220
Asn Ala Ser Asn Pro Leu Ala His Tyr Asp Thr Thr Ala Asp Glu Ile
225 230 235 240
Leu Gln Gln Cys Asp Gly Lys Leu Asp Met Leu Val Ala Ser Val Gly
245 250 255
Thr Gly Gly Thr Ile Thr Gly Ile Ala Arg Lys Leu Lys Glu Lys Cys
260 265 270
Pro Gly Cys Arg Ile Ile Gly Val Asp Pro Glu Gly Ser Ile Leu Ala
275 280 285
Glu Pro Glu Glu Leu Asn Gln Thr Glu Gln Thr Thr Tyr Glu Val Glu
290 295 300
Gly Ile Gly Tyr Asp Phe Ile Pro Thr Val Leu Asp Arg Thr Val Val
305 310 315 320
Asp Lys Trp Phe Lys Ser Asn Asp Glu Glu Ala Phe Thr Phe Ala Arg
325 330 335
Met Leu Ile Ala Gln Glu Gly Leu Leu Cys Gly Gly Ser Ala Gly Ser
340 345 350
Thr Val Ala Val Ala Val Lys Ala Ala Gln Glu Leu Gln Glu Gly Gln
355 360 365
Arg Cys Val Val Ile Leu Pro Asp Ser Val Arg Asn Tyr Met Thr Lys
370 375 380
Phe Leu Ser Asp Arg Trp Met Leu Gln Lys Gly Phe Leu Lys Glu Glu
385 390 395 400
Asp Leu Thr Glu Lys Lys Pro Trp Trp Trp His Leu Arg Val Gln Glu
405 410 415
Leu Gly Leu Ser Ala Pro Leu Thr Val Leu Pro Thr Ile Thr Cys Gly
420 425 430
His Thr Ile Glu Ile Leu Arg Glu Lys Gly Phe Asp Gln Ala Pro Val
435 440 445
Val Asp Glu Ala Gly Val Ile Leu Gly Met Val Thr Leu Gly Asn Met
450 455 460
Leu Ser Ser Leu Leu Ala Gly Lys Val Gln Pro Ser Asp Gln Val Gly
465 470 475 480
Lys Val Ile Tyr Lys Gln Phe Lys Gln Ile Arg Leu Thr Asp Thr Leu
485 490 495
Gly Arg Leu Ser His Ile Leu Glu Met Asp His Phe Ala Leu Val Val
500 505 510
His Glu Gln Ile Gln Tyr His Ser Thr Gly Lys Ser Ser Gln Arg Gln
515 520 525
Met Val Phe Gly Val Val Thr Ala Ile Asp Leu Leu Asn Phe Val Ala
530 535 540
Ala Gln Glu Arg Asp Gln Lys
545 550
<210> 67
<211> 1428
<212> DNA
<213> 智人
<400> 67
atggagagca aagccctgct cgtgctgact ctggccgtgt ggctccagag tctgaccgcc 60
tcccgcggag gggtggccgc cgccgaccaa agaagagatt ttatcgacat cgaaagtaaa 120
tttgccctaa ggacccctga agacacagct gaggacactt gccacctcat tcccggagta 180
gcagagtccg tggctacctg tcatttcaat cacagcagca aaaccttcat ggtgatccat 240
ggctggacgg taacaggaat gtatgagagt tgggtgccaa aacttgtggc cgccctgtac 300
aagagagaac cagactccaa tgtcattgtg gtggactggc tgtcacgggc tcaggagcat 360
tacccagtgt ccgcgggcta caccaaactg gtgggacagg atgtggcccg gtttatcaac 420
tggatggagg aggagtttaa ctaccctctg gacaatgtcc atctcttggg atacagcctt 480
ggagcccatg ctgctggcat tgcaggaagt ctgaccaata agaaagtcaa cagaattact 540
ggcctcgatc cagctggacc taactttgag tatgcagaag ccccgagtcg tctttctcct 600
gatgatgcag attttgtaga cgtcttacac acattcacca gagggtcccc tggtcgaagc 660
attggaatcc agaaaccagt tgggcatgtt gacatttacc cgaatggagg tacttttcag 720
ccaggatgta acattggaga agctatccgc gtgattgcag agagaggact tggagatgtg 780
gaccagctag tgaagtgctc ccacgagcgc tccattcatc tcttcatcga ctctctgttg 840
aatgaagaaa atccaagtaa ggcctacagg tgcagttcca aggaagcctt tgagaaaggg 900
ctctgcttga gttgtagaaa gaaccgctgc aacaatctgg gctatgagat caataaagtc 960
agagccaaaa gaagcagcaa aatgtacctg aagactcgtt ctcagatgcc ctacaaagtc 1020
ttccattacc aagtaaagat tcatttttct gggactgaga gtgaaaccca taccaatcag 1080
gcctttgaga tttctctgta tggcaccgtg gccgagagtg agaacatccc attcactctg 1140
cctgaagttt ccacaaataa gacctactcc ttcctaattt acacagaggt agatattgga 1200
gaactactca tgttgaagct caaatggaag agtgattcat actttagctg gtcagactgg 1260
tggagcagtc ccggcttcgc cattcagaag atcagagtaa aagcaggaga gactcagaaa 1320
aaggtgatct tctgttctag ggagaaagtg tctcatttgc agaaaggaaa ggcacctgcg 1380
gtatttgtga aatgccatga caagtctctg aataagaagt caggctga 1428
<210> 68
<211> 475
<212> PRT
<213> 智人
<400> 68
Met Glu Ser Lys Ala Leu Leu Val Leu Thr Leu Ala Val Trp Leu Gln
1 5 10 15
Ser Leu Thr Ala Ser Arg Gly Gly Val Ala Ala Ala Asp Gln Arg Arg
20 25 30
Asp Phe Ile Asp Ile Glu Ser Lys Phe Ala Leu Arg Thr Pro Glu Asp
35 40 45
Thr Ala Glu Asp Thr Cys His Leu Ile Pro Gly Val Ala Glu Ser Val
50 55 60
Ala Thr Cys His Phe Asn His Ser Ser Lys Thr Phe Met Val Ile His
65 70 75 80
Gly Trp Thr Val Thr Gly Met Tyr Glu Ser Trp Val Pro Lys Leu Val
85 90 95
Ala Ala Leu Tyr Lys Arg Glu Pro Asp Ser Asn Val Ile Val Val Asp
100 105 110
Trp Leu Ser Arg Ala Gln Glu His Tyr Pro Val Ser Ala Gly Tyr Thr
115 120 125
Lys Leu Val Gly Gln Asp Val Ala Arg Phe Ile Asn Trp Met Glu Glu
130 135 140
Glu Phe Asn Tyr Pro Leu Asp Asn Val His Leu Leu Gly Tyr Ser Leu
145 150 155 160
Gly Ala His Ala Ala Gly Ile Ala Gly Ser Leu Thr Asn Lys Lys Val
165 170 175
Asn Arg Ile Thr Gly Leu Asp Pro Ala Gly Pro Asn Phe Glu Tyr Ala
180 185 190
Glu Ala Pro Ser Arg Leu Ser Pro Asp Asp Ala Asp Phe Val Asp Val
195 200 205
Leu His Thr Phe Thr Arg Gly Ser Pro Gly Arg Ser Ile Gly Ile Gln
210 215 220
Lys Pro Val Gly His Val Asp Ile Tyr Pro Asn Gly Gly Thr Phe Gln
225 230 235 240
Pro Gly Cys Asn Ile Gly Glu Ala Ile Arg Val Ile Ala Glu Arg Gly
245 250 255
Leu Gly Asp Val Asp Gln Leu Val Lys Cys Ser His Glu Arg Ser Ile
260 265 270
His Leu Phe Ile Asp Ser Leu Leu Asn Glu Glu Asn Pro Ser Lys Ala
275 280 285
Tyr Arg Cys Ser Ser Lys Glu Ala Phe Glu Lys Gly Leu Cys Leu Ser
290 295 300
Cys Arg Lys Asn Arg Cys Asn Asn Leu Gly Tyr Glu Ile Asn Lys Val
305 310 315 320
Arg Ala Lys Arg Ser Ser Lys Met Tyr Leu Lys Thr Arg Ser Gln Met
325 330 335
Pro Tyr Lys Val Phe His Tyr Gln Val Lys Ile His Phe Ser Gly Thr
340 345 350
Glu Ser Glu Thr His Thr Asn Gln Ala Phe Glu Ile Ser Leu Tyr Gly
355 360 365
Thr Val Ala Glu Ser Glu Asn Ile Pro Phe Thr Leu Pro Glu Val Ser
370 375 380
Thr Asn Lys Thr Tyr Ser Phe Leu Ile Tyr Thr Glu Val Asp Ile Gly
385 390 395 400
Glu Leu Leu Met Leu Lys Leu Lys Trp Lys Ser Asp Ser Tyr Phe Ser
405 410 415
Trp Ser Asp Trp Trp Ser Ser Pro Gly Phe Ala Ile Gln Lys Ile Arg
420 425 430
Val Lys Ala Gly Glu Thr Gln Lys Lys Val Ile Phe Cys Ser Arg Glu
435 440 445
Lys Val Ser His Leu Gln Lys Gly Lys Ala Pro Ala Val Phe Val Lys
450 455 460
Cys His Asp Lys Ser Leu Asn Lys Lys Ser Gly
465 470 475
<210> 69
<211> 1239
<212> DNA
<213> 智人
<400> 69
atgtccagca aaggctccgt ggttctggcc tacagtggcg gcctggacac ctcgtgcatc 60
ctcgtgtggc tgaaggaaca aggctatgac gtcattgcct atctggccaa cattggccag 120
aaggaagact tcgaggaagc caggaagaag gcactgaagc ttggggccaa aaaggtgttc 180
attgaggatg tcagcaggga gtttgtggag gagttcatct ggccggccat ccagtccagc 240
gcactgtatg aggaccgcta cctcctgggc acctctcttg ccaggccctg catcgcccgc 300
aaacaagtgg aaatcgccca gcgggagggg gccaagtatg tgtcccacgg cgccacagga 360
aaggggaacg atcaggtccg gtttgagctc agctgctact cactggcccc ccagataaag 420
gtcattgctc cctggaggat gcctgaattc tacaaccggt tcaagggccg caatgacctg 480
atggagtacg caaagcaaca cgggattccc atcccggtca ctcccaagaa cccgtggagc 540
atggatgaga acctcatgca catcagctac gaggctggaa tcctggagaa ccccaagaac 600
caagcgcctc caggtctcta cacgaagacc caggacccag ccaaagcccc caacacccct 660
gacattctcg agatcgagtt caaaaaaggg gtccctgtga aggtgaccaa cgtcaaggat 720
ggcaccaccc accagacctc cttggagctc ttcatgtacc tgaacgaagt cgcgggcaag 780
catggcgtgg gccgtattga catcgtggag aaccgcttca ttggaatgaa gtcccgaggt 840
atctacgaga ccccagcagg caccatcctt taccatgctc atttagacat cgaggccttc 900
accatggacc gggaagtgcg caaaatcaaa caaggcctgg gcttgaaatt tgctgagctg 960
gtgtataccg gtttctggca cagccctgag tgtgaatttg tccgccactg catcgccaag 1020
tcccaggagc gagtggaagg gaaagtgcag gtgtccgtcc tcaagggcca ggtgtacatc 1080
ctcggccggg agtccccact gtctctctac aatgaggagc tggtgagcat gaacgtgcag 1140
ggtgattatg agccaactga tgccaccggg ttcatcaaca tcaattccct caggctgaag 1200
gaatatcatc gtctccagag caaggtcact gccaaatag 1239
<210> 70
<211> 412
<212> PRT
<213> 智人
<400> 70
Met Ser Ser Lys Gly Ser Val Val Leu Ala Tyr Ser Gly Gly Leu Asp
1 5 10 15
Thr Ser Cys Ile Leu Val Trp Leu Lys Glu Gln Gly Tyr Asp Val Ile
20 25 30
Ala Tyr Leu Ala Asn Ile Gly Gln Lys Glu Asp Phe Glu Glu Ala Arg
35 40 45
Lys Lys Ala Leu Lys Leu Gly Ala Lys Lys Val Phe Ile Glu Asp Val
50 55 60
Ser Arg Glu Phe Val Glu Glu Phe Ile Trp Pro Ala Ile Gln Ser Ser
65 70 75 80
Ala Leu Tyr Glu Asp Arg Tyr Leu Leu Gly Thr Ser Leu Ala Arg Pro
85 90 95
Cys Ile Ala Arg Lys Gln Val Glu Ile Ala Gln Arg Glu Gly Ala Lys
100 105 110
Tyr Val Ser His Gly Ala Thr Gly Lys Gly Asn Asp Gln Val Arg Phe
115 120 125
Glu Leu Ser Cys Tyr Ser Leu Ala Pro Gln Ile Lys Val Ile Ala Pro
130 135 140
Trp Arg Met Pro Glu Phe Tyr Asn Arg Phe Lys Gly Arg Asn Asp Leu
145 150 155 160
Met Glu Tyr Ala Lys Gln His Gly Ile Pro Ile Pro Val Thr Pro Lys
165 170 175
Asn Pro Trp Ser Met Asp Glu Asn Leu Met His Ile Ser Tyr Glu Ala
180 185 190
Gly Ile Leu Glu Asn Pro Lys Asn Gln Ala Pro Pro Gly Leu Tyr Thr
195 200 205
Lys Thr Gln Asp Pro Ala Lys Ala Pro Asn Thr Pro Asp Ile Leu Glu
210 215 220
Ile Glu Phe Lys Lys Gly Val Pro Val Lys Val Thr Asn Val Lys Asp
225 230 235 240
Gly Thr Thr His Gln Thr Ser Leu Glu Leu Phe Met Tyr Leu Asn Glu
245 250 255
Val Ala Gly Lys His Gly Val Gly Arg Ile Asp Ile Val Glu Asn Arg
260 265 270
Phe Ile Gly Met Lys Ser Arg Gly Ile Tyr Glu Thr Pro Ala Gly Thr
275 280 285
Ile Leu Tyr His Ala His Leu Asp Ile Glu Ala Phe Thr Met Asp Arg
290 295 300
Glu Val Arg Lys Ile Lys Gln Gly Leu Gly Leu Lys Phe Ala Glu Leu
305 310 315 320
Val Tyr Thr Gly Phe Trp His Ser Pro Glu Cys Glu Phe Val Arg His
325 330 335
Cys Ile Ala Lys Ser Gln Glu Arg Val Glu Gly Lys Val Gln Val Ser
340 345 350
Val Leu Lys Gly Gln Val Tyr Ile Leu Gly Arg Glu Ser Pro Leu Ser
355 360 365
Leu Tyr Asn Glu Glu Leu Val Ser Met Asn Val Gln Gly Asp Tyr Glu
370 375 380
Pro Thr Asp Ala Thr Gly Phe Ile Asn Ile Asn Ser Leu Arg Leu Lys
385 390 395 400
Glu Tyr His Arg Leu Gln Ser Lys Val Thr Ala Lys
405 410
<210> 71
<211> 1359
<212> DNA
<213> 智人
<400> 71
atgtccactg cggtcctgga aaacccaggc ttgggcagga aactctctga ctttggacag 60
gaaacaagct atattgaaga caactgcaat caaaatggtg ccatatcact gatcttctca 120
ctcaaagaag aagttggtgc attggccaaa gtattgcgct tatttgagga gaatgatgta 180
aacctgaccc acattgaatc tagaccttct cgtttaaaga aagatgagta tgaatttttc 240
acccatttgg ataaacgtag cctgcctgct ctgacaaaca tcatcaagat cttgaggcat 300
gacattggtg ccactgtcca tgagctttca cgagataaga agaaagacac agtgccctgg 360
ttcccaagaa ccattcaaga gctggacaga tttgccaatc agattctcag ctatggagcg 420
gaactggatg ctgaccaccc tggttttaaa gatcctgtgt accgtgcaag acggaagcag 480
tttgctgaca ttgcctacaa ctaccgccat gggcagccca tccctcgagt ggaatacatg 540
gaggaagaaa agaaaacatg gggcacagtg ttcaagactc tgaagtcctt gtataaaacc 600
catgcttgct atgagtacaa tcacattttt ccacttcttg aaaagtactg tggcttccat 660
gaagataaca ttccccagct ggaagacgtt tctcagttcc tgcagacttg cactggtttc 720
cgcctccgac ctgtggctgg cctgctttcc tctcgggatt tcttgggtgg cctggccttc 780
cgagtcttcc actgcacaca gtacatcaga catggatcca agcccatgta tacccccgaa 840
cctgacatct gccatgagct gttgggacat gtgcccttgt tttcagatcg cagctttgcc 900
cagttttccc aggaaattgg ccttgcctct ctgggtgcac ctgatgaata cattgaaaag 960
ctcgccacaa tttactggtt tactgtggag tttgggctct gcaaacaagg agactccata 1020
aaggcatatg gtgctgggct cctgtcatcc tttggtgaat tacagtactg cttatcagag 1080
aagccaaagc ttctccccct ggagctggag aagacagcca tccaaaatta cactgtcacg 1140
gagttccagc ccctctatta cgtggcagag agttttaatg atgccaagga gaaagtaagg 1200
aactttgctg ccacaatacc tcggcccttc tcagttcgct acgacccata cacccaaagg 1260
attgaggtct tggacaatac ccagcagctt aagattttgg ctgattccat taacagtgaa 1320
attggaatcc tttgcagtgc cctccagaaa ataaagtaa 1359
<210> 72
<211> 452
<212> PRT
<213> 智人
<400> 72
Met Ser Thr Ala Val Leu Glu Asn Pro Gly Leu Gly Arg Lys Leu Ser
1 5 10 15
Asp Phe Gly Gln Glu Thr Ser Tyr Ile Glu Asp Asn Cys Asn Gln Asn
20 25 30
Gly Ala Ile Ser Leu Ile Phe Ser Leu Lys Glu Glu Val Gly Ala Leu
35 40 45
Ala Lys Val Leu Arg Leu Phe Glu Glu Asn Asp Val Asn Leu Thr His
50 55 60
Ile Glu Ser Arg Pro Ser Arg Leu Lys Lys Asp Glu Tyr Glu Phe Phe
65 70 75 80
Thr His Leu Asp Lys Arg Ser Leu Pro Ala Leu Thr Asn Ile Ile Lys
85 90 95
Ile Leu Arg His Asp Ile Gly Ala Thr Val His Glu Leu Ser Arg Asp
100 105 110
Lys Lys Lys Asp Thr Val Pro Trp Phe Pro Arg Thr Ile Gln Glu Leu
115 120 125
Asp Arg Phe Ala Asn Gln Ile Leu Ser Tyr Gly Ala Glu Leu Asp Ala
130 135 140
Asp His Pro Gly Phe Lys Asp Pro Val Tyr Arg Ala Arg Arg Lys Gln
145 150 155 160
Phe Ala Asp Ile Ala Tyr Asn Tyr Arg His Gly Gln Pro Ile Pro Arg
165 170 175
Val Glu Tyr Met Glu Glu Glu Lys Lys Thr Trp Gly Thr Val Phe Lys
180 185 190
Thr Leu Lys Ser Leu Tyr Lys Thr His Ala Cys Tyr Glu Tyr Asn His
195 200 205
Ile Phe Pro Leu Leu Glu Lys Tyr Cys Gly Phe His Glu Asp Asn Ile
210 215 220
Pro Gln Leu Glu Asp Val Ser Gln Phe Leu Gln Thr Cys Thr Gly Phe
225 230 235 240
Arg Leu Arg Pro Val Ala Gly Leu Leu Ser Ser Arg Asp Phe Leu Gly
245 250 255
Gly Leu Ala Phe Arg Val Phe His Cys Thr Gln Tyr Ile Arg His Gly
260 265 270
Ser Lys Pro Met Tyr Thr Pro Glu Pro Asp Ile Cys His Glu Leu Leu
275 280 285
Gly His Val Pro Leu Phe Ser Asp Arg Ser Phe Ala Gln Phe Ser Gln
290 295 300
Glu Ile Gly Leu Ala Ser Leu Gly Ala Pro Asp Glu Tyr Ile Glu Lys
305 310 315 320
Leu Ala Thr Ile Tyr Trp Phe Thr Val Glu Phe Gly Leu Cys Lys Gln
325 330 335
Gly Asp Ser Ile Lys Ala Tyr Gly Ala Gly Leu Leu Ser Ser Phe Gly
340 345 350
Glu Leu Gln Tyr Cys Leu Ser Glu Lys Pro Lys Leu Leu Pro Leu Glu
355 360 365
Leu Glu Lys Thr Ala Ile Gln Asn Tyr Thr Val Thr Glu Phe Gln Pro
370 375 380
Leu Tyr Tyr Val Ala Glu Ser Phe Asn Asp Ala Lys Glu Lys Val Arg
385 390 395 400
Asn Phe Ala Ala Thr Ile Pro Arg Pro Phe Ser Val Arg Tyr Asp Pro
405 410 415
Tyr Thr Gln Arg Ile Glu Val Leu Asp Asn Thr Gln Gln Leu Lys Ile
420 425 430
Leu Ala Asp Ser Ile Asn Ser Glu Ile Gly Ile Leu Cys Ser Ala Leu
435 440 445
Gln Lys Ile Lys
450
<210> 73
<211> 2583
<212> DNA
<213> 智人
<400> 73
atggggccct ggggctggaa attgcgctgg accgtcgcct tgctcctcgc cgcggcgggg 60
actgcagtgg gcgacagatg cgaaagaaac gagttccagt gccaagacgg gaaatgcatc 120
tcctacaagt gggtctgcga tggcagcgct gagtgccagg atggctctga tgagtcccag 180
gagacgtgct tgtctgtcac ctgcaaatcc ggggacttca gctgtggggg ccgtgtcaac 240
cgctgcattc ctcagttctg gaggtgcgat ggccaagtgg actgcgacaa cggctcagac 300
gagcaaggct gtccccccaa gacgtgctcc caggacgagt ttcgctgcca cgatgggaag 360
tgcatctctc ggcagttcgt ctgtgactca gaccgggact gcttggacgg ctcagacgag 420
gcctcctgcc cggtgctcac ctgtggtccc gccagcttcc agtgcaacag ctccacctgc 480
atcccccagc tgtgggcctg cgacaacgac cccgactgcg aagatggctc ggatgagtgg 540
ccgcagcgct gtaggggtct ttacgtgttc caaggggaca gtagcccctg ctcggccttc 600
gagttccact gcctaagtgg cgagtgcatc cactccagct ggcgctgtga tggtggcccc 660
gactgcaagg acaaatctga cgaggaaaac tgcgctgtgg ccacctgtcg ccctgacgaa 720
ttccagtgct ctgatggaaa ctgcatccat ggcagccggc agtgtgaccg ggaatatgac 780
tgcaaggaca tgagcgatga agttggctgc gttaatgtga cactctgcga gggacccaac 840
aagttcaagt gtcacagcgg cgaatgcatc accctggaca aagtctgcaa catggctaga 900
gactgccggg actggtcaga tgaacccatc aaagagtgcg ggaccaacga atgcttggac 960
aacaacggcg gctgttccca cgtctgcaat gaccttaaga tcggctacga gtgcctgtgc 1020
cccgacggct tccagctggt ggcccagcga agatgcgaag atatcgatga gtgtcaggat 1080
cccgacacct gcagccagct ctgcgtgaac ctggagggtg gctacaagtg ccagtgtgag 1140
gaaggcttcc agctggaccc ccacacgaag gcctgcaagg ctgtgggctc catcgcctac 1200
ctcttcttca ccaaccggca cgaggtcagg aagatgacgc tggaccggag cgagtacacc 1260
agcctcatcc ccaacctgag gaacgtggtc gctctggaca cggaggtggc cagcaataga 1320
atctactggt ctgacctgtc ccagagaatg atctgcagca cccagcttga cagagcccac 1380
ggcgtctctt cctatgacac cgtcatcagc agagacatcc aggcccccga cgggctggct 1440
gtggactgga tccacagcaa catctactgg accgactctg tcctgggcac tgtctctgtt 1500
gcggatacca agggcgtgaa gaggaaaacg ttattcaggg agaacggctc caagccaagg 1560
gccatcgtgg tggatcctgt tcatggcttc atgtactgga ctgactgggg aactcccgcc 1620
aagatcaaga aagggggcct gaatggtgtg gacatctact cgctggtgac tgaaaacatt 1680
cagtggccca atggcatcac cctagatctc ctcagtggcc gcctctactg ggttgactcc 1740
aaacttcact ccatctcaag catcgatgtc aacgggggca accggaagac catcttggag 1800
gatgaaaaga ggctggccca ccccttctcc ttggccgtct ttgaggacaa agtattttgg 1860
acagatatca tcaacgaagc cattttcagt gccaaccgcc tcacaggttc cgatgtcaac 1920
ttgttggctg aaaacctact gtccccagag gatatggttc tcttccacaa cctcacccag 1980
ccaagaggag tgaactggtg tgagaggacc accctgagca atggcggctg ccagtatctg 2040
tgcctccctg ccccgcagat caacccccac tcgcccaagt ttacctgcgc ctgcccggac 2100
ggcatgctgc tggccaggga catgaggagc tgcctcacag aggctgaggc tgcagtggcc 2160
acccaggaga catccaccgt caggctaaag gtcagctcca cagccgtaag gacacagcac 2220
acaaccaccc gacctgttcc cgacacctcc cggctgcctg gggccacccc tgggctcacc 2280
acggtggaga tagtgacaat gtctcaccaa gctctgggcg acgttgctgg cagaggaaat 2340
gagaagaagc ccagtagcgt gagggctctg tccattgtcc tccccatcgt gctcctcgtc 2400
ttcctttgcc tgggggtctt ccttctatgg aagaactggc ggcttaagaa catcaacagc 2460
atcaactttg acaaccccgt ctatcagaag accacagagg atgaggtcca catttgccac 2520
aaccaggacg gctacagcta cccctcgaga cagatggtca gtctggagga tgacgtggcg 2580
tga 2583
<210> 74
<211> 860
<212> PRT
<213> 智人
<400> 74
Met Gly Pro Trp Gly Trp Lys Leu Arg Trp Thr Val Ala Leu Leu Leu
1 5 10 15
Ala Ala Ala Gly Thr Ala Val Gly Asp Arg Cys Glu Arg Asn Glu Phe
20 25 30
Gln Cys Gln Asp Gly Lys Cys Ile Ser Tyr Lys Trp Val Cys Asp Gly
35 40 45
Ser Ala Glu Cys Gln Asp Gly Ser Asp Glu Ser Gln Glu Thr Cys Leu
50 55 60
Ser Val Thr Cys Lys Ser Gly Asp Phe Ser Cys Gly Gly Arg Val Asn
65 70 75 80
Arg Cys Ile Pro Gln Phe Trp Arg Cys Asp Gly Gln Val Asp Cys Asp
85 90 95
Asn Gly Ser Asp Glu Gln Gly Cys Pro Pro Lys Thr Cys Ser Gln Asp
100 105 110
Glu Phe Arg Cys His Asp Gly Lys Cys Ile Ser Arg Gln Phe Val Cys
115 120 125
Asp Ser Asp Arg Asp Cys Leu Asp Gly Ser Asp Glu Ala Ser Cys Pro
130 135 140
Val Leu Thr Cys Gly Pro Ala Ser Phe Gln Cys Asn Ser Ser Thr Cys
145 150 155 160
Ile Pro Gln Leu Trp Ala Cys Asp Asn Asp Pro Asp Cys Glu Asp Gly
165 170 175
Ser Asp Glu Trp Pro Gln Arg Cys Arg Gly Leu Tyr Val Phe Gln Gly
180 185 190
Asp Ser Ser Pro Cys Ser Ala Phe Glu Phe His Cys Leu Ser Gly Glu
195 200 205
Cys Ile His Ser Ser Trp Arg Cys Asp Gly Gly Pro Asp Cys Lys Asp
210 215 220
Lys Ser Asp Glu Glu Asn Cys Ala Val Ala Thr Cys Arg Pro Asp Glu
225 230 235 240
Phe Gln Cys Ser Asp Gly Asn Cys Ile His Gly Ser Arg Gln Cys Asp
245 250 255
Arg Glu Tyr Asp Cys Lys Asp Met Ser Asp Glu Val Gly Cys Val Asn
260 265 270
Val Thr Leu Cys Glu Gly Pro Asn Lys Phe Lys Cys His Ser Gly Glu
275 280 285
Cys Ile Thr Leu Asp Lys Val Cys Asn Met Ala Arg Asp Cys Arg Asp
290 295 300
Trp Ser Asp Glu Pro Ile Lys Glu Cys Gly Thr Asn Glu Cys Leu Asp
305 310 315 320
Asn Asn Gly Gly Cys Ser His Val Cys Asn Asp Leu Lys Ile Gly Tyr
325 330 335
Glu Cys Leu Cys Pro Asp Gly Phe Gln Leu Val Ala Gln Arg Arg Cys
340 345 350
Glu Asp Ile Asp Glu Cys Gln Asp Pro Asp Thr Cys Ser Gln Leu Cys
355 360 365
Val Asn Leu Glu Gly Gly Tyr Lys Cys Gln Cys Glu Glu Gly Phe Gln
370 375 380
Leu Asp Pro His Thr Lys Ala Cys Lys Ala Val Gly Ser Ile Ala Tyr
385 390 395 400
Leu Phe Phe Thr Asn Arg His Glu Val Arg Lys Met Thr Leu Asp Arg
405 410 415
Ser Glu Tyr Thr Ser Leu Ile Pro Asn Leu Arg Asn Val Val Ala Leu
420 425 430
Asp Thr Glu Val Ala Ser Asn Arg Ile Tyr Trp Ser Asp Leu Ser Gln
435 440 445
Arg Met Ile Cys Ser Thr Gln Leu Asp Arg Ala His Gly Val Ser Ser
450 455 460
Tyr Asp Thr Val Ile Ser Arg Asp Ile Gln Ala Pro Asp Gly Leu Ala
465 470 475 480
Val Asp Trp Ile His Ser Asn Ile Tyr Trp Thr Asp Ser Val Leu Gly
485 490 495
Thr Val Ser Val Ala Asp Thr Lys Gly Val Lys Arg Lys Thr Leu Phe
500 505 510
Arg Glu Asn Gly Ser Lys Pro Arg Ala Ile Val Val Asp Pro Val His
515 520 525
Gly Phe Met Tyr Trp Thr Asp Trp Gly Thr Pro Ala Lys Ile Lys Lys
530 535 540
Gly Gly Leu Asn Gly Val Asp Ile Tyr Ser Leu Val Thr Glu Asn Ile
545 550 555 560
Gln Trp Pro Asn Gly Ile Thr Leu Asp Leu Leu Ser Gly Arg Leu Tyr
565 570 575
Trp Val Asp Ser Lys Leu His Ser Ile Ser Ser Ile Asp Val Asn Gly
580 585 590
Gly Asn Arg Lys Thr Ile Leu Glu Asp Glu Lys Arg Leu Ala His Pro
595 600 605
Phe Ser Leu Ala Val Phe Glu Asp Lys Val Phe Trp Thr Asp Ile Ile
610 615 620
Asn Glu Ala Ile Phe Ser Ala Asn Arg Leu Thr Gly Ser Asp Val Asn
625 630 635 640
Leu Leu Ala Glu Asn Leu Leu Ser Pro Glu Asp Met Val Leu Phe His
645 650 655
Asn Leu Thr Gln Pro Arg Gly Val Asn Trp Cys Glu Arg Thr Thr Leu
660 665 670
Ser Asn Gly Gly Cys Gln Tyr Leu Cys Leu Pro Ala Pro Gln Ile Asn
675 680 685
Pro His Ser Pro Lys Phe Thr Cys Ala Cys Pro Asp Gly Met Leu Leu
690 695 700
Ala Arg Asp Met Arg Ser Cys Leu Thr Glu Ala Glu Ala Ala Val Ala
705 710 715 720
Thr Gln Glu Thr Ser Thr Val Arg Leu Lys Val Ser Ser Thr Ala Val
725 730 735
Arg Thr Gln His Thr Thr Thr Arg Pro Val Pro Asp Thr Ser Arg Leu
740 745 750
Pro Gly Ala Thr Pro Gly Leu Thr Thr Val Glu Ile Val Thr Met Ser
755 760 765
His Gln Ala Leu Gly Asp Val Ala Gly Arg Gly Asn Glu Lys Lys Pro
770 775 780
Ser Ser Val Arg Ala Leu Ser Ile Val Leu Pro Ile Val Leu Leu Val
785 790 795 800
Phe Leu Cys Leu Gly Val Phe Leu Leu Trp Lys Asn Trp Arg Leu Lys
805 810 815
Asn Ile Asn Ser Ile Asn Phe Asp Asn Pro Val Tyr Gln Lys Thr Thr
820 825 830
Glu Asp Glu Val His Ile Cys His Asn Gln Asp Gly Tyr Ser Tyr Pro
835 840 845
Ser Arg Gln Met Val Ser Leu Glu Asp Asp Val Ala
850 855 860
<210> 75
<211> 1290
<212> DNA
<213> 智人
<400> 75
atgcagctga ggaacccaga actacatctg ggctgcgcgc ttgcgcttcg cttcctggcc 60
ctcgtttcct gggacatccc tggggctaga gcactggaca atggattggc aaggacgcct 120
accatgggct ggctgcactg ggagcgcttc atgtgcaacc ttgactgcca ggaagagcca 180
gattcctgca tcagtgagaa gctcttcatg gagatggcag agctcatggt ctcagaaggc 240
tggaaggatg caggttatga gtacctctgc attgatgact gttggatggc tccccaaaga 300
gattcagaag gcagacttca ggcagaccct cagcgctttc ctcatgggat tcgccagcta 360
gctaattatg ttcacagcaa aggactgaag ctagggattt atgcagatgt tggaaataaa 420
acctgcgcag gcttccctgg gagttttgga tactacgaca ttgatgccca gacctttgct 480
gactggggag tagatctgct aaaatttgat ggttgttact gtgacagttt ggaaaatttg 540
gcagatggtt ataagcacat gtccttggcc ctgaatagga ctggcagaag cattgtgtac 600
tcctgtgagt ggcctcttta tatgtggccc tttcaaaagc ccaattatac agaaatccga 660
cagtactgca atcactggcg aaattttgct gacattgatg attcctggaa aagtataaag 720
agtatcttgg actggacatc ttttaaccag gagagaattg ttgatgttgc tggaccaggg 780
ggttggaatg acccagatat gttagtgatt ggcaactttg gcctcagctg gaatcagcaa 840
gtaactcaga tggccctctg ggctatcatg gctgctcctt tattcatgtc taatgacctc 900
cgacacatca gccctcaagc caaagctctc cttcaggata aggacgtaat tgccatcaat 960
caggacccct tgggcaagca agggtaccag cttagacagg gagacaactt tgaagtgtgg 1020
gaacgacctc tctcaggctt agcctgggct gtagctatga taaaccggca ggagattggt 1080
ggacctcgct cttataccat cgcagttgct tccctgggta aaggagtggc ctgtaatcct 1140
gcctgcttca tcacacagct cctccctgtg aaaaggaagc tagggttcta tgaatggact 1200
tcaaggttaa gaagtcacat aaatcccaca ggcactgttt tgcttcagct agaaaataca 1260
atgcagatgt cattaaaaga cttactttaa 1290
<210> 76
<211> 429
<212> PRT
<213> 智人
<400> 76
Met Gln Leu Arg Asn Pro Glu Leu His Leu Gly Cys Ala Leu Ala Leu
1 5 10 15
Arg Phe Leu Ala Leu Val Ser Trp Asp Ile Pro Gly Ala Arg Ala Leu
20 25 30
Asp Asn Gly Leu Ala Arg Thr Pro Thr Met Gly Trp Leu His Trp Glu
35 40 45
Arg Phe Met Cys Asn Leu Asp Cys Gln Glu Glu Pro Asp Ser Cys Ile
50 55 60
Ser Glu Lys Leu Phe Met Glu Met Ala Glu Leu Met Val Ser Glu Gly
65 70 75 80
Trp Lys Asp Ala Gly Tyr Glu Tyr Leu Cys Ile Asp Asp Cys Trp Met
85 90 95
Ala Pro Gln Arg Asp Ser Glu Gly Arg Leu Gln Ala Asp Pro Gln Arg
100 105 110
Phe Pro His Gly Ile Arg Gln Leu Ala Asn Tyr Val His Ser Lys Gly
115 120 125
Leu Lys Leu Gly Ile Tyr Ala Asp Val Gly Asn Lys Thr Cys Ala Gly
130 135 140
Phe Pro Gly Ser Phe Gly Tyr Tyr Asp Ile Asp Ala Gln Thr Phe Ala
145 150 155 160
Asp Trp Gly Val Asp Leu Leu Lys Phe Asp Gly Cys Tyr Cys Asp Ser
165 170 175
Leu Glu Asn Leu Ala Asp Gly Tyr Lys His Met Ser Leu Ala Leu Asn
180 185 190
Arg Thr Gly Arg Ser Ile Val Tyr Ser Cys Glu Trp Pro Leu Tyr Met
195 200 205
Trp Pro Phe Gln Lys Pro Asn Tyr Thr Glu Ile Arg Gln Tyr Cys Asn
210 215 220
His Trp Arg Asn Phe Ala Asp Ile Asp Asp Ser Trp Lys Ser Ile Lys
225 230 235 240
Ser Ile Leu Asp Trp Thr Ser Phe Asn Gln Glu Arg Ile Val Asp Val
245 250 255
Ala Gly Pro Gly Gly Trp Asn Asp Pro Asp Met Leu Val Ile Gly Asn
260 265 270
Phe Gly Leu Ser Trp Asn Gln Gln Val Thr Gln Met Ala Leu Trp Ala
275 280 285
Ile Met Ala Ala Pro Leu Phe Met Ser Asn Asp Leu Arg His Ile Ser
290 295 300
Pro Gln Ala Lys Ala Leu Leu Gln Asp Lys Asp Val Ile Ala Ile Asn
305 310 315 320
Gln Asp Pro Leu Gly Lys Gln Gly Tyr Gln Leu Arg Gln Gly Asp Asn
325 330 335
Phe Glu Val Trp Glu Arg Pro Leu Ser Gly Leu Ala Trp Ala Val Ala
340 345 350
Met Ile Asn Arg Gln Glu Ile Gly Gly Pro Arg Ser Tyr Thr Ile Ala
355 360 365
Val Ala Ser Leu Gly Lys Gly Val Ala Cys Asn Pro Ala Cys Phe Ile
370 375 380
Thr Gln Leu Leu Pro Val Lys Arg Lys Leu Gly Phe Tyr Glu Trp Thr
385 390 395 400
Ser Arg Leu Arg Ser His Ile Asn Pro Thr Gly Thr Val Leu Leu Gln
405 410 415
Leu Glu Asn Thr Met Gln Met Ser Leu Lys Asp Leu Leu
420 425
<210> 77
<211> 1257
<212> DNA
<213> 智人
<400> 77
atgccgtctt ctgtctcgtg gggcatcctc ctgctggcag gcctgtgctg cctggtccct 60
gtctccctgg ctgaggatcc ccagggagat gctgcccaga agacagatac atcccaccat 120
gatcaggatc acccaacctt caacaagatc acccccaacc tggctgagtt cgccttcagc 180
ctataccgcc agctggcaca ccagtccaac agcaccaata tcttcttctc cccagtgagc 240
atcgctacag cctttgcaat gctctccctg gggaccaagg ctgacactca cgatgaaatc 300
ctggagggcc tgaatttcaa cctcacggag attccggagg ctcagatcca tgaaggcttc 360
caggaactcc tccgtaccct caaccagcca gacagccagc tccagctgac caccggcaat 420
ggcctgttcc tcagcgaggg cctgaagcta gtggataagt ttttggagga tgttaaaaag 480
ttgtaccact cagaagcctt cactgtcaac ttcggggaca ccgaagaggc caagaaacag 540
atcaacgatt acgtggagaa gggtactcaa gggaaaattg tggatttggt caaggagctt 600
gacagagaca cagtttttgc tctggtgaat tacatcttct ttaaaggcaa atgggagaga 660
ccctttgaag tcaaggacac cgaggaagag gacttccacg tggaccaggt gaccaccgtg 720
aaggtgccta tgatgaagcg tttaggcatg tttaacatcc agcactgtaa gaagctgtcc 780
agctgggtgc tgctgatgaa atacctgggc aatgccaccg ccatcttctt cctgcctgat 840
gaggggaaac tacagcacct ggaaaatgaa ctcacccacg atatcatcac caagttcctg 900
gaaaatgaag acagaaggtc tgccagctta catttaccca aactgtccat tactggaacc 960
tatgatctga agagcgtcct gggtcaactg ggcatcacta aggtcttcag caatggggct 1020
gacctctccg gggtcacaga ggaggcaccc ctgaagctct ccaaggccgt gcataaggct 1080
gtgctgacca tcgacgagaa agggactgaa gctgctgggg ccatgttttt agaggccata 1140
cccatgtcta tcccccccga ggtcaagttc aacaaaccct ttgtcttctt aatgattgaa 1200
caaaatacca agtctcccct cttcatggga aaagtggtga atcccaccca aaaataa 1257
<210> 78
<211> 418
<212> PRT
<213> 智人
<400> 78
Met Pro Ser Ser Val Ser Trp Gly Ile Leu Leu Leu Ala Gly Leu Cys
1 5 10 15
Cys Leu Val Pro Val Ser Leu Ala Glu Asp Pro Gln Gly Asp Ala Ala
20 25 30
Gln Lys Thr Asp Thr Ser His His Asp Gln Asp His Pro Thr Phe Asn
35 40 45
Lys Ile Thr Pro Asn Leu Ala Glu Phe Ala Phe Ser Leu Tyr Arg Gln
50 55 60
Leu Ala His Gln Ser Asn Ser Thr Asn Ile Phe Phe Ser Pro Val Ser
65 70 75 80
Ile Ala Thr Ala Phe Ala Met Leu Ser Leu Gly Thr Lys Ala Asp Thr
85 90 95
His Asp Glu Ile Leu Glu Gly Leu Asn Phe Asn Leu Thr Glu Ile Pro
100 105 110
Glu Ala Gln Ile His Glu Gly Phe Gln Glu Leu Leu Arg Thr Leu Asn
115 120 125
Gln Pro Asp Ser Gln Leu Gln Leu Thr Thr Gly Asn Gly Leu Phe Leu
130 135 140
Ser Glu Gly Leu Lys Leu Val Asp Lys Phe Leu Glu Asp Val Lys Lys
145 150 155 160
Leu Tyr His Ser Glu Ala Phe Thr Val Asn Phe Gly Asp Thr Glu Glu
165 170 175
Ala Lys Lys Gln Ile Asn Asp Tyr Val Glu Lys Gly Thr Gln Gly Lys
180 185 190
Ile Val Asp Leu Val Lys Glu Leu Asp Arg Asp Thr Val Phe Ala Leu
195 200 205
Val Asn Tyr Ile Phe Phe Lys Gly Lys Trp Glu Arg Pro Phe Glu Val
210 215 220
Lys Asp Thr Glu Glu Glu Asp Phe His Val Asp Gln Val Thr Thr Val
225 230 235 240
Lys Val Pro Met Met Lys Arg Leu Gly Met Phe Asn Ile Gln His Cys
245 250 255
Lys Lys Leu Ser Ser Trp Val Leu Leu Met Lys Tyr Leu Gly Asn Ala
260 265 270
Thr Ala Ile Phe Phe Leu Pro Asp Glu Gly Lys Leu Gln His Leu Glu
275 280 285
Asn Glu Leu Thr His Asp Ile Ile Thr Lys Phe Leu Glu Asn Glu Asp
290 295 300
Arg Arg Ser Ala Ser Leu His Leu Pro Lys Leu Ser Ile Thr Gly Thr
305 310 315 320
Tyr Asp Leu Lys Ser Val Leu Gly Gln Leu Gly Ile Thr Lys Val Phe
325 330 335
Ser Asn Gly Ala Asp Leu Ser Gly Val Thr Glu Glu Ala Pro Leu Lys
340 345 350
Leu Ser Lys Ala Val His Lys Ala Val Leu Thr Ile Asp Glu Lys Gly
355 360 365
Thr Glu Ala Ala Gly Ala Met Phe Leu Glu Ala Ile Pro Met Ser Ile
370 375 380
Pro Pro Glu Val Lys Phe Asn Lys Pro Phe Val Phe Leu Met Ile Glu
385 390 395 400
Gln Asn Thr Lys Ser Pro Leu Phe Met Gly Lys Val Val Asn Pro Thr
405 410 415
Gln Lys
<210> 79
<211> 2859
<212> DNA
<213> 智人
<400> 79
atgggagtga ggcacccgcc ctgctcccac cggctcctgg ccgtctgcgc cctcgtgtcc 60
ttggcaaccg ctgcactcct ggggcacatc ctactccatg atttcctgct ggttccccga 120
gagctgagtg gctcctcccc agtcctggag gagactcacc cagctcacca gcagggagcc 180
agcagaccag ggccccggga tgcccaggca caccccggcc gtcccagagc agtgcccaca 240
cagtgcgacg tcccccccaa cagccgcttc gattgcgccc ctgacaaggc catcacccag 300
gaacagtgcg aggcccgcgg ctgttgctac atccctgcaa agcaggggct gcagggagcc 360
cagatggggc agccctggtg cttcttccca cccagctacc ccagctacaa gctggagaac 420
ctgagctcct ctgaaatggg ctacacggcc accctgaccc gtaccacccc caccttcttc 480
cccaaggaca tcctgaccct gcggctggac gtgatgatgg agactgagaa ccgcctccac 540
ttcacgatca aagatccagc taacaggcgc tacgaggtgc ccttggagac cccgcatgtc 600
cacagccggg caccgtcccc actctacagc gtggagttct ccgaggagcc cttcggggtg 660
atcgtgcgcc ggcagctgga cggccgcgtg ctgctgaaca cgacggtggc gcccctgttc 720
tttgcggacc agttccttca gctgtccacc tcgctgccct cgcagtatat cacaggcctc 780
gccgagcacc tcagtcccct gatgctcagc accagctgga ccaggatcac cctgtggaac 840
cgggaccttg cgcccacgcc cggtgcgaac ctctacgggt ctcacccttt ctacctggcg 900
ctggaggacg gcgggtcggc acacggggtg ttcctgctaa acagcaatgc catggatgtg 960
gtcctgcagc cgagccctgc ccttagctgg aggtcgacag gtgggatcct ggatgtctac 1020
atcttcctgg gcccagagcc caagagcgtg gtgcagcagt acctggacgt tgtgggatac 1080
ccgttcatgc cgccatactg gggcctgggc ttccacctgt gccgctgggg ctactcctcc 1140
accgctatca cccgccaggt ggtggagaac atgaccaggg cccacttccc cctggacgtc 1200
cagtggaacg acctggacta catggactcc cggagggact tcacgttcaa caaggatggc 1260
ttccgggact tcccggccat ggtgcaggag ctgcaccagg gcggccggcg ctacatgatg 1320
atcgtggatc ctgccatcag cagctcgggc cctgccggga gctacaggcc ctacgacgag 1380
ggtctgcgga ggggggtttt catcaccaac gagaccggcc agccgctgat tgggaaggta 1440
tggcccgggt ccactgcctt ccccgacttc accaacccca cagccctggc ctggtgggag 1500
gacatggtgg ctgagttcca tgaccaggtg cccttcgacg gcatgtggat tgacatgaac 1560
gagccttcca acttcatcag gggctctgag gacggctgcc ccaacaatga gctggagaac 1620
ccaccctacg tgcctggggt ggttgggggg accctccagg cggccaccat ctgtgcctcc 1680
agccaccagt ttctctccac acactacaac ctgcacaacc tctacggcct gaccgaagcc 1740
atcgcctccc acagggcgct ggtgaaggct cgggggacac gcccatttgt gatctcccgc 1800
tcgacctttg ctggccacgg ccgatacgcc ggccactgga cgggggacgt gtggagctcc 1860
tgggagcagc tcgcctcctc cgtgccagaa atcctgcagt ttaacctgct gggggtgcct 1920
ctggtcgggg ccgacgtctg cggcttcctg ggcaacacct cagaggagct gtgtgtgcgc 1980
tggacccagc tgggggcctt ctaccccttc atgcggaacc acaacagcct gctcagtctg 2040
ccccaggagc cgtacagctt cagcgagccg gcccagcagg ccatgaggaa ggccctcacc 2100
ctgcgctacg cactcctccc ccacctctac acactgttcc accaggccca cgtcgcgggg 2160
gagaccgtgg cccggcccct cttcctggag ttccccaagg actctagcac ctggactgtg 2220
gaccaccagc tcctgtgggg ggaggccctg ctcatcaccc cagtgctcca ggccgggaag 2280
gccgaagtga ctggctactt ccccttgggc acatggtacg acctgcagac ggtgccagta 2340
gaggcccttg gcagcctccc acccccacct gcagctcccc gtgagccagc catccacagc 2400
gaggggcagt gggtgacgct gccggccccc ctggacacca tcaacgtcca cctccgggct 2460
gggtacatca tccccctgca gggccctggc ctcacaacca cagagtcccg ccagcagccc 2520
atggccctgg ctgtggccct gaccaagggt ggggaggccc gaggggagct gttctgggac 2580
gatggagaga gcctggaagt gctggagcga ggggcctaca cacaggtcat cttcctggcc 2640
aggaataaca cgatcgtgaa tgagctggta cgtgtgacca gtgagggagc tggcctgcag 2700
ctgcagaagg tgactgtcct gggcgtggcc acggcgcccc agcaggtcct ctccaacggt 2760
gtccctgtct ccaacttcac ctacagcccc gacaccaagg tcctggacat ctgtgtctcg 2820
ctgttgatgg gagagcagtt tctcgtcagc tggtgttag 2859
<210> 80
<211> 952
<212> PRT
<213> 智人
<400> 80
Met Gly Val Arg His Pro Pro Cys Ser His Arg Leu Leu Ala Val Cys
1 5 10 15
Ala Leu Val Ser Leu Ala Thr Ala Ala Leu Leu Gly His Ile Leu Leu
20 25 30
His Asp Phe Leu Leu Val Pro Arg Glu Leu Ser Gly Ser Ser Pro Val
35 40 45
Leu Glu Glu Thr His Pro Ala His Gln Gln Gly Ala Ser Arg Pro Gly
50 55 60
Pro Arg Asp Ala Gln Ala His Pro Gly Arg Pro Arg Ala Val Pro Thr
65 70 75 80
Gln Cys Asp Val Pro Pro Asn Ser Arg Phe Asp Cys Ala Pro Asp Lys
85 90 95
Ala Ile Thr Gln Glu Gln Cys Glu Ala Arg Gly Cys Cys Tyr Ile Pro
100 105 110
Ala Lys Gln Gly Leu Gln Gly Ala Gln Met Gly Gln Pro Trp Cys Phe
115 120 125
Phe Pro Pro Ser Tyr Pro Ser Tyr Lys Leu Glu Asn Leu Ser Ser Ser
130 135 140
Glu Met Gly Tyr Thr Ala Thr Leu Thr Arg Thr Thr Pro Thr Phe Phe
145 150 155 160
Pro Lys Asp Ile Leu Thr Leu Arg Leu Asp Val Met Met Glu Thr Glu
165 170 175
Asn Arg Leu His Phe Thr Ile Lys Asp Pro Ala Asn Arg Arg Tyr Glu
180 185 190
Val Pro Leu Glu Thr Pro His Val His Ser Arg Ala Pro Ser Pro Leu
195 200 205
Tyr Ser Val Glu Phe Ser Glu Glu Pro Phe Gly Val Ile Val Arg Arg
210 215 220
Gln Leu Asp Gly Arg Val Leu Leu Asn Thr Thr Val Ala Pro Leu Phe
225 230 235 240
Phe Ala Asp Gln Phe Leu Gln Leu Ser Thr Ser Leu Pro Ser Gln Tyr
245 250 255
Ile Thr Gly Leu Ala Glu His Leu Ser Pro Leu Met Leu Ser Thr Ser
260 265 270
Trp Thr Arg Ile Thr Leu Trp Asn Arg Asp Leu Ala Pro Thr Pro Gly
275 280 285
Ala Asn Leu Tyr Gly Ser His Pro Phe Tyr Leu Ala Leu Glu Asp Gly
290 295 300
Gly Ser Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met Asp Val
305 310 315 320
Val Leu Gln Pro Ser Pro Ala Leu Ser Trp Arg Ser Thr Gly Gly Ile
325 330 335
Leu Asp Val Tyr Ile Phe Leu Gly Pro Glu Pro Lys Ser Val Val Gln
340 345 350
Gln Tyr Leu Asp Val Val Gly Tyr Pro Phe Met Pro Pro Tyr Trp Gly
355 360 365
Leu Gly Phe His Leu Cys Arg Trp Gly Tyr Ser Ser Thr Ala Ile Thr
370 375 380
Arg Gln Val Val Glu Asn Met Thr Arg Ala His Phe Pro Leu Asp Val
385 390 395 400
Gln Trp Asn Asp Leu Asp Tyr Met Asp Ser Arg Arg Asp Phe Thr Phe
405 410 415
Asn Lys Asp Gly Phe Arg Asp Phe Pro Ala Met Val Gln Glu Leu His
420 425 430
Gln Gly Gly Arg Arg Tyr Met Met Ile Val Asp Pro Ala Ile Ser Ser
435 440 445
Ser Gly Pro Ala Gly Ser Tyr Arg Pro Tyr Asp Glu Gly Leu Arg Arg
450 455 460
Gly Val Phe Ile Thr Asn Glu Thr Gly Gln Pro Leu Ile Gly Lys Val
465 470 475 480
Trp Pro Gly Ser Thr Ala Phe Pro Asp Phe Thr Asn Pro Thr Ala Leu
485 490 495
Ala Trp Trp Glu Asp Met Val Ala Glu Phe His Asp Gln Val Pro Phe
500 505 510
Asp Gly Met Trp Ile Asp Met Asn Glu Pro Ser Asn Phe Ile Arg Gly
515 520 525
Ser Glu Asp Gly Cys Pro Asn Asn Glu Leu Glu Asn Pro Pro Tyr Val
530 535 540
Pro Gly Val Val Gly Gly Thr Leu Gln Ala Ala Thr Ile Cys Ala Ser
545 550 555 560
Ser His Gln Phe Leu Ser Thr His Tyr Asn Leu His Asn Leu Tyr Gly
565 570 575
Leu Thr Glu Ala Ile Ala Ser His Arg Ala Leu Val Lys Ala Arg Gly
580 585 590
Thr Arg Pro Phe Val Ile Ser Arg Ser Thr Phe Ala Gly His Gly Arg
595 600 605
Tyr Ala Gly His Trp Thr Gly Asp Val Trp Ser Ser Trp Glu Gln Leu
610 615 620
Ala Ser Ser Val Pro Glu Ile Leu Gln Phe Asn Leu Leu Gly Val Pro
625 630 635 640
Leu Val Gly Ala Asp Val Cys Gly Phe Leu Gly Asn Thr Ser Glu Glu
645 650 655
Leu Cys Val Arg Trp Thr Gln Leu Gly Ala Phe Tyr Pro Phe Met Arg
660 665 670
Asn His Asn Ser Leu Leu Ser Leu Pro Gln Glu Pro Tyr Ser Phe Ser
675 680 685
Glu Pro Ala Gln Gln Ala Met Arg Lys Ala Leu Thr Leu Arg Tyr Ala
690 695 700
Leu Leu Pro His Leu Tyr Thr Leu Phe His Gln Ala His Val Ala Gly
705 710 715 720
Glu Thr Val Ala Arg Pro Leu Phe Leu Glu Phe Pro Lys Asp Ser Ser
725 730 735
Thr Trp Thr Val Asp His Gln Leu Leu Trp Gly Glu Ala Leu Leu Ile
740 745 750
Thr Pro Val Leu Gln Ala Gly Lys Ala Glu Val Thr Gly Tyr Phe Pro
755 760 765
Leu Gly Thr Trp Tyr Asp Leu Gln Thr Val Pro Val Glu Ala Leu Gly
770 775 780
Ser Leu Pro Pro Pro Pro Ala Ala Pro Arg Glu Pro Ala Ile His Ser
785 790 795 800
Glu Gly Gln Trp Val Thr Leu Pro Ala Pro Leu Asp Thr Ile Asn Val
805 810 815
His Leu Arg Ala Gly Tyr Ile Ile Pro Leu Gln Gly Pro Gly Leu Thr
820 825 830
Thr Thr Glu Ser Arg Gln Gln Pro Met Ala Leu Ala Val Ala Leu Thr
835 840 845
Lys Gly Gly Glu Ala Arg Gly Glu Leu Phe Trp Asp Asp Gly Glu Ser
850 855 860
Leu Glu Val Leu Glu Arg Gly Ala Tyr Thr Gln Val Ile Phe Leu Ala
865 870 875 880
Arg Asn Asn Thr Ile Val Asn Glu Leu Val Arg Val Thr Ser Glu Gly
885 890 895
Ala Gly Leu Gln Leu Gln Lys Val Thr Val Leu Gly Val Ala Thr Ala
900 905 910
Pro Gln Gln Val Leu Ser Asn Gly Val Pro Val Ser Asn Phe Thr Tyr
915 920 925
Ser Pro Asp Thr Lys Val Leu Asp Ile Cys Val Ser Leu Leu Met Gly
930 935 940
Glu Gln Phe Leu Val Ser Trp Cys
945 950
Claims (53)
1.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)基因编辑载体，其包含编码靶向PCSK9基因的核酸酶的核酸序列；和
(b)供体载体，其包含转基因盒，所述转基因盒包含编码转基因的核酸序列和指导所述转基因在靶细胞中的表达的调控序列，所述供体载体进一步包含所述转基因盒的5′和3′的同源定向重组(HDR)臂，其中所述转基因不是PCSK9。
2.根据权利要求1所述的系统，进一步包含指导所述核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列
3.根据权利要求1或权利要求2所述的系统，其中所述核酸酶靶向PCSK9外显子7。
4.根据权利要求1至3中任一项所述的系统，其中所述核酸酶是针对PCSK9特异性的大范围核酸酶。
5.根据权利要求4所述的系统，其中所述大范围核酸酶是ARCUS大范围核酸酶。
6.根据权利要求1或2所述的系统，其中所述基因编辑载体包含侧翼为核定位信号的编码Cas9的序列。
7.根据权利要求6所述的系统，其中所述基因编辑载体进一步包含含有至少20个核苷酸的sgRNA，所述sgRNA特异性结合所述PCSK9基因中的靶位点，所述靶位点位于被所述Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
8.根据权利要求6所述的系统，其中所述供体载体进一步包含含有至少20个核苷酸的种子区的sgRNA，其中所述sgRNA特异性结合所述PCSK9基因中的靶位点，所述靶位点位于被所述Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
9.根据权利要求6至8中任一项所述的系统，进一步包含RNA聚合酶启动子。
10.根据权利要求9所述的系统，其中所述RNA聚合酶启动子是U6启动子。
11.根据权利要求10所述的系统，其中所述U6启动子位于所述sgRNA的5′。
12.根据权利要求7至11中任一项所述的系统，其中所述种子区与所述靶位点序列100％互补。
13.根据权利要求7至11中任一项所述的系统，其中所述种子区与所述靶位点序列小于100％互补。
14.根据权利要求1至13中任一项所述的系统，其中所述转基因是OTC、PKU、CTLN1或LDLR。
15.根据权利要求1至14中任一项所述的系统，其中所述供体载体和基因编辑载体中的至少一者为腺相关病毒(AAV)载体，并且所述AAV载体包含AAV 5′ITR和AAV 3′ITR。
16.根据权利要求15所述的系统，其中(a)的基因编辑AAV载体与(b)的供体AAV载体的比率使得(b)的供体AAV载体超过(a)的基因编辑载体。
17.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)基因编辑AAV，其包含AAV衣壳和第一载体基因组，所述第一载体基因组包含：5′ITR；编码大范围核酸酶的序列，所述大范围核酸酶在指导所述大范围核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列控制下靶向PCSK9；和3′ITR；以及
(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，所述第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导所述转基因在所述靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
18.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)基因编辑AAV，其包含AAV衣壳和第一载体基因组，所述第一载体基因组包含：5′ITR；5′核定位信号(NLS)；编码Cas9的序列和指导saCas9在包含PCSK9基因的靶细胞中的表达的调控序列；3′NLS；和3′ITR；以及
(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，所述第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导所述转基因在所述靶细胞中的表达的调控序列；3′HDR臂；U6启动子；包含特异性结合所述PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被所述Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；和3′ITR。
19.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)基因编辑AAV载体，其包含AAV衣壳和第一载体基因组，所述第一载体基因组包含：5′ITR；U6启动子；包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；5′核定位信号(NLS)；编码Cas9的序列和指导所述Cas9在包含所述PCSK9基因的靶细胞中的表达的调控序列；3′NLS；和3′ITR；以及
(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，所述第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导所述转基因在所述靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
20.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)基因编辑载体，其包含：
(i)脂质纳米颗粒；
(ii)包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸的sgRNA，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′；
(iii)包含5′核定位信号(NLS)、编码所述Cas9的序列、3′NLS的mRNA；以及
(b)供体AAV载体，其包含AAV衣壳和第二载体基因组，所述第二载体基因组包含：5′ITR；5′同源定向重组(HDR)臂；转基因和指导所述转基因在靶细胞中的表达的调控序列；3′HDR臂；和3′ITR。
21.根据权利要求17至19中任一项所述的系统，其中(a)的所述基因编辑AAV载体和(b)的所述供体AAV载体具有相同的AAV衣壳。
22.根据权利要求21所述的系统，其中所述AAV衣壳选自AAV8、AAV9、rh10、AAV6.2、AAV3B、hu37、rh79和rh64。
23.根据权利要求6至18或18至22中任一项所述的系统，其中Cas9选自金黄色葡萄球菌或化脓性链球菌Cas9。
24.根据权利要求2至19中任一项所述的系统，其中所述核酸酶处于组织特异性启动子的控制之下。
25.根据权利要求2至19中任一项所述的系统，其中所述核酸酶处于组成型启动子的控制之下。
26.根据权利要求24所述的系统，其中所述核酸酶处于肝特异性启动子的控制之下，任选地为人甲状腺素结合球蛋白(TBG)启动子或杂合肝启动子(HLP)。
27.一种通过共同施用根据权利要求1至26中任一项所述的系统来治疗人类疾患的方法。
28.一种在新生儿受试者中治疗肝代谢疾患的方法，所述方法包括：向患有肝代谢疾患的所述受试者共同施用：
(a)基因编辑AAV载体，其包含编码核酸酶的序列和指导所述核酸酶在包含PCSK9基因的靶细胞中的表达的调控序列；和
(b)供体AAV载体，其包含转基因和指导所述转基因在所述靶细胞中的表达的调控序列，所述供体载体进一步包含转基因盒的5′和3′的同源定向重组(HDR)臂。
29.根据权利要求28所述的方法，其中(a)的所述基因编辑AAV载体和(b)的所述供体载体经由相同途径基本上同时递送。
30.根据权利要求28或权利要求29所述的方法，其中(a)的所述基因编辑AAV载体以约2x1011GC/mL至约2x1012GC/mL的浓度悬浮于注射用载剂中。
31.根据权利要求28或权利要求29所述的方法，其中(a)的所述AAV靶向载体以约2x1012GC/mL至约1x1013GC/mL的浓度悬浮于注射用载剂中。
32.根据权利要求28至31中任一项所述的方法，其中所述肝代谢疾患是鸟氨酸氨甲酰基转移酶。
33.根据权利要求28至31中任一项所述的方法，其中所述肝代谢疾患是OTC、FH、瓜氨酸血症I型(CTLN1)或苯丙酮尿症。
34.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)包含编码核酸酶的mRNA序列的脂质纳米颗粒(LNP)；以及
(b)供体AAV载体，其包含转基因和指导其在靶细胞中的表达的调控序列，所述供体载体进一步包含所述转基因的5′和3′的同源定向重组(HDR)臂。
35.根据权利要求34所述的系统，其中所述核酸酶靶向PCSK9基因。
36.根据权利要求34所述的系统，其中所述核酸酶靶向PCSK9外显子7。
37.根据权利要求34所述的系统，其中所述核酸酶是针对PCSK9特异性的大范围核酸酶。
38.根据权利要求37所述的系统，其中所述大范围核酸酶是ARCUS大范围核酸酶。
39.根据权利要求34所述的系统，其中所述核酸酶是Cas9核酸酶并且其中所述LNP包含sgRNA。
40.根据权利要求39所述的系统，其中所述Cas9核酸酶侧翼为核定位信号。
41.根据权利要求39或40所述的系统，其中所述sgRNA包含特异性结合PCSK9基因中的靶位点的至少20个核苷酸，所述靶位点位于被Cas9特异性识别的原型间隔子相邻基序(PAM)的5′。
42.根据权利要求34至41中任一项所述的系统，进一步包含RNA聚合酶启动子。
43.根据权利要求43所述的系统，其中所述RNA聚合酶启动子是U6启动子。
44.根据权利要求46所述的系统，其中所述U6启动子位于所述sgRNA的5′。
45.根据权利要求34至44中任一项所述的系统，其中所述sgRNA与所述靶位点序列100％互补。
46.根据权利要求34至44中任一项所述的系统，其中所述sgRNA与所述靶位点序列小于100％互补。
47.根据权利要求34至46中任一项所述的系统，其中所述转基因是肝表达的基因。
48.根据权利要求34至47中任一项所述的系统，其中所述转基因选自OTC、PKU、CTLN1和FH。
49.一种用于治疗遗传性疾患的系统，所述系统包括：
(a)包含编码核酸酶的核酸序列的基因编辑载体；以及
(b)供体载体，其包含编码用于从PCSK9基因座表达的外源产物的核酸序列，其中插入的核酸序列不编码PCSK9，
其中所述系统进一步包含指导所述核酸酶特异性靶向天然PCSK9基因座的序列；并且
其中所述靶细胞中的天然PCSK9用所述双载体系统给药后任选地被消除或减少。
50.一种使用根据权利要求49所述的系统治疗患者的方法，其中所述患者的天然PCSK9表达水平降低并且其中所述患者表达所述外源产物。
51.一种表达盒，其包含SEQ ID NO：17的工程化的编码序列，或与其共有至少90％同一性的序列。
52.根据权利要求51所述的表达盒，进一步包含AAV 5′和3′ITR。
53.一种AAV载体，其包含根据权利要求51或52所述的表达盒。
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| US63/180603 | 2021-04-27 | ||
| US63/242474 | 2021-09-09 | ||
| US63/244205 | 2021-09-14 | ||
| US63/301933 | 2022-01-21 | ||
| US202263331385P | 2022-04-15 | 2022-04-15 | |
| US63/331385 | 2022-04-15 | ||
| PCT/US2022/026483 WO2022232232A1 (en) | 2021-04-27 | 2022-04-27 | Compositions and methods for in vivo nuclease-mediated gene targeting for the treatment of genetic disorders |
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