CN117716043A - G蛋白门控的k+通道介导的视杆-视锥细胞营养不良(rcd)中光敏感性的增强 - Google Patents
G蛋白门控的k+通道介导的视杆-视锥细胞营养不良(rcd)中光敏感性的增强 Download PDFInfo
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Abstract
本发明涉及一种新型基因治疗方法,通过退化视锥细胞中表达的视锥细胞视蛋白募集的G蛋白激活的G蛋白门控的K+通道(GIRK)、特别是GIRK1F137S介导,增加晚期视杆‑视锥细胞营养不良(RCD)中退化视锥细胞的光敏感性。
Description
技术领域
本发明涉及一种新型基因治疗方法,通过退化视锥细胞中表达的视锥细胞视蛋白募集的G蛋白激活的G蛋白门控的K+通道(GIRK)、特别是GIRK1 F137S介导,增加晚期视杆-视锥细胞营养不良(RCD)中退化视锥细胞的光敏感性。
在以下描述中,方括号([])中的参考文献是指文本末尾的参考文献列表。
背景技术
视网膜是眼睛的光敏组织,由通过突触相互连接的三层神经元组成。视网膜的主要神经元是光感测感光细胞(PR),其分为两种类型:用于夜视的视杆细胞和用于日光视觉的视锥细胞。视锥细胞介导的视觉主要由中央凹支持,并负责对日常视觉任务最有价值的高敏锐度中心视觉(Sinha等人,2017年)[1]。将光子捕获与细胞内信号传导联系起来、导致感光细胞膜超极化的光敏G蛋白偶联受体被称为视蛋白(Yau和Hardie,2009年)[2]。在灵长类动物的视网膜中,视杆细胞中有一种视杆细胞视蛋白,视锥细胞中有三种视锥细胞视蛋白(负责三色视觉)。这些视蛋白的结构特性和光转导级联反应相似。
光转导级联反应由集中在正常视网膜的感光细胞外节的几种蛋白质组成(图1A)。感光细胞的作用是通过这种光转导级联反应来感测光线,并引起电信号,然后对该电信号进行处理并传输至下游神经元(Ebrey和Koutalos,2001年)[3]。
光子的吸收激活了由两部分组成的视蛋白:蛋白质部分和光吸收部分,即视黄醛(维生素A的衍生物)。后者从11-顺式视黄醛(暗适应状态)异构化为全反式视黄醛构型(光适应状态)。结果是视蛋白变得具有催化活性,募集G蛋白转导蛋白。转导蛋白的α亚基通过GTP取代GDP而激活。之后,α亚基与βγ亚基解离,通过结合其两个抑制性γ亚基来激活膜相关的磷酸二酯酶6(PDE)。激活的PDE将cGMP水解成GMP。cGMP的减少克隆了核苷酸门控通道(CNG),这阻止了阳离子进入,导致PR超极化和感光细胞释放的谷氨酸减少(Larhammar等人,2009年)[4]。
为响应另一个光子,这种光转导级联反应通过两种机制失活:(i)转导蛋白通过水解结合的GTP使自身失活,(ii)视紫红质激酶(GRK)磷酸化与调节蛋白抑制蛋白相互作用的视蛋白,导致视蛋白失活。视黄醛随后被视网膜色素上皮(RPE)和米勒神经胶质细胞回收。这种级联反应的每种蛋白质均在将光信号转换为传送至二阶和三阶神经元的电信号方面发挥着重要作用(Maeda等人,2003年)[5]。
遗传性视网膜退化主要是由于感光细胞或RPE细胞发生突变,导致视杆细胞退化,随后视锥细胞外节退化,最终导致失明(Buch等人,2004)[6]。其中,视杆-视锥细胞营养不良(RCD)是最大的一类,其遗传原因具有高度异质性。涉及视杆感光细胞或视网膜色素上皮中表达的60多种不同基因(Wright等人,2010年)[7]。第一个与RCD相关的基因是视紫红质基因RHO,该基因占RCD常染色体显性遗传病例的25%。许多其他致病基因也已被鉴定:cGMP-PDE亚基基因和环GMP门控的通道蛋白α亚基基因。虽然致病基因有很多,但不同突变产生的RCD表型是相同的(Ferrari等人,2011年)[8]。常见的RCD表型的特征是进行性视杆细胞退化,导致夜盲症,随后是进行性周边视锥细胞退化,导致“管状视野(tunnelvision)”,完全由保留的中心凹视锥细胞介导,并且最终在疾病的最晚期导致完全失明。通常,当患者被诊断患有RCD时,他们已经出现了夜盲症,这意味着他们的视杆细胞已经退化。然而,视锥细胞一直保留到疾病的晚期;特别是在负责高敏锐度的中央凹区域,其导致早期的管状视野(Li等人,1995年)[9]。在疾病的晚期,这些视锥细胞失去其外节结构,导致在视锥细胞体和蒂完全丧失之前完全失明(Li等人,1995年)[9]。
为保留这些表现出光敏性视锥细胞体的患者的视力,一种创新策略是视网膜基因治疗,其广义上是指将治疗基因转移到视网膜细胞中以介导治疗效果(Bennet,2017年)[10]。虽然首批成功的基因治疗临床试验集中在基因置换上,即用功能性cDNA拷贝替换携带隐性突变的基因,但这种策略是受限的,因为其无法用于大多数视网膜退化(Bennet,2017年)[10]。例如,在RCD中,突变巨大的可变性使得很难适用于每个特定的突变。此外,显性突变不能使用这种方法治疗。此外,在50%的病例中,致病突变尚未明确,或者携带最常见突变的视杆感光细胞已经丧失(Dalkara等人,2015年)[11]。由于这些原因,必须开发出可以在视杆细胞丧失的情况下应用的与突变无关的基因治疗,以在不知晓突变基因的情况下治疗大量患者。
考虑到这一目标,先前的研究使用微生物视蛋白的异位表达,例如双极细胞中的光敏感通道蛋白或视锥细胞PR中的盐细菌视紫红质,以调节膜电位,并分别诱导去极化或超极化(Busskamp等人,2012年;Dalkara和Sahel,2014年;Scholl等人,2016年)[12-14]。因此,在RCD中,光遗传学可以用作恢复失明视网膜视力的治疗策略(Baker和Flannery,2008年)[15]。有很多参数需要考虑:(i)选择细胞靶点,以充分利用视网膜电路向大脑发送最易解读的信号(ii)选择适当的光遗传学工具,以在这些靶细胞中获得接近自然的电生理反应。关于第二点,微生物视蛋白相对较弱的能力是一个主要的限制因素:使用原核物种的视蛋白的潜在免疫原性,由于这些直接光门控的通道和源自单细胞微生物的泵缺乏信号放大而需要高强度,如盐细菌视紫红质的情况(Baker和Flannery,2008年)[15],(Cehajic-Kapetanovic等人,2015年;Gaub等人,2015年;Van Gelder和Kaur,2015年;van Wyk等人,2015年)[16-19]。与视紫红质或视锥细胞视蛋白不同,微生物视蛋白不能激活G蛋白偶联的级联反应,例如健康视网膜中存在的光转导级联反应。超越微生物视蛋白限制的可能方法之一是使用动物视蛋白,它们均是G蛋白偶联受体。然而,迄今为止,这一领域的所有工作都集中在视网膜内部神经元上(Berry等人,2019年;Cehajic-Kapetanovic等人,2015年;DeSilva等人,2017年;Gaub等人,2015年;Lin等人,2008年;van Wyk等人,2015年)[20、16、21、17、22、19]。
先前的一项研究表明,两种动物视锥细胞视蛋白的光激活可以在体外和体内刺激人肾细胞和神经元细胞中的Gi/o信号传导途径(Masseck等人,2014年)[23]。这一途径参与快速抑制神经元活动和抑制固有离子通道。然而,也有研究表明,动物视锥细胞视蛋白在任何给定细胞中共表达时可以直接调节G蛋白门控的内向整流钾(GIRK)通道(Berry等人,2019年;Masseck等人,2014年)[20、23]。GIRK通道由两个亚基组成。亚基有四种类型:GIRK1至GIRK4。GIRK1和GIRK3不能形成同源四聚体;它们必须与GIRK2相关联才能发挥作用(Mark和Herlitze,2000年)[24]。相反,GIRK2可以单独形成同源四聚体。单点突变体GIRK1 F137S被认为可形成功能性同源聚体通道(Chan等人,1996年)[31]。GIRK通道在静息膜电位时主要处于关闭状态。在其被Gi/o蛋白的βγ亚基激活后,钾离子流出细胞,从而使神经元超极化(图1B)。因此,可以使用脊椎动物视锥细胞视蛋白SWO(短波长视蛋白)和LWO(长波长视蛋白)在体内焦虑回路中重复激活特定波长的Gi/o,并且在低光强度下,视锥细胞视蛋白与GIRK的结合已经证明比微生物视蛋白更有效(Masseck等人,2014年)[23]。
发明内容
因此,本发明人研究了是否可以在视力恢复环境中实施这种基于视锥细胞视蛋白的系统,并且研究了患者视网膜,为临床候选者选择做准备。因此,为了开发光敏性视锥细胞再激活策略,首先在两种RCD小鼠模型中检查了视锥细胞退化过程中光转导级联反应元件的表达。在探索了两种RCD小鼠模型中的磷酸转导级联反应后,首次提出了一种通过激活保留的视锥细胞视蛋白募集的Gi/o蛋白而发挥作用的靶分子方法。其因此创造了一种新的“短光转导级联反应”,与PDE和转导蛋白的表达无关。
首先,研究了疾病进展过程中退化视锥细胞中内源性光转导级联反应的状态。在两种小鼠模型中,发现仅有视蛋白和抑制蛋白在外节退化后迁移到视锥细胞体。因此,假设基于视锥细胞视蛋白信号传导的视锥细胞再激活可能是可行的,这进而又将能够恢复高灵敏度视觉。研究发现,在rd10小鼠模型中,内源性视锥细胞视蛋白水平仍在视锥细胞体水平表达(图3),这表明即使在缺乏转导蛋白和磷酸二酯酶的情况下,也可能将其活性与GIRK通道(例如GIRK2通道)相联系(图1B)。在这种配置中,由于休眠视锥细胞的静息膜电位,GIRK通道的开放将使得钾离子流出(Busskamp,2010年)[25]。经由GIRK通道的K+流出将使视锥细胞响应光而超极化,正如在两种RCD小鼠模型中所见。
接下来,由视锥细胞视蛋白募集的G蛋白激活的GIRK2通道在退化视锥细胞中表达。此外,由于视锥细胞体中保留的视蛋白仍具有功能并且足以在退化的视锥细胞中诱导光响应,因此在所有视锥细胞中插入GIRK2会导致光响应,其遵循每种视蛋白的光谱特性,从而保留色觉。结果表明,在视锥细胞外节退化期间和之后,RCD视网膜的视锥细胞的光敏感性增强。因此,结果表明,脊椎动物光敏性蛋白与由内源性G蛋白激活的GIRK通道、特别是GIRK2通道相结合,可以改善两种小鼠模型的视觉功能,如视网膜电图和行为所证明的。这是第一次将对光不敏感性的哺乳动物离子通道与固有视蛋白相联系,为视觉恢复提供了新途径,甚至可以在外节完全退化之前就提高光敏感性。由于这一新系统利用了退化视锥细胞中表达的固有视蛋白,因此其还首次实现了色觉恢复/维持。
与RCD小鼠模型类似,视锥细胞视蛋白和视锥细胞抑制蛋白保留在RP人类患者的视锥细胞体中(图12)。这一结果证明了利用短GIRK2/视蛋白光转导级联反应重新激活RCD人类患者中心凹区域中视锥细胞功能的可行性。光刺激激活保留的视锥细胞视蛋白将触发短光转导级联反应,从而使RCD患者恢复视觉,即使是在疾病的中期或晚期。
因此,这种新方法有可能维持和/或恢复人类患者仅需低光强度的高敏锐度和色觉。
微生物视蛋白的一个明显优势是其稳健性和毫秒级动力学(Packer等人,2013年)[26]。对于使用其他视蛋白的系统,应当考虑到,为响应另一种光刺激,必须使级联反应失效以恢复光敏感性。如果没有这种情况,视锥细胞可能在GIRK2通道激活后保持超极化状态,从而限制它们以与运动视觉兼容的移动速率调节突触传递的能力。在目前的方法中,由于两种RCD模型中在疾病的晚期仍然维持的抑制蛋白,使得视锥细胞去极化成为可能。这在闪烁ERG迹线中很明显,该迹线示出了在重复光刺激期间视网膜的反应,并且经治疗的小鼠改善的视动反射也证明了这点。
最后,GIRK2的加入甚至在外节完全丧失之前就增强了视锥细胞中现有的光响应,这一事实为在疾病中期实施这种基因治疗提供了可能性。小鼠视网膜退化的速度比人类快得多,因此小鼠几天的治疗效果相当于人类几年的治疗效果。尽管如此,即使内源性光响应消失,表达GIRK2的视网膜仍然能够对光做出响应,产生与保留的视锥细胞数量相对应的响应幅度。这表明,即使在治疗开始时没有可检测到的光感,具有保留的中心凹视锥细胞的患者仍可从这种治疗中受益(图10)。因此,只要视锥细胞保留下来,就可以使用这种方法。事实上,记录到经治疗的视锥细胞对光刺激的响应减少,这与视锥细胞数量的减少一致,并且由于视网膜下注射,没有转导所有视锥细胞,这进一步限制了有益效果。显示出更好的横向扩散的AAV载体可用于增加泡之外的转导的视锥细胞数量(Khabou等人,2018年;国际专利申请WO 2018134168)[27、28]。为增加治疗窗,神经营养因子可以与本发明的方法一起实施。事实上,AAV介导的神经营养因子(例如视杆细胞衍生的视锥细胞活力因子(RdCVF))的分泌已被证明可以延缓视锥细胞的死亡,并可与GIRK2介导的致敏作用相结合(Byrne等人,2015年)[29]。
现已发现,在短GIRK/视蛋白光转导级联反应的情况下,GIRK1通道的突变形式GIRK1 F137S比GIRK2诱导明显更多的离子流出。这一结果表明,与GIRK2基因治疗RCD相比,在视锥细胞中加入GIRK1 F137S将提供改进的基因治疗。
因此,本发明的一个目的是一种载体,其包含编码G蛋白门控的内向整流钾(GIRK1)通道F137S的亚基1的核苷酸序列。
编码GIRK1 F137Scan的核苷酸序列处于视锥细胞特异性启动子例如pR1.7或其功能变体,或者最小M-视蛋白启动子,特别是在pMNTC表达盒中,或者GRK启动子或其截短形式(G蛋白偶联的受体激酶,特别是GRK1)的控制下。
本发明的载体还可以包含编码哺乳动物视锥细胞视蛋白的核苷酸序列。例如,哺乳动物视锥细胞视蛋白是短波长视锥细胞视蛋白(SWO),例如来自小家鼠(mus musculus)或人视锥细胞视蛋白。当存在于同一载体中时,编码GIRK1 F137S的核苷酸序列和编码哺乳动物视锥细胞视蛋白的核苷酸序列优选地处于同一启动子的控制下,特别是视锥细胞特异性启动子例如pR1.7或其功能变体,或者最小M-视蛋白启动子,特别是在pMNTC表达盒中,或者GRK启动子或其截短形式(G蛋白偶联的受体激酶,特别是GRK1)。
出于本发明的目的,“GIRK1 F137S”是指编码野生型人GIRK1(SEQ ID NO:1)或小鼠GIRK1(SEQ ID NO:4)的突变形式的核苷酸序列,该突变形式包括Ser取代Phe137,并且在与视蛋白共表达时,所述核苷酸序列保持对光响应的能力。GIRK1 F137S与野生型GIRK1的不同之处在于,仅用Ser取代Phe137(例如,如SEQ ID NO:2中所示),或者有限数量的突变,例如除了用Ser取代Phe137外,至多取代和/或缺失和/或插入1、2、3、4或5个氨基酸。例如,编码GIRK1 F137S的核苷酸序列包含编码序列SEQ ID NO:2的多肽的核苷酸序列或由其组成,或者包含核苷酸序列SEQ ID NO:3或由其组成,或者包含编码序列SEQ ID NO:5的多肽的核苷酸序列或由其组成。
本发明的另一个目的是包含本发明的载体的药学上可接受的运载体。
根据本发明的一个具体实施方案,药学上可接受的运载体可以包括包含如上所述的编码GIRK1 F137S的核苷酸序列的载体和包含编码哺乳动物视椎细胞视蛋白的核苷酸序列的载体。例如,哺乳动物视锥细胞视蛋白是短波长视锥细胞视蛋白(SWO),例如来自小家鼠或人的长波长敏感性(OPN1LW)、中波长敏感性(OPN1MW)、短波长敏感性(OPN1SW)视蛋白。根据一个实施方案,哺乳动物视锥细胞视蛋白是人长波敏感性视蛋白1(SEQ ID NO:6)。
根据本发明的一个具体实施方式,药学上可接受的运载体(Carrier)例如选自固体-脂质纳米颗粒、壳聚糖纳米颗粒、脂质体、脂质复合物或阳离子聚合物。
根据本发明的一个具体实施方式,本发明的载体(vector)是病毒,其选自腺相关病毒(AAV)、腺病毒、慢病毒、SV40病毒载体。根据本发明的一个具体实施方式,本发明的尺寸等于或小于30nm。例如,其是腺相关病毒(AAV),优选AAV8,或国际专利申请WO 2012/145601中所述的AAV2-7m8或AAV9-7m8衣壳变体。
AAV2-7m8或AAV9-7m8衣壳变体是在VP1衣壳蛋白的GH环中包含7至11个氨基酸长插入肽的AAV2或AAV9病毒,其中该插入肽包含氨基酸序列LGETTRP(SEQ ID NO:7)。
AAV的各种血清型的基因组和多肽序列以及天然反向末端重复序列(ITR)、Rep蛋白和衣壳亚基(包括VP1蛋白)的序列是本领域已知的。此类序列可以在文献中或公共数据库(例如GenBank或蛋白质数据库(PDB))中找到。参见例如GenBank和PDB AF043303和1LP3(AAV2)、AY530579和3UX1(AAV9(分离株hu.14)),其公开内容通过引用并入本文,用于教导AAV核酸和氨基酸序列。AAV9和AAV2的野生型VP1的示例性氨基酸序列分别示于SEQ ID NO:8和SEQ ID NO:9中。
优选地,插入肽在VP1衣壳蛋白的GH环中的插入位点在AAV2野生型VP1衣壳蛋白的氨基酸587和588之间,在AAV9野生型VP1衣壳蛋白的氨基酸588和589之间。
根据一些实施方式,插入肽的长度为7个氨基酸、8个氨基酸、9个氨基酸、10个氨基酸或11个氨基酸。
插入肽可以在氨基酸序列LGETTRP(SEQ ID NO:7)的N末端和/或C末端包含一个或多个间隔子氨基酸。优选地,间隔子氨基酸选自Ala、Leu、Gly、Ser和Thr,更优选地选自Ala、Leu和Gly。
根据一个实施方式,插入肽包含以下序列或由以下序列组成:AALGETTRPA(SEQ IDNO:10)、LALGETTRPA(SEQ ID NO:11)或GLGETTRPA(SEQ ID NO:12),优选地包含以下序列或由以下序列组成:AALGETTRPA(SEQ ID NO:10)或LALGETTRPA(SEQ ID NO:11)。
根据一个具体的实施方式,病毒载体,特别是AAV、AAV8、AAV2-7m8或AAV9-7m8,包含在视锥细胞特异性启动子(优选pR1.7或其功能性变体)或最小M-视蛋白启动子(特别是在pMNTC表达盒中)的控制下的感兴趣的多核苷酸(编码GIRK1 F137S或其功能性衍生物的核苷酸序列,和/或编码哺乳动物视锥细胞视蛋白的核苷酸序列)。在所述AAV中,与视锥细胞特异性启动子(例如,启动子pR1.7)、最小M-视蛋白启动子或pMNTC可操作地连接的感兴趣的多核苷酸优选侧翼有两个腺相关病毒反向末端重复序列(AAV ITR),优选AAV2 ITR。
pR1.7是基于《人类基因疗法》(Hum Gene Ther.2016Jan;27(1):72-82)2016年1月;27(1):72-82中描述的人红视蛋白启动子序列的1.7千碱基合成启动子。如本文所用,“pR1.7”表示序列SEQ ID NO:13的启动子及其功能性变体。pR7.1启动子的“功能性变体”相对于天然pR7.1启动子(SEQ ID NO:13)通常具有一个或多个核苷酸突变(例如,核苷酸缺失、添加和/或取代),这不会显著改变感兴趣的多核苷酸的转录。在本发明的上下文中,所述功能性变体保留驱动感兴趣的多核苷酸在视锥感光细胞中强表达的能力。这种能力可以如Ye等人(《人类基因疗法》2016年;27(1):72–82》(Hum Gene Ther.2016Jan;27(1):72-82))和Khabou等人(《JCI洞察力》2018年,3(2):e96029(JCI Insight.2018,3(2):e96029))所述进行测试。
可以使用的视锥细胞特异性启动子的另一个示例是最小M-视蛋白启动子区域,例如WO2015142941中公开的,特别是WO2015142941中公开的SEQ ID NO:55或SEQ ID NO:93中的最小M-视蛋白启动子区域。即时序列SEQ ID NO:14与WO2015142941的SEQ ID NO:93相同。
在一个实施方式中,将置于最小M-视蛋白启动子区域控制下的感兴趣的多核苷酸插入pMNTC表达盒中,该pMNTC表达盒包含优化的增强子、优化的启动子、优化的5’UTR、优化的内含子、优化的kozak和优化的polyA区域(WO2015142941的SEQ ID NO:95)。
启动子与感兴趣的多核苷酸可操作地连接。如本文所用,术语“可操作地连接”是指两个或更多个核酸或氨基酸序列元件以彼此具有功能关系的方式物理连接。例如,如果启动子能够启动或以其他方式控制/调节编码序列的转录和/或表达,则该启动子与编码序列可操作地连接,在这种情况下,该编码序列应被理解为处于该启动子的“控制下”。通常,当两个核酸序列可操作地连接时,它们将处于相同的定向,并且通常也在相同的阅读框中。它们通常也基本上是相接的,尽管这可能不是必需的。
根据一个实施方式,载体是AAV9(AAV9-7m8-pR1.7)或AAV2(AAV2-7m8-pR1.7),其包含:
-VP1衣壳蛋白,其中相对于野生型AAV9 VP1衣壳蛋白,在野生型AAV9 VP1衣壳蛋白的氨基酸588和589之间的位置,7至11个氨基酸长的插入肽被插入所述VP1衣壳蛋白的GH环中,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:7);和
-在pR1.7启动子的控制下的感兴趣的多核苷酸(编码GIRK1 F137S的核苷酸序列和/或编码哺乳动物视锥细胞视蛋白的核苷酸序列)。
在所述AAV9-7m8或AAV2-7m8中,插入肽的长度为7个氨基酸、8个氨基酸、9个氨基酸、10个氨基酸或11个氨基酸。优选地,插入肽在氨基酸序列LGETTRP(SEQ ID NO:7)的N末端和/或C末端包含一个或多个间隔子氨基酸。优选地,间隔子氨基酸选自Ala、Leu、Gly、Ser和Thr,更优选地选自Ala、Leu和Gly。根据一个实施方式,插入肽包含以下序列或由以下序列组成:AALGETTRPA(SEQ ID NO:10)、LALGETTRPA(SEQ ID NO:11)或GLGETTRPA(SEQ IDNO:12),优选地包含以下序列或由以下序列组成:AALGETTRPA(SEQ ID NO:10)或LALGETTRPA(SEQ ID NO:11)。
本发明的载体是使用本领域已知的方法产生的。简而言之,方法通常涉及(a)将AAV载体引入宿主细胞,(b)将AAV辅助构建体引入宿主细胞,其中辅助构建体包含AAV载体缺失的病毒功能,以及(c)将辅助病毒引入宿主细胞。AAV病毒粒子复制和包装的所有功能均需要具备,以实现AAV载体复制和包装到AAV病毒粒子中。可以使用标准病毒学技术同时或依次进行引入宿主细胞。最后,培养宿主细胞以产生AAV病毒粒子,并使用标准技术(例如碘克沙醇或CsCl梯度)或其他纯化方法进行纯化。纯化的AAV病毒粒子即可使用。
本发明的另一个目的是一种包含上述的编码GIRK1 F137S的核苷酸序列的核酸,其用作药物。具体地,所述核酸用于治疗视杆-视锥细胞营养不良(RCD)。换言之,本发明的另一个目的是一种治疗有需要的哺乳动物的RCD的方法,该方法包括向该哺乳动物施用包含上述的编码GIRK1 F137S的核苷酸序列的核酸。
在一个实施方式中,包含编码GIRK1 F137S的核苷酸序列的核酸包含编码序列SEQID NO:2的多肽的核苷酸序列或由其组成,或者包含核苷酸序列SEQ ID NO:3或由其组成。
包含编码GIRK1 F137S的核苷酸序列的核酸可以在选自腺相关病毒(AAV)、腺病毒、慢病毒和SV40病毒载体的载体中。
根据一个实施方式,包含编码GIRK1 F137S的核苷酸序列的核酸处于pR1.7启动子或所述启动子的功能性变体的控制下。
根据一个实施方式,包含编码GIRK1 F137S的核苷酸序列的核酸在载体中,该载体是在VP1衣壳蛋白的GH环中包含7至11个氨基酸长的插入肽的AAV2或AVV9病毒,其中该插入肽包含氨基酸序列LGETTRP(SEQ ID NO:7)。
优选地,载体是重组AAV2或AAV9载体,其包含:
-VP1衣壳蛋白,其中相对于野生型AAV9 VP1衣壳蛋白,在野生型AAV9 VP1衣壳蛋白的氨基酸588和589之间的位置,7至11个氨基酸长的插入肽被插入所述VP1衣壳蛋白的GH环中,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:7);和
-在pR1.7启动子的控制下的编码哺乳动物视锥细胞视蛋白的核苷酸序列。
根据一个实施方式,所述插入肽包含氨基酸序列AALGETTRPA(SEQ ID NO:8)、LALGETTRPA(SEQ ID NO:9)或GLGETTRPA(SEQ ID NO:10)或由氨基酸序列AALGETTRPA(SEQID NO:8)、LALGETTRPA(SEQ ID NO:9)或GLGETTRPA(SEQ ID NO:10)组成。
根据一个实施方式,包含编码GIRK1 F137S的核苷酸序列的核酸还包含编码哺乳动物视锥细胞视蛋白的序列,如上所述。
根据另一个实施方式,包含编码GIRK1 F137S的核苷酸序列的核酸与编码哺乳动物视锥细胞视蛋白的另一种核酸组合用于治疗RCD,如上所述。换言之,本发明的另一个目的是一种治疗有需要的哺乳动物的RCD的方法,该方法包括向该哺乳动物施用包含编码GIRK1 F137S的核苷酸序列的核酸和编码哺乳动物视锥细胞视蛋白的另一种核酸。因此,在所述方法中,核酸以单独的形式存在,并且可以被配制成单个药物组合物或单独的药物组合物。
在一个实施方式中,包含编码GIRK1 F137S的核苷酸序列的核酸包含来自质粒pAAV2-5’ITR-pR1.7-hGIRK-F137S-BGHpA-AAV2-3’ITR(具有如SEQ ID NO:16中所示的序列)、pAAV2-5’ITR-pR1.7-hGIRK-F137S-WPREmut6-BGHpA-AAV2-3’ITR(具有如SEQ ID NO:17中所示的序列)或pAAV2-5’ITR-pR1.7-hGIRK-F137S-WPREmut6deltaATG-BGHpA-AAV2-3’I TR(具有如SEQ ID NO:18所示的序列)的表达盒。
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本发明的另一个目的是一种药物组合物,其包含本发明的载体或药学上可接受的运载体以及药学上可接受的运载体、稀释剂或赋形剂。
本发明的另一个目的是一种本发明的载体、运载体或药物组合物,其用于治疗视杆-视锥细胞营养不良(RCD)。
视杆-视锥细胞营养不良(RCD)是一组异质性疾病,例如视网膜色素变性(RP),特别是非综合征性X连锁色素性视网膜炎(XLRP)、常染色体隐性RP、常染色体显性RP。RCD最常见的综合征形式包括Usher综合征(Usher syndrome)、巴尔得—别德尔综合征(Bardet-Biedl syndrome)、雷夫叙姆病(Refsum disease)、巴森-科茨威格综合征(Bassen-Kornzweig syndrome)和巴顿病(Batten disease)。
待治疗的RCD受试者是哺乳动物,特别是非人类或人类灵长类动物,优选人类。哺乳动物的RCD可能处于疾病的早期、中期或晚期。在处于疾病中期或晚期的RCD受试者中,只要患者的视锥细胞体中仍然表达视锥细胞视蛋白和视锥细胞抑制蛋白,则用编码GIRK1F137S的核苷酸序列转导受试者的视锥细胞将足以实现视觉恢复。在视锥细胞体不再表达视锥细胞视蛋白的RCD受试者中,需要用编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的核苷酸序列转导受试者的视锥细胞。
因此,RCD的治疗可以通过向哺乳动物施用本发明的载体、运载体或药物组合物来实施,从而实现用GIRK1 F137S转基因或GIRK1 F137S和哺乳动物视锥细胞视蛋白转基因转导视锥细胞。
换言之,本发明的另一个目的是一种治疗有需要的哺乳动物的RCD的方法,该方法包括向该哺乳动物施用有效量的本发明的药物组合物的载体或媒介物。
因此,在第一个实施方式中,包含编码GIRK1 F137S的核苷酸序列的载体、包含所述载体的运载体或包含所述载体或运载体的药物组合物用于治疗其视锥细胞仍表达内源性视锥细胞视蛋白的RCD哺乳动物受试者的视杆-视锥细胞营养不良。根据一个实施方式,载体还包含编码哺乳动物视锥细胞视蛋白的核苷酸序列。根据另一个实施方式,载体不包含编码哺乳动物视锥细胞视蛋白的核苷酸序列。根据一个实施方式,运载体还包含含有编码哺乳动物视锥细胞视蛋白的核苷酸序列的载体。根据另一个实施方式,运载体不包含含有编码哺乳动物视锥细胞视蛋白的核苷酸序列的载体。
在第二实施方式中,包含编码GIRK1 F137S的核苷酸序列的载体、包含所述载体的运载体或包含所述载体或运载体的药物组合物用于治疗其视锥细胞不再表达内源性视锥细胞视蛋白的RCD哺乳动物受试者的视杆-视锥细胞营养不良。根据该实施方式,载体还包含编码哺乳动物视锥细胞视蛋白的核苷酸序列,或者运载体还包含含有编码哺乳动物视锥细胞视蛋白的核苷酸序列的载体。
RCD的治疗也可以通过用本发明的载体、运载体或药物组合物转导哺乳动物视锥前体细胞,并将转导的哺乳动物视锥前体细胞施用至RCD哺乳动物的视网膜、特别是中央凹区域来实施。
换言之,本发明的另一个目的是一种治疗有需要的哺乳动物的RCD的方法,该方法包括向该哺乳动物施用有效量的用本发明的药物组合物的载体或运载体转导的哺乳动物视锥前体细胞。
本发明还涉及一种包含编码GIRK1 F137S或编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的异源核酸的视锥前体细胞,其用于治疗RCD的方法中。因此,本发明还提供了一种治疗有需要的哺乳动物的RCD的方法,该方法包括向哺乳动物施用包含编码GIRK1 F137S或编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的异源核酸的视锥前体细胞。如本文所用,术语“异源核酸”是指不在其自然环境中的基因、多核苷酸或核酸序列。
视锥前体细胞是未完全分化的非分裂细胞,致力于分化为视锥细胞。
在一个实施方式中,视锥前体细胞获自供体(例如尸体眼球供体)的视网膜或获自待治疗的RCD受试者,优选地获自待治疗的RCD受试者。在另一个实施方式中,视锥前体细胞获自干细胞,特别是胚胎干细胞、诱导性多能干细胞(iPS细胞)、成体干细胞或胎儿干细胞。在另一个实施方式中,视锥前体细胞获自分化的胚胎干细胞。根据一个实施方式,胚胎干细胞是非人胚胎干细胞。根据另一个实施方式,可以使用人胚胎干细胞,条件是该方法本身或任何相关行为不包括破坏人胚胎。优选地,视锥前体细胞通过待治疗的RCD受试者的干细胞的分化获得,优选地通过成体干细胞或诱导性多能干细胞的分化获得,更优选地通过获自体细胞(例如成纤维细胞)的诱导性多能干细胞的分化获得。
胚胎干细胞能够维持未分化状态,或者可以按照源自所有三个胚层(外胚层、内胚层和中胚层)的谱系定向成熟。如国际专利申请WO2018055131中所述,通过操纵关键的发育信号传导通路,可以将胚胎干细胞重新编程为视锥细胞。例如,除了激活素A和血清之外,还可以使用nodal和wnt途径的拮抗剂(Watanabe K等人,《自然-神经科学》2005年3月;8(3):288-96.),或者可以实施Notch信号传导通路的抑制(Osakada F等人,《自然-实验室指南》200;4(6):811-24)。可以使用本领域技术人员已知的任何方案从胚胎干细胞获得视锥前体细胞(Osakada F等人,《自然-生物技术》,2008年2月;26(2):215-24;Amirpour N等人,《干细胞与发育》2012年1月;21(l):42-53;Nakano T等人,《细胞·干细胞》2012年6月;10(6):771-85;Zhu Y等人,《公共科学图书馆:综合》25,2013年;8(l):e54552;Yanai A等人,《组织工程C部分方法》2013年10月;19(10):755-64;Kuwahara A等人,《自然-通讯》2015年2月19日;6:6286;Mellough CB等人,《干细胞》2015年8月;33(8):2416-30;Singh K等人,《干细胞与发育》2015年12月1日;24(23):2778-95(Osakada F et al.Nat Biotechnol.2008Feb;26(2):215-24;Amirpour N et al.Stem Cells Dev.2012Jan;21(l):42-53;Nakano T etal.Cell Stem Cell.2012Jun 14;10(6):771-85;Zhu Y et al.Plos One.25 2013;8(l):e54552;Yanai A et al.Tissue Eng Part C Methods.2013Oct;19(10):755-64;KuwaharaA et al.Nat Commun.2015Feb 19;6:6286;Mellough CB et al.Stem Cells.2015Aug;33(8):2416-30;Singh K et al.Stem Cells Dev.2015Dec l;24(23):2778-95))。
优选地,视锥前体细胞获自iPS细胞或成体干细胞,更优选地获自iPS细胞。诱导性多能干细胞(iPS cell)通过称为重新编程的过程从非多能细胞(通常是成体体细胞)衍生而来,其中只需引入少数特异性基因即可使细胞具有多能性(例如人体细胞中的OCT4、SOX2、KLF4和C-MYC)。使用iPS细胞的一个益处是完全避免使用胚胎细胞,从而避免任何伦理问题。感光细胞前体细胞可以使用本领域技术人员已知的任何分化方法从iPS细胞获得。
具体地,感光细胞前体细胞可以通过Garita Hernandez等人,2019年,《自然-通讯》10,4524(Garita-Hernandez et al.,2019,Nat Commun 10,4524)中公开的方法从人iPS细胞获得。人iPS在iPS培养基(例如Essential 8TM培养基,GIBCO,生命技术公司(LifeTechnologies))中扩增至汇合。80%汇合后,将培养基切换为原神经培养基(例如补充有1%N2补充剂的Essential 6TM培养基(100X);GIBCO,Life Technologies)。每2-3天更换培养基。分化4周后,神经视网膜样结构从培养物中生长出来,并进行机械分离。小心地除去产生RPE的着色部分。在成熟培养基(补充有2%B-27TM补充剂(50X)、无血清和1%MEM非必需氨基酸溶液(100X)的DMEM/F-12培养基;GIBCO,Life Technologies)中的扩展3D培养可以形成视网膜类器官。此时添加10ng/ml成纤维细胞生长因子2(FGF2,Preprotech)有利于视网膜类器官的生长以及向视网膜神经元而非RPE谱系的形成。为促进视网膜祖细胞向感光细胞的转化,从分化的第42天开始,使用γ分泌酶抑制剂DAPT(10μM,Selleckchem)特异性阻断Notch信号传导一周。漂浮的类器官在6孔板中培养(每孔10个类器官),每2天更换培养基。
感光细胞前体细胞也可以使用本领域技术人员已知的任何其他方案从人iPS细胞获得(Lamba、Osakada及其同事(Lamba等人,《美国国家科学院院刊》2006年8月22日;103(34):12769-74;Lamba等人,《公共科学图书馆:综合》2010年1月20日;5(l):e8763;Osakada等人,《自然实验室指南》2009年;4(6):811-24;Meyer JS等人,《美国国家科学院院刊》2009年9月29日;106(19):16698-703;Meyer JS等人,《干细胞》2011年8月;29(8):1206-18;Mellough CB等人,《干细胞》2012年4月;30(4):673-86;Boucherie C等人,《干细胞》2013年2月;31(2):408-14;Sridhar A等人,《干细胞转化医学》2013年;2(4):255-64;Tucker BA等人,《Elife》2013年8月27日,2:e00824;Tucker BA等人,《干细胞转化医学》2013年1月;2(1):16-24;eichman S等人,《美国国家科学院院刊》2014年6月10日;111(23):8518-23;Zhong X等人,《自然-通讯》2014年6月10日;5:4047;Wang X等人,《生物材料》2015年6月;53:40-9(Lamba,Osakada and colleagues(Lamba et al.Proc Natl Acad SciUSA.2006Aug22;103(34):12769-74;,Lamba et al.Plos one.2010Jan 20;5(l):e8763;Osakada et al.Nat.Protoc.2009;4(6):811-24;Meyer JS et al.Proc Natl Acad SciUSA.2009Sep 29;106(39):16698-703;Meyer JS et al.Stem Cells.2011Aug;29(8):1206-18;Mellough CB et al.Stem Cells.2012Apr;30(4):673-86;Boucherie C etal.Stem Cells.2013Feb;31(2):408-14;Sridhar A et al.Stem Cells TransIMed.2013;2(4):255-64;Tucker BA et al.Elife.2013Aug27,2:e00824;Tucker BA etal.Stem Cells TransI Med.2013Jan;2(1):16-24;eichman S et al.Proc Natl AcadSci USA.2014Jun 10;111(23):8518-23;Zhong X et al.Nat Commin.2014Jun 10;5:4047;Wang X et al.Biomaterials.2015Jun;53:40-9))。
视锥前体细胞包含编码i)GIRK1 F137S或ii)编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的异源核酸。当视锥前体细胞包含编码GIRK1F137S或其功能性衍生物和哺乳动物视锥细胞视蛋白的异源核酸时,视锥前体细胞包含i)编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的异源核酸,或ii)编码GIRK1的异源核酸,和编码哺乳动物视锥细胞视蛋白的另一种异源核酸。
所述视锥前体细胞可以通过本领域技术人员已知的任何方法将所述异源核酸或包含所述核酸的表达盒或载体引入所述视锥前体细胞中进行制备。根据一个实施方式,通过用上述病毒载体、特别是AAV载体、优选AAV8、AAV2-7m8或AAV9-7m8感染视锥前体细胞来制备包含编码GIRK1 F137Sf或编码GIRK1 F137S和哺乳动物视锥细胞视蛋白的异源核酸的视锥前体细胞。
因此,在另一个方面,本发明还涉及一种制备包含编码GIRK1 F137S或编码GIRK1F137S和哺乳动物视锥细胞视蛋白的异源核酸的视锥前体细胞的方法,所述方法包括用病毒载体或根据本发明的运载体感染视锥前体细胞,并回收受感染的视锥前体细胞。
该载体、运载体或药物组合物或视锥前体细胞可以通过本领域技术人员已知的任何合适的途径施用,特别是通过玻璃体内或视网膜下或脉络膜上施用。
在一个实施方式中,病毒载体、运载体或药物组合物以107至1015vg/眼、优选1011至1015vg/眼、甚至更优选1011至1013VG/眼的剂量注射。
在一个实施方式中,病毒载体、运载体或药物组合物通过玻璃体内注射施用。
在一个实施方式中,AAV载体是AAV2或AAV9或其修饰版本,例如AAV2-7m8或AAV9-7m8,并且所述载体通过玻璃体内注射施用。
在一个实施方式中,病毒载体、运载体或药物组合物通过视网膜下注射施用。
中央凹是灵长类动物视网膜中央的一个小区域,直径大约等于或小于0.5mm,仅含有视锥细胞,并且是整个视网膜中视锥细胞密度最高的区域。中央凹通过提供高敏锐度的色觉来主导灵长类动物的视觉感知。中央凹的中心(距中央凹中心<0.3mm)处视锥细胞密度最高,没有视杆感光细胞。随着与中央凹距离的增加,视锥细胞密度降低最多达100倍。
中央凹中的视锥细胞是旨在治疗视网膜色素变性等遗传性视网膜疾病的基因治疗的主要靶点。通常,编码治疗蛋白的病毒载体被“视网膜下”注射,即注射到感光细胞与视网膜色素上皮(RPE)细胞之间的视网膜下腔,以将基因递送至视锥细胞。
视网膜下递送导致“泡(bleb)”的形成,“泡”是指被注射眼的视网膜下腔内充满流体的袋。在这种方法中,基因递送仅限于接触注射流体的局部泡的细胞。视网膜下注射过程中发生的视网膜脱离、特别是中心凹脱离是视网膜退化的眼睛的一个问题。
有利地,当载体是AAV9-7m8载体(特别是AAV9-7m8-pR1.7载体)时,载体(或包含所述载体的药物组合物的运载体)可以通过远端视网膜下注射或者在中央凹外周施用然后横向扩散至中央凹区域来施用。根据一个实施方式,泡在距离中央凹中心大于或等于0.5mm处形成,而不会脱离中央凹区域。在一个实施方式中,将所述AAV9-7m8病毒载体配制在溶液中,并在20至30秒内连续注射50μL至100μL溶液。在一个实施方式中,所述AAV9-7m8病毒载体以1x1010 vg/mL至1x1012 vg/mL(病毒基因组/mL)、优选0.5x1011 vg/mL至5x1011 vg/mL、仍优选1x1011 vg/mL的浓度配制在溶液中。优选地,视锥前体细胞通过眼内注射、优选地通过视网膜下腔注射、更优选地通过在神经视网膜和上覆PE之间注射来施用。待施用的视锥前体细胞的量可以通过本领域普通技术人员熟知的标准程序来确定。必须考虑患者的生理数据(例如年龄、体型和体重)以及正在治疗的疾病的类型和严重程度,以确定适当的剂量。视锥前体细胞可以单剂量或多剂量施用。具体地,每个单位剂量可含有100,000至300,000个视锥前体细胞/μl,优选200,000至300,000个视锥前体细胞/μl。
附图的简要说明
图1表示光转导级联反应(A)正常光转导级联反应(B)具有动物视蛋白和GIRK2通道的短光转导级联反应。PDE:磷酸二酯酶。CNG:环核苷酸门控通道。cGMP:环磷酸鸟苷。
图2表示质粒(A)CMV-GIRK2-GFP和(B)CMV-SWO-mCherry。
图3表示使用用(A)视蛋白、(B)转导蛋白、(C)PDE和(D)视锥细胞抑制蛋白染色的对照WT小鼠的免疫组织化学(A-D)视网膜横截面的rd10小鼠中光转导级联反应中的残留物。(E-H)用(E)视蛋白、(F)转导蛋白、(G)PDE和(H)视锥细胞抑制蛋白染色的rd10小鼠在P14时的视网膜横截面。(I-L)用(I)视蛋白、(J)转导蛋白、(K)PDE和(L)视锥细胞抑制蛋白染色的rd10小鼠在P150时的视网膜横截面。ONL:外核层。INL:内核层。Gc:神经节细胞。比例尺为50μm。插入比例尺为25μm。
图4表示初步数据。(A)注射后一周rd10小鼠眼底GIRK2-GFP表达(*注射部位)(B)注射AAV-SWO-tdTomato和AAV-GIRK2-GFP的rd10小鼠在P33时的明视ERG振幅。对照小鼠注射AAV-GFP(n=12)。P=0,0002。(C)P33时的代表性闪烁ERG。(D)通过视动性眼震试验测量注射AAV-SWO-tdTomato和AAV-GIRK2-GFP的rd10小鼠的视觉敏锐度。对照小鼠注射AAV-GFP。对照小鼠注射AAV-GFP(n=8)。
图5表示GIRK2介导的视觉。(A)注射AAV-SWO-tdTomato和/或AAV-GIRK2-GFP的rd10小鼠在P41时的明视ERG振幅。对照小鼠注射AAV-GFP(n=12)。PSWO+GIRK2=0,0381和PGIRK2=0,0021。(B)通过视动性眼震试验测量注射AAV-SWO-tdTomato和/或AAV-GIRK2-GFP的rd10小鼠的视觉敏锐度。对照小鼠注射AAV-GFP。对照小鼠注射AAV-GFP(n=7)。(C)P41时的代表性闪烁ERG。
图6表示长期效力。(A)注射AAV-GIRK2-GFP的rd10小鼠的明视ERG振幅。对照小鼠注射PBS(n=6)。(B)通过视动性眼震试验测量注射AAV-GIRK2-GFP的rd10小鼠的视觉敏锐度。对照小鼠注射PBS(n=6)。(C)随着时间的推移,野生型小鼠和未注射的rd10小鼠(n=6)的视锥细胞数量。P值(P50-P365)=0.0022。(D)rd10小鼠(n=6)中ERG振幅与视锥细胞数量之间的线性回归相关性。P值未注射=0,0482。P值AAV-GIRK2-GFP=0,0007。P值PBS=0,0104。
图7表示使用免疫组织化学的huP347S+/-小鼠的光转导级联反应中的残留物。(A-D)用(A)视蛋白、(B)转导蛋白、(C)PDE和(D)视锥细胞抑制蛋白染色的对照WT小鼠的视网膜横截面。(E-H)用(E)视蛋白、(F)转导蛋白、(G)PDE和(H)视锥细胞抑制蛋白染色的huP347S+/-小鼠在P14时的视网膜横截面。(I-L)用(I)视蛋白、(J)转导蛋白、(K)PDE和(L)视锥细胞抑制蛋白染色的huP347S+/-小鼠在P150时的视网膜横截面。ONL:外核层。INL:内核层。Gc:神经节细胞。比例尺为50μm。插入比例尺为25μm。
图8表示方法的普遍性。(A)注射AAV-GIRK2-GFP的huP347S+/-小鼠中的明视ERG振幅。对照小鼠注射PBS(n=6)。(B)通过视动性眼震试验测量注射AAV-GIRK2-GFP的huP347S+/-小鼠的视觉敏锐度。对照小鼠注射PBS(n=6)。(C)随着时间的推移,野生型小鼠和未注射的huP347S+/-小鼠(n=6)的视锥细胞数量。P值(P50-P365)=0,0022。(D)huP347S+/-小鼠(n=5)中ERG振幅与视锥细胞数量之间的线性回归相关性。P值未注射=0,0313。P值AAV-GIRK2-GFP=0,0146。P值PBS=0,0497。
图9表示小鼠GIRK2在用两种质粒转染的HEK细胞中的效力:CMV-SWO-mCherry和CMV-GIRK2-GFP。
图10表示符合条件的患者群体的正常志愿者和视网膜色素变性患者的表型。上部图(A)示出正常个体眼睛后部的眼底和OCT图像,以及视网膜视锥细胞主导区域的自适应光学图像。中部图(B)示出晚期RCD患者的饼图分布。下部图表示不同患者的OCT和AOSLO图像。视网膜色素变性患者(77岁,男性)的AOSLO共焦(上)和AOSLO分割检测(下)体内视网膜图像。获取的视野位于假定休眠视锥细胞区域(即形态完整——如OCT中可见的IS/OS线、AOSLO分割检测中可见清晰内节镶嵌以及AOSLO共焦中显示完整内节和外节的清晰视锥细胞镶嵌所示——尽管根据患者的视觉敏锐度,功能有所减退;黄色条)与受损或缺失视锥细胞区域(分别由OCT中IS/OS线缺失以及AOSLO分割检测和共焦中模糊的内节和视锥细胞镶嵌所示;红色条)之间的过渡区域。黄色箭头表示似乎正在退化的视锥细胞,共焦中不存在OS,但在分割检测中存在IS。比例尺,200μm。
图11表示正常和RP人视网膜中的免疫组织化学标记视锥细胞光转导级联反应蛋白。(A)86岁对照人视网膜的视网膜横截面(20x)。(B)75岁受视网膜色素变性(RP)影响并患有夜盲症和周边视觉丧失的人视网膜的视网膜横截面(40x)。(A-B)用Opn1mw(亮)和核染剂DAPI(暗)染色。ONL:外核层。INL:内核层。Gc:神经节细胞。比例尺为50μm。插入比例尺为25μm。
图12示出HEK293细胞中mOpn4L的激活引发的GIRK1 F137S电流的表征。A)当用蓝光(471nm,在横坐标轴上曝光10秒至20秒)激活时,mOpn4L诱导强烈的GIRK1 F137S介导的电流,该电流在用石灰光(560nm,在横坐标轴上曝光20秒至60秒)刺激后结束,并导致B)通过HEK293膜的离子通量和C)单位电容的电流密度存在统计显著性差异。
图13示出了当用蓝光(471nm,在横坐标轴上曝光10秒至20秒)激活并在用石灰光(560nm,在横坐标轴上曝光20秒至60秒)刺激后终止时,HEK293细胞中mOpn4L的激活引发的GIRK1或GIRK2电流的表征。
图14示出了表达A1)hGIRK1F137S、B1)hGIRK2或C1)截短的rGIRK2的HEK293细胞的单位电容电流密度。示出了与c末端eGFP融合的构建体和未转染的细胞相比,由mOpn4的激活引发的电流响应。单个数据点显示了单个细胞的电流密度。条件之间的显著差异用*标记(采用所有成对多重比较程序(Dunn方法)的秩的Kruskal-Wallis单因素方差分析,P<0.05)。条件之间的显著差异用*标记(曼-惠特尼秩和检验;P=0.002)。当用蓝光激活时,mOpn4诱导GIRK介导的电流,该电流在用石灰光刺激后结束,如在A2)hGIRK1 F137S、B2)hGIRK2和C2)截短的rGIRK2 T构建体的示例性迹线中可见。
图15A)刺激表达mOpn4和hGIRK1 F137S、hGIRK1 F137S–eGFP或hGIRK2的HEK293细胞在全细胞膜片钳记录中产生可靠的可观察电流,而mOpn4激活后hGIRK2-eGFP、rGIRK2或rGIRK2-eGFP的电流不太可能被观察到。B)表达不同GIRK构建体(顶部)或其eGFP标记版本(底部)的HEK293细胞的单位电容电流密度。单个数据点显示了单个细胞的电流密度。条件之间的显著差异用*标记(采用所有成对多重比较程序(Dunn方法)的秩的Kruskal-Wallis单因素方差分析(Kruskal-Wallis One Way Analysis of Variance on Ranks with allpairwise multiple comparison procedures(Dunn's Method)),P<0.05)。
图16表示在P15时以5E7 vg/眼或5E8 vg/眼双侧视网膜下注射AAV8-pR1.7-hGIRK1F137S后的rd10小鼠与注射媒介物(Vehicle)的rd10小鼠或原始(naive)(未注射)rd10小鼠相比的视觉敏锐度。
图17表示质粒pAAV2-5’ITR-pR1.7-hGIRK-F137S-BGHpA-AAV2-3’ITR。
图18表示质粒pAAV2-5’ITR-pR1.7-hGIRK-F137S-WPREmut6-BGHpA-AAV2-3’ITR。
图19表示质粒pAAV2-5’ITR-pR1.7-hGIRK-F137S-WPREmut6deltaATG-BGHpA-AAV2-3’ITR。
实施例
实施例1:材料与方法
1.动物
C57BL/6jrd10/rd10(rd10)小鼠用于这些实验。它们的视杆细胞PDE基因发生突变,导致光转导级联反应功能障碍和视杆-视锥细胞营养不良。使用的第二个模型是huRhoP347S+/-小鼠。该小鼠的纯合链呈现出小鼠视紫红质(mRho)基因的KO和带有突变(P347S)的人视紫红质(huRho)的KI(Millington-Ward等人,2011年)[30]。将纯合雄性小鼠与C57BL/6j(野生型)雌性小鼠杂交以获得杂合小鼠。这些小鼠具有与rd10小鼠相似的表型,但退化率较低。
2.AAV注射
首先通过腹膜内注射在0.9%NaCl中稀释的0.2ml/20g氯胺酮(Ketamine 500,Vibrac France)和甲苯噻嗪(甲苯噻嗪2%,Rompun)对小鼠进行麻醉。用在0.9%NaCl中稀释的8%新福林(Neosynephrine)(Neosynephrine Faure 10%,Europhta)和42%托品酰胺(Mydriaticum)(托品酰胺0.5%,Thea)散瞳。
视网膜下注射总体积为1μl的载体溶液。Fradexam,一种眼膏,注射后使用。注射的病毒载体列表如下:
3.眼底检查
视网膜下注射一周后,小鼠通过吸入异氟烷进行麻醉。散瞳,然后用Lubrithal眼部凝胶(VetXX)保护眼睛。使用配备特定滤光片的眼底相机(Micron III;Phoenix研究实验室)进行眼底成像,以监测活体麻醉小鼠中的GFP或tdTomato表达。
4.视网膜电图(ERG)记录
为评估视网膜功能,记录视网膜电图记录(ERG)(espion E2 ERG系统;Diagnosys)。在注射病毒载体后的不同时间点进行了多项测试。通过腹膜内注射在0.9%NaCl中稀释的0.2ml/20g氯胺酮(Ketamine 500,Vibrac France)和甲苯噻嗪(甲苯噻嗪2%,Rompun)对小鼠进行麻醉。然后将小鼠置于37℃的加热垫上。用在0.9%NaCl中稀释的新福林(Neosynephrine)(Neosynephrine Faure 10%,Europhta)和托品酰胺(Mydriaticum)(托品酰胺0.5%,Thea)散瞳。在将电极放在每只眼睛的角膜表面之前,用Lubrithal眼部凝胶保护眼睛。将参比电极插入前额皮下,将接地电极插入背部皮下。
ERG记录在两种条件下进行:(I)明视条件,其反映视锥细胞驱动的光响应——在20cd s/m下适应5分钟后,在60秒内以增加的光强度(0.1/1/10/50cd s/m)每秒施加6ms光闪——和(ii)闪烁条件,这是反映视锥细胞功能的快速频率光刺激(10Hz和1cd s/m下70次闪烁)。
使用GraphPad进行图表和统计分析。
5.视动性眼震试验
使用视动性眼震试验测量视觉敏锐度,该试验对置于移动杆前面的小鼠的转头运动进行评分。测试使用基于计算机的机器进行,该机器由四台排列成正方形的计算机显示器组成,以形成视动室。指定计算机程序来生成由移动的交替黑白条纹组成的视动刺激。空间频率范围为0.03cyc/deg至0.6cyc/deg。该程序能够调节条纹宽度和杆移动方向。
6.免疫组织化学和共焦成像
通过CO2吸入处死动物,摘除眼睛并在4%多聚甲醛-PBS中于室温下固定1小时。将眼睛解剖为用于免疫组织化学的眼杯或制备为用于细胞计数的扁平装片。然后用10%PBS-蔗糖梯度冷冻保护眼杯1小时,然后在30%PBS-蔗糖中冷冻保护过夜。将眼杯嵌入OCT中,然后切割12μm厚的低温恒温器切片(ThermoFisher)并安装在载玻片上。将切片在PBS中洗涤(3x5分钟),并针对不同的抗体(见下表)和DAPI(1:2000)进行染色。最后将切片在PBS中洗涤,安装在Fluoromount Vactashield(Vector Laboratories)中,盖上盖玻片,使用激光共聚焦显微镜(Olympus(奥林巴斯)IX81)成像。对于扁平装片视网膜染色,方案是相同的,只是组织没有经过冷冻保护。使用FIJI软件分析图像。
7.细胞计数
使用抗小鼠视锥细胞抑制蛋白的抗体——mCAR(1:10000)和DAPI(1:2000)对rd10和huRhoP347S+/-小鼠的扁平装片视网膜进行染色。对不同年龄的双染细胞进行计数。每个年龄使用5只动物(n=10)的视网膜,并将其进行背腹和鼻颞定向。获得连续光学切片以覆盖整个外核层(ONL)的厚度。在所有视网膜的四个区域中,每个区域都有两个211.97x211.97μm的扫描区域。使用FIJI软件通过重构覆盖ONL整个厚度的图像(z堆栈)手动进行视锥细胞计数。计算每个视网膜的平均密度值,以获得不同年龄每平方毫米视锥细胞的数量。
8.小鼠GIRK2效力的体外测试
根据本领域熟知的程序,用两种质粒转染HEK细胞:CMV-SWO-mCherry和CMV-GIRK2-GFP(图2)。HEK293细胞转染后在暗室条件下培养并记录。将细胞置于配备25x水浸物镜(XLPlanN-25×-W-MP/NA1.05,Olympus)的显微镜记录室中,温度为36℃,在添加1mM9-顺式视黄醛的富集含氧(95%O2/5%CO2)的Ames培养基中(Sigma-Aldrich)。将KGluconate添加到外部溶液中以获得高细胞外钾浓度,从而使细胞钾反转电位为-40mV。
对于全细胞记录,使用Axon Multiclamp 700B放大器(Molecular DeviceCellular Neurosciences),使用硼硅酸盐玻璃移液器(BF100-50-10,Sutter Instrument)在-80mV的电压钳配置中记录GIRK介导的K+-电流,该移液器被拉至5MΩ,并填充115mMK葡萄糖酸盐、10mM KCl、1mM MgCl2、0.5mM CaCl2、1.5mM EGTA、10mM HEPES和4mM ATP-Na2(pH7.2)。
在实验过程中,使用CCD相机(Hamamatsu Corp.(滨松光子学株式会社))通过透射式照明的红外光来观察细胞。在电生理学实验中,使用单色光源(Polychrome V,TILLphotonics)用400nm的闪光刺激细胞。
9.患者眼底成像
自适应光学扫描激光检眼镜(AOSLO)(Roorda等人,《光学快讯》2002年(Roorda etal Opt Exp 2002))用于以细胞分辨率对视锥感光细胞镶嵌进行成像。所用的AOSLO设备(MAORI,PSI,安多佛,马萨诸塞州,美国)可以在完整视锥细胞的2度视场上同时成像,包括来自沿光轴散射的光的内节和外节(IS,OS)(共焦模式)以及来自离轴散射的多重散射光的内节(IS)(分割检测模式)。这使得能够通过每个视锥细胞的IS与IS+OS的差异成像来评估视锥细胞的存在和健康状况。
实施例2:结果
1.退化视锥细胞中光转导级联反应的变化
首先在视网膜退化过程中的不同时间点,通过使用免疫组织化学研究其成分,在rd10小鼠模型中分析光转导级联反应。对直接与视锥细胞视蛋白相互作用的光转导级联反应的视锥细胞视蛋白、转导蛋白、磷酸二酯酶和视锥细胞抑制蛋白进行免疫荧光染色。
图3显示,在疾病晚期,只有视锥细胞视蛋白和抑制蛋白仍然在视锥细胞体周围表达并定位。
2.视锥细胞视蛋白和GIRK2介导的视觉恢复
基于免疫组织化学和先前对神经元中表达的视锥细胞视蛋白的研究结果,首先研究了为什么使用以等摩尔比混合的两种AAV载体传递与tdTomato融合的小鼠短波长视锥细胞视蛋白(SWO)和与GFP融合的大鼠截短的GIRK2会增强视锥细胞对光的响应。因此,在p15时将两种AAV视网膜下注射到退化的rd10小鼠视网膜中(图4A)。与对照相比,这使得经治疗眼睛的明视ERG振幅显著增加(图4B)。闪烁ERG证实,在这些表达GIRK2的视锥细胞中,恢复机制仍然活跃,使它们能够遵循快速刺激(图4C)。与对照相比,接受GIRK2治疗的rd10动物的视动反射也有所改善(图4D)。
接下来,研究了在该小鼠模型中仍然存在于退化视锥细胞中的内源性视锥细胞视蛋白是否具有功能并足以激活GIRK2通道。为此,提供了编码与GFP融合的GIRK2的单个AAV8载体。与对照相比,这使得经治疗眼睛的明视ERG振幅和视动反射出现类似的增加,证实GIRK2本身足以通过涉及视锥细胞视蛋白的G蛋白耦联信号传导来增加光敏感性(图5A-B)。通过这种方法,闪烁ERG也得到有力的放大(图5C)。
3.GIRK2介导的视觉恢复:长期效力
在接受GIRK2治疗后和未治疗的不同时间点进行明视ERG记录,以监测视锥细胞对光刺激的响应。这些ERG是在两种条件下进行的:(i)明视,在60秒内以增加的光强度每秒施加光闪,和(ii)闪烁刺激,在60秒内进行重复闪光。每周收集一次数据,直至p50,然后每10天至13天收集一次数据,直至11周龄,结果显示对照和经治疗眼睛的ERG振幅均逐渐减小(图6A)。此外,这些结果与视动性眼震试验一致,对照和接受GIRK2治疗的眼睛均显示出随着时间的推移视动反射减弱(图6B)。这种减弱是预料之中的,因为rd10小鼠的视锥细胞数量也随着时间的推移而减少(图6C)。对rd10视网膜中剩余的视锥细胞数量进行计数,以将视锥细胞数量的减少与ERG振幅的减小相关联。事实上,光响应的减少与剩余感光细胞的数量成正比(图6D)。因此得出结论,只要视锥细胞仍然存活,GIRK2就会增加剩余视锥细胞的光响应,但正如预期的那样,其并没有减缓视锥细胞的丧失。
4.突变视紫红质引起的RCD模型中GIRK2介导的视觉恢复
考虑到创建一种与突变无关的疗法的目标,在另一种具有不同致病突变的小鼠模型中对该方法进行了测试。为此,在名为mRho-/-huRhoP347S+/-的杂合小鼠模型中进行了实验,该模型携带P347S突变人视紫红质敲入。突变的人视紫红质和小鼠视紫红质的缺失导致了该互补模型中的视杆-视锥细胞营养不良。此处,重复与在rd10小鼠模型中所做的相同的一组实验。首先,分析了不同时间点与视锥细胞视蛋白相互作用的光转导级联反应蛋白(图7)。注意到:(i)与rd10相比,退化速度较慢;(ii)与rd10模型相似,只有视蛋白和抑制蛋白在P150时持续存在于视锥细胞体中。
接下来,在P15时给小鼠注射编码与GFP融合的GIRK2的相同AAV载体,并记录ERG以监测不同时间点视锥细胞对光刺激的响应(图8A)。直至P100,经治疗眼睛的响应幅度显著高于对照眼睛。此外,在该小鼠模型中,闪烁ERG响应也得到了类似的改善。与rd10小鼠类似,该小鼠模型也显示出改善的视动反射,在对照组和治疗组中,视动反射均会随着时间的推移而减弱(图8B)。这种减弱是预料之中的,因为该RCD小鼠模型中的视锥细胞数量也随着时间的推移而减少(图8C)。在该模型中,ERG振幅时间的减少也与视锥细胞数量的减少相关(图8D)。这再次与该方法无法阻止退化但可以通过GIRK2增强光敏感性的事实一致。
5.小鼠GIRK2在体外测试中的效力
光刺激(400nm,5秒,全场)激活表达GIRK和SWO(短波长视蛋白)的HEK细胞中的GIRK电流(图9)。GIRK通道通过Gi/o途径以膜分隔的快速方式进行调节,并且小鼠GIRK通道的表达是膜结合的。在5s光脉冲期间,光诱导的具有SWO的GIRK通道的激活和失活的幅度和动力学诱导了较大的GILK电流幅度。
实施例3:在蓝光(471nm)刺激下,GIRK1 F137S比GIRK2引发更强的电流
将稳定表达小鼠Opn4L-mCherry的人胚肾293(HEK293)于37℃下维持在达尔伯克改良伊格尔培养基(Dulbecco’s modified Eagle’s medium,DMEM)中,4.5g/l D-葡萄糖、补充有10%胎牛血清(Gibco)和青霉素/链霉素,在5%CO2的加湿培养箱中。根据制造商的方案,用HD(Promega)转染HEK293细胞,并在记录前孵育18-24小时。添加视黄醛至1μM的最终培养基浓度。
对于GIRK通道记录,GIRK构建体在稳定表达Opn4L-mCherry的HEK293细胞中表达。转染后在暗室条件下培养和记录细胞。如下所述测量和分析GIRK介导的K电流。外部溶液如下:20mM NaCl、120mM KCl、2mM CaCl2、1mM MgCl2、10mM HEPES-KOH,pH 7.3(KOH)。贴片移液器(2–5MΩ)充满内部溶液:100mM天冬氨酸钾、40mM KCl、5mM MgATP、10mM HEPES-KOH、5mMNaCl、2mM EGTA、2mM MgCl2、0.01mM GTP,pH 7.3(KOH)。在含有1μM 9-反式视黄醛(Sigma)的外部溶液中记录细胞。在实验操作过程中,使用透射式照明的红光(590nm)或绿光滤光片(480nm)观察细胞。使用EPC10放大器(HEKA)进行HEK293细胞的全细胞膜片钳记录。通过EPC10放大器的内部10kHz三极点贝塞尔滤波器(滤波器1)与2.9kHz四极点贝塞尔滤波器(滤波器2)串联对电流进行数字化和滤波。串联电阻得到70%至90%部分补偿。
为分析和比较GIRK电流,HEK293细胞的电压钳位在-60mV。为测定基线电流,在施加光之前施加-100到+50mV的500ms长的电压斜坡。然后在-60mV下施加471nm的10秒光脉冲。GIRK电流的大小与光激活前后细胞的电导有关。
为分析不同GIRK电流之间G蛋白调制和脱敏效率可能存在的差异,应用0.1秒至60秒的光脉冲,并如出版物中所述改变光的强度(ickelbeck,D.等人,《通讯-生物学》2,(2019年);Spoida,K.等人,黑视素《当代生物学》26,1206–1212(2016年);Masseck,O.a.O.A.等人,《神经元》81,1263–1273(2014年)(Eickelbeck,D.et al.Commun.Biol.2,(2019);Spoida,K.et al.Melanopsin Curr.Biol.26,1206–1212(2016);Masseck,O.a.O.A.etal.Neuron 81,1263–1273(2014))。
从图12和图13的比较中可以看出,在HEK细胞中短GIRK/视蛋白光转导级联反应的情况下,GIRK1 F137S比截短的大鼠GIRK2诱导显著更多的离子流出(约高17倍),而野生型GIRK1则不能有效地诱导离子流出。这一结果表明,与GIRK2基因治疗RCD相比,在视锥细胞中加入GIRK1F137S将提供改进的基因治疗。
图14和图15还证实,与人或大鼠GIRK2(有或没有GFP标签)相比,GIRK1 F137S(有或没有GFP标签)诱导显著的离子流出。
实施例4:突变视紫红质引起的RCD模型中GIRK1 F137S视觉恢复
使用与实施例2.2中相同的实验模型,以证明如通过视动性眼震试验所确定的,rd10小鼠眼睛中AAV介导的人GIRK1 F137S的表达在P37时提高了视觉敏锐度。结果如图16所示。P15 rd10/rd10小鼠接受AAV8-PR1.7-hGIRK1 F137S的视网膜下注射,剂量为5e8vg/眼或5e7vg/眼。在P30和P37时,进行OKT测量以评估视觉功能。在P37时,以5e8vg/眼施用3周后,观察到显著的视觉改善。
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SEQUENCE LISTING
<110> 节约视觉公司
波鸿鲁尔大学
法国国家健康与医学研究院
法国国家科学研究中心
索邦大学
<120> G蛋白门控的K+通道介导的视杆-视锥细胞营养不良(RCD)中光敏感性的增强
<130> BET 21P0381
<160> 18
<170> PatentIn version 3.5
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<213> 智人(Homo sapiens)
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Thr Ser Ser Ser Gly Ser Gly Leu Gln Pro Gln Gly Pro Gly Gln Asp
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Pro Gln Gln Gln Leu Val Pro Lys Lys Lys Arg Gln Arg Phe Val Asp
35 40 45
Lys Asn Gly Arg Cys Asn Val Gln His Gly Asn Leu Gly Ser Glu Thr
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Ser Arg Tyr Leu Ser Asp Leu Phe Thr Thr Leu Val Asp Leu Lys Trp
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Arg Trp Asn Leu Phe Ile Phe Ile Leu Thr Tyr Thr Val Ala Trp Leu
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Phe Met Ala Ser Met Trp Trp Val Ile Ala Tyr Thr Arg Gly Asp Leu
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Asn Lys Ala His Val Gly Asn Tyr Thr Pro Cys Val Ala Asn Val Tyr
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Asn Phe Pro Ser Ala Phe Leu Phe Phe Ile Glu Thr Glu Ala Thr Ile
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Gly Tyr Gly Tyr Arg Tyr Ile Thr Asp Lys Cys Pro Glu Gly Ile Ile
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Leu Phe Leu Phe Gln Ser Ile Leu Gly Ser Ile Val Asp Ala Phe Leu
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Ile Gly Cys Met Phe Ile Lys Met Ser Gln Pro Lys Lys Arg Ala Glu
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Leu Thr Leu Met Phe Arg Val Gly Asn Leu Arg Asn Ser His Met Val
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Ser Ala Gln Ile Arg Cys Lys Leu Leu Lys Ser Arg Gln Thr Pro Glu
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Gly Glu Phe Leu Pro Leu Asp Gln Leu Glu Leu Asp Val Gly Phe Ser
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35 40 45
Lys Asn Gly Arg Cys Asn Val Gln His Gly Asn Leu Gly Ser Glu Thr
50 55 60
Ser Arg Tyr Leu Ser Asp Leu Phe Thr Thr Leu Val Asp Leu Lys Trp
65 70 75 80
Arg Trp Asn Leu Phe Ile Phe Ile Leu Thr Tyr Thr Val Ala Trp Leu
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Phe Met Ala Ser Met Trp Trp Val Ile Ala Tyr Thr Arg Gly Asp Leu
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Asn Lys Ala His Val Gly Asn Tyr Thr Pro Cys Val Ala Asn Val Tyr
115 120 125
Asn Phe Pro Ser Ala Phe Leu Phe Ser Ile Glu Thr Glu Ala Thr Ile
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Leu Phe Leu Phe Gln Ser Ile Leu Gly Ser Ile Val Asp Ala Phe Leu
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Ile Gly Cys Met Phe Ile Lys Met Ser Gln Pro Lys Lys Arg Ala Glu
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Thr Leu Met Phe Ser Glu His Ala Val Ile Ser Met Arg Asp Gly Lys
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Leu Thr Leu Met Phe Arg Val Gly Asn Leu Arg Asn Ser His Met Val
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Ser Ala Gln Ile Arg Cys Lys Leu Leu Lys Ser Arg Gln Thr Pro Glu
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Gly Glu Phe Leu Pro Leu Asp Gln Leu Glu Leu Asp Val Gly Phe Ser
245 250 255
Thr Gly Ala Asp Gln Leu Phe Leu Val Ser Pro Leu Thr Ile Cys His
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Val Ile Asp Ala Lys Ser Pro Phe Tyr Asp Leu Ser Gln Arg Ser Met
275 280 285
Gln Thr Glu Gln Phe Glu Ile Val Val Ile Leu Glu Gly Ile Val Glu
290 295 300
Thr Thr Gly Met Thr Cys Gln Ala Arg Thr Ser Tyr Thr Glu Asp Glu
305 310 315 320
Val Leu Trp Gly His Arg Phe Phe Pro Val Ile Ser Leu Glu Glu Gly
325 330 335
Phe Phe Lys Val Asp Tyr Ser Gln Phe His Ala Thr Phe Glu Val Pro
340 345 350
Thr Pro Pro Tyr Ser Val Lys Glu Gln Glu Glu Met Leu Leu Met Ser
355 360 365
Ser Pro Leu Ile Ala Pro Ala Ile Thr Asn Ser Lys Glu Arg His Asn
370 375 380
Ser Val Glu Cys Leu Asp Gly Leu Asp Asp Ile Thr Thr Lys Leu Pro
385 390 395 400
Ser Lys Leu Gln Lys Ile Thr Gly Arg Glu Asp Phe Pro Lys Lys Leu
405 410 415
Leu Arg Met Ser Ser Thr Thr Ser Glu Lys Ala Tyr Ser Leu Gly Asp
420 425 430
Leu Pro Met Lys Leu Gln Arg Ile Ser Ser Val Pro Gly Asn Ser Glu
435 440 445
Glu Lys Leu Val Ser Lys Thr Thr Lys Met Leu Ser Asp Pro Met Ser
450 455 460
Gln Ser Val Ala Asp Leu Pro Pro Lys Leu Gln Lys Met Ala Gly Gly
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Ala Ala Arg Met Glu Gly Asn Leu Pro Ala Lys Leu Arg Lys Met Asn
485 490 495
Ser Asp Arg Phe Thr
500
<210> 3
<211> 1503
<212> DNA
<213> 智人(Homo sapiens)
<400> 3
atgagcgccc tgagaagaaa gttcggcgac gactaccagg tggtcaccac aagcagctct 60
ggctctggac tgcagcctca aggacctgga caggatcctc agcagcagct ggtgcccaag 120
aagaaacggc agagattcgt ggacaagaac ggccggtgca atgtgcagca cggcaatctg 180
ggcagcgaga caagcagata cctgagcgac ctgttcacca cactggtgga cctgaagtgg 240
cggtggaacc tgttcatctt catcctgacc tacaccgtgg cctggctgtt catggccagc 300
atgtggtggg ttatcgccta caccagaggc gacctgaaca aggcccatgt gggcaactac 360
accccttgcg tggccaacgt gtacaacttc cctagcgcct tcctgttcag catcgagaca 420
gaggccacaa tcggctacgg ctaccggtac atcaccgaca agtgccccga gggaattatc 480
ctgttcctgt tccagtccat cctgggctct atcgtggatg ccttcctgat cggctgcatg 540
ttcatcaaga tgagccagcc taagaagcgg gccgagacac tgatgtttag cgagcacgcc 600
gtgatcagca tgcgcgacgg aaaactgacc ctgatgttca gagtgggcaa cctgcggaac 660
agccacatgg tgtcagccca gatcagatgc aagctgctga agtccagaca gacccctgag 720
ggcgagttcc tgcctctgga tcagctggaa ctggacgtgg gctttagcac aggcgccgat 780
cagctgtttc tggtgtcccc tctgaccatc tgccacgtga tcgacgctaa gagccccttc 840
tacgatctga gccagcggag catgcagacc gagcagtttg agatcgtggt catcctggaa 900
ggcattgtgg aaaccaccgg catgacctgc caggccagaa ccagctacac agaggatgag 960
gtgctgtggg gccacagatt cttccccgtg atctctctgg aagagggctt cttcaaggtg 1020
gactacagcc agttccacgc cacctttgag gtgcccacac ctccttacag cgtgaaagaa 1080
caagaggaaa tgctgctgat gagcagccct ctgatcgccc ctgccatcac caacagcaaa 1140
gaacggcaca acagcgtgga atgcctggac ggcctggatg acatcaccac caagctgcct 1200
tccaagctgc agaagatcac cggcagagag gacttcccca agaaactgct gagaatgagc 1260
agcaccacca gcgagaaggc ctactctctg ggcgacctgc ctatgaagct gcagcggatc 1320
tctagcgtgc ccggcaactc tgaggaaaag ctggtttcca agaccaccaa gatgctgagc 1380
gatcccatga gccagtccgt ggctgatctg ccacctaaac tgcagaaaat ggctggcgga 1440
gccgccagaa tggaaggcaa tctgcctgcc aaactgcgca agatgaactc cgaccggttc 1500
acc 1503
<210> 4
<211> 501
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 4
Met Ser Ala Leu Arg Arg Lys Phe Gly Asp Asp Tyr Gln Val Val Thr
1 5 10 15
Thr Ser Ser Ser Gly Ser Gly Leu Gln Pro Gln Gly Pro Gly Gln Gly
20 25 30
Pro Gln Gln Gln Leu Val Pro Lys Lys Lys Arg Gln Arg Phe Val Asp
35 40 45
Lys Asn Gly Arg Cys Asn Val Gln His Gly Asn Leu Gly Ser Glu Thr
50 55 60
Ser Arg Tyr Leu Ser Asp Leu Phe Thr Thr Leu Val Asp Leu Lys Trp
65 70 75 80
Arg Trp Asn Leu Phe Ile Phe Ile Leu Thr Tyr Thr Val Ala Trp Leu
85 90 95
Phe Met Ala Ser Met Trp Trp Val Ile Ala Tyr Thr Arg Gly Asp Leu
100 105 110
Asn Lys Ala His Val Gly Asn Tyr Thr Pro Cys Val Ala Asn Val Tyr
115 120 125
Asn Phe Pro Ser Ala Phe Leu Phe Phe Ile Glu Thr Glu Ala Thr Ile
130 135 140
Gly Tyr Gly Tyr Arg Tyr Ile Thr Asp Lys Cys Pro Glu Gly Ile Ile
145 150 155 160
Leu Phe Leu Phe Gln Ser Ile Leu Gly Ser Ile Val Asp Ala Phe Leu
165 170 175
Ile Gly Cys Met Phe Ile Lys Met Ser Gln Pro Lys Lys Arg Ala Glu
180 185 190
Thr Leu Met Phe Ser Glu His Ala Val Ile Ser Met Arg Asp Gly Lys
195 200 205
Leu Thr Leu Met Phe Arg Val Gly Asn Leu Arg Asn Ser His Met Val
210 215 220
Ser Ala Gln Ile Arg Cys Lys Leu Leu Lys Ser Arg Gln Thr Pro Glu
225 230 235 240
Gly Glu Phe Leu Pro Leu Asp Gln Leu Glu Leu Asp Val Gly Phe Ser
245 250 255
Thr Gly Ala Asp Gln Leu Phe Leu Val Ser Pro Leu Thr Ile Cys His
260 265 270
Val Ile Asp Ala Lys Ser Pro Phe Tyr Asp Leu Ser Gln Arg Ser Met
275 280 285
Gln Thr Glu Gln Phe Glu Val Val Val Ile Leu Glu Gly Ile Val Glu
290 295 300
Thr Thr Gly Met Thr Cys Gln Ala Arg Thr Ser Tyr Thr Glu Asp Glu
305 310 315 320
Val Leu Trp Gly His Arg Phe Phe Pro Val Ile Ser Leu Glu Glu Gly
325 330 335
Phe Phe Lys Val Asp Tyr Ser Gln Phe His Ala Thr Phe Glu Val Pro
340 345 350
Thr Pro Pro Tyr Ser Val Lys Glu Gln Glu Glu Met Leu Leu Met Ser
355 360 365
Ser Pro Leu Ile Ala Pro Ala Ile Thr Asn Ser Lys Glu Arg His Asn
370 375 380
Ser Val Glu Cys Leu Asp Gly Leu Asp Asp Ile Ser Thr Lys Leu Pro
385 390 395 400
Ser Lys Leu Gln Lys Ile Thr Gly Arg Glu Asp Phe Pro Lys Lys Leu
405 410 415
Leu Arg Met Ser Ser Thr Thr Ser Glu Lys Ala Tyr Ser Leu Gly Asp
420 425 430
Leu Pro Met Lys Leu Gln Arg Ile Ser Ser Val Pro Gly Asn Ser Glu
435 440 445
Glu Lys Leu Val Ser Lys Thr Thr Lys Met Leu Ser Asp Pro Met Ser
450 455 460
Gln Ser Val Ala Asp Leu Pro Pro Lys Leu Gln Lys Met Ala Gly Gly
465 470 475 480
Pro Thr Arg Met Glu Gly Asn Leu Pro Ala Lys Leu Arg Lys Met Asn
485 490 495
Ser Asp Arg Phe Thr
500
<210> 5
<211> 501
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 5
Met Ser Ala Leu Arg Arg Lys Phe Gly Asp Asp Tyr Gln Val Val Thr
1 5 10 15
Thr Ser Ser Ser Gly Ser Gly Leu Gln Pro Gln Gly Pro Gly Gln Gly
20 25 30
Pro Gln Gln Gln Leu Val Pro Lys Lys Lys Arg Gln Arg Phe Val Asp
35 40 45
Lys Asn Gly Arg Cys Asn Val Gln His Gly Asn Leu Gly Ser Glu Thr
50 55 60
Ser Arg Tyr Leu Ser Asp Leu Phe Thr Thr Leu Val Asp Leu Lys Trp
65 70 75 80
Arg Trp Asn Leu Phe Ile Phe Ile Leu Thr Tyr Thr Val Ala Trp Leu
85 90 95
Phe Met Ala Ser Met Trp Trp Val Ile Ala Tyr Thr Arg Gly Asp Leu
100 105 110
Asn Lys Ala His Val Gly Asn Tyr Thr Pro Cys Val Ala Asn Val Tyr
115 120 125
Asn Phe Pro Ser Ala Phe Leu Phe Ser Ile Glu Thr Glu Ala Thr Ile
130 135 140
Gly Tyr Gly Tyr Arg Tyr Ile Thr Asp Lys Cys Pro Glu Gly Ile Ile
145 150 155 160
Leu Phe Leu Phe Gln Ser Ile Leu Gly Ser Ile Val Asp Ala Phe Leu
165 170 175
Ile Gly Cys Met Phe Ile Lys Met Ser Gln Pro Lys Lys Arg Ala Glu
180 185 190
Thr Leu Met Phe Ser Glu His Ala Val Ile Ser Met Arg Asp Gly Lys
195 200 205
Leu Thr Leu Met Phe Arg Val Gly Asn Leu Arg Asn Ser His Met Val
210 215 220
Ser Ala Gln Ile Arg Cys Lys Leu Leu Lys Ser Arg Gln Thr Pro Glu
225 230 235 240
Gly Glu Phe Leu Pro Leu Asp Gln Leu Glu Leu Asp Val Gly Phe Ser
245 250 255
Thr Gly Ala Asp Gln Leu Phe Leu Val Ser Pro Leu Thr Ile Cys His
260 265 270
Val Ile Asp Ala Lys Ser Pro Phe Tyr Asp Leu Ser Gln Arg Ser Met
275 280 285
Gln Thr Glu Gln Phe Glu Val Val Val Ile Leu Glu Gly Ile Val Glu
290 295 300
Thr Thr Gly Met Thr Cys Gln Ala Arg Thr Ser Tyr Thr Glu Asp Glu
305 310 315 320
Val Leu Trp Gly His Arg Phe Phe Pro Val Ile Ser Leu Glu Glu Gly
325 330 335
Phe Phe Lys Val Asp Tyr Ser Gln Phe His Ala Thr Phe Glu Val Pro
340 345 350
Thr Pro Pro Tyr Ser Val Lys Glu Gln Glu Glu Met Leu Leu Met Ser
355 360 365
Ser Pro Leu Ile Ala Pro Ala Ile Thr Asn Ser Lys Glu Arg His Asn
370 375 380
Ser Val Glu Cys Leu Asp Gly Leu Asp Asp Ile Ser Thr Lys Leu Pro
385 390 395 400
Ser Lys Leu Gln Lys Ile Thr Gly Arg Glu Asp Phe Pro Lys Lys Leu
405 410 415
Leu Arg Met Ser Ser Thr Thr Ser Glu Lys Ala Tyr Ser Leu Gly Asp
420 425 430
Leu Pro Met Lys Leu Gln Arg Ile Ser Ser Val Pro Gly Asn Ser Glu
435 440 445
Glu Lys Leu Val Ser Lys Thr Thr Lys Met Leu Ser Asp Pro Met Ser
450 455 460
Gln Ser Val Ala Asp Leu Pro Pro Lys Leu Gln Lys Met Ala Gly Gly
465 470 475 480
Pro Thr Arg Met Glu Gly Asn Leu Pro Ala Lys Leu Arg Lys Met Asn
485 490 495
Ser Asp Arg Phe Thr
500
<210> 6
<211> 410
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Met Val Leu Lys Ala Glu His Thr Arg Ser Pro Ser Ala Thr Leu Pro
1 5 10 15
Ser Asn Val Pro Ser Cys Arg Ser Leu Ser Ser Ser Glu Asp Gly Pro
20 25 30
Ser Gly Pro Ser Ser Leu Ala Asp Gly Gly Leu Ala His Asn Leu Gln
35 40 45
Asp Ser Val Arg His Arg Ile Leu Tyr Leu Ser Glu Gln Leu Arg Val
50 55 60
Glu Lys Ala Ser Arg Asp Gly Asn Thr Val Ser Tyr Leu Lys Leu Val
65 70 75 80
Ser Lys Ala Asp Arg His Gln Val Pro His Ile Gln Gln Ala Phe Glu
85 90 95
Lys Val Asn Gln Arg Ala Ser Ala Thr Ile Ala Gln Ile Glu His Arg
100 105 110
Leu His Gln Cys His Gln Gln Leu Gln Glu Leu Glu Glu Gly Cys Arg
115 120 125
Pro Glu Gly Leu Leu Leu Met Ala Glu Ser Asp Pro Ala Asn Cys Glu
130 135 140
Pro Pro Ser Glu Lys Ala Leu Leu Ser Glu Pro Pro Glu Pro Gly Gly
145 150 155 160
Glu Asp Gly Pro Val Asn Leu Pro His Ala Ser Arg Pro Phe Ile Leu
165 170 175
Glu Ser Arg Phe Gln Ser Leu Gln Gln Gly Thr Cys Leu Glu Thr Glu
180 185 190
Asp Val Ala Gln Gln Gln Asn Leu Leu Leu Gln Lys Val Lys Ala Glu
195 200 205
Leu Glu Glu Ala Lys Arg Phe His Ile Ser Leu Gln Glu Ser Tyr His
210 215 220
Ser Leu Lys Glu Arg Ser Leu Thr Asp Leu Gln Leu Leu Leu Glu Ser
225 230 235 240
Leu Gln Glu Glu Lys Cys Arg Gln Ala Leu Met Glu Glu Gln Val Asn
245 250 255
Gly Arg Leu Gln Gly Gln Leu Asn Glu Ile Tyr Asn Leu Lys His Asn
260 265 270
Leu Ala Cys Ser Glu Glu Arg Met Ala Tyr Leu Ser Tyr Glu Arg Ala
275 280 285
Lys Glu Ile Trp Glu Ile Thr Glu Thr Phe Lys Ser Arg Ile Ser Lys
290 295 300
Leu Glu Met Leu Gln Gln Val Thr Gln Leu Glu Ala Ala Glu His Leu
305 310 315 320
Gln Ser Arg Pro Pro Gln Met Leu Phe Lys Phe Leu Ser Pro Arg Leu
325 330 335
Ser Leu Ala Thr Val Leu Leu Val Phe Val Ser Thr Leu Cys Ala Cys
340 345 350
Pro Ser Ser Leu Ile Ser Ser Arg Leu Cys Thr Cys Thr Met Leu Met
355 360 365
Leu Ile Gly Leu Gly Val Leu Ala Trp Gln Arg Trp Arg Ala Ile Pro
370 375 380
Ala Thr Asp Trp Gln Glu Trp Val Pro Ser Arg Cys Arg Leu Tyr Ser
385 390 395 400
Lys Asp Ser Gly Pro Pro Ala Asp Gly Pro
405 410
<210> 7
<211> 7
<212> PRT
<213> 人工序列(artificial Sequence)
<220>
<223> 插入肽(insertion peptide)
<400> 7
Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 8
<211> 732
<212> PRT
<213> 腺相关病毒9(adeno-associated virus 9)
<400> 8
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu Phe
405 410 415
Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Lys
435 440 445
Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser Val
450 455 460
Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro Gly
465 470 475 480
Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn Asn
485 490 495
Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn Gly
500 505 510
Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys Glu
515 520 525
Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly Lys
530 535 540
Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile Thr
545 550 555 560
Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser Tyr
565 570 575
Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Gln Ala Gln Thr Gly
580 585 590
Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln Asp Arg
595 600 605
Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp
610 615 620
Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met Lys His
625 630 635 640
Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asp Pro
645 650 655
Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr Gln Tyr
660 665 670
Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu
675 680 685
Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr
690 695 700
Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val Tyr Ser
705 710 715 720
Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730
<210> 9
<211> 735
<212> PRT
<213> 腺相关病毒2(adeno-associated virus 2)
<400> 9
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser 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
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Arg Gln Ala Ala Thr
580 585 590
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Ser Thr Thr Phe Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 10
<211> 10
<212> PRT
<213> 人工序列(artificial Sequence)
<220>
<223> 插入肽(insertion peptide)
<400> 10
Ala Ala Leu Gly Glu Thr Thr Arg Pro Ala
1 5 10
<210> 11
<211> 9
<212> PRT
<213> 人工序列(artificial Sequence)
<220>
<223> 插入肽(insertion peptide)
<400> 11
Leu Ala Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列(artificial Sequence)
<220>
<223> 插入肽(insertion peptide)
<400> 12
Gly Leu Gly Glu Thr Thr Arg Pro Ala
1 5
<210> 13
<211> 1724
<212> DNA
<213> 人工序列(artificial Sequence)
<220>
<223> pR1.7 启动子(pR1.7 promoter)
<400> 13
ggaggctgag gggtggggaa agggcatggg tgtttcatga ggacagagct tccgtttcat 60
gcaatgaaaa gagtttggag acggatggtg gtgactggac tatacactta cacacggtag 120
cgatggtaca ctttgtatta tgtatatttt accacgatct ttttaaagtg tcaaaggcaa 180
atggccaaat ggttccttgt cctatagctg tagcagccat cggctgttag tgacaaagcc 240
cctgagtcaa gatgacagca gcccccataa ctcctaatcg gctctcccgc gtggagtcat 300
ttaggagtag tcgcattaga gacaagtcca acatctaatc ttccaccctg gccagggccc 360
cagctggcag cgagggtggg agactccggg cagagcagag ggcgctgaca ttggggcccg 420
gcctggcttg ggtccctctg gcctttcccc aggggccctc tttccttggg gctttcttgg 480
gccgccactg ctcccgctcc tctcccccca tcccaccccc tcaccccctc gttcttcata 540
tccttctcta gtgctccctc cactttcatc cacccttctg caagagtgtg ggaccacaaa 600
tgagttttca cctggcctgg ggacacacgt gcccccacag gtgctgagtg actttctagg 660
acagtaatct gctttaggct aaaatgggac ttgatcttct gttagcccta atcatcaatt 720
agcagagccg gtgaaggtgc agaacctacc gcctttccag gcctcctccc acctctgcca 780
cctccactct ccttcctggg atgtgggggc tggcacacgt gtggcccagg gcattggtgg 840
gattgcactg agctgggtca ttagcgtaat cctggacaag ggcagacagg gcgagcggag 900
ggccagctcc ggggctcagg caaggctggg ggcttccccc agacacccca ctcctcctct 960
gctggacccc cacttcatag ggcacttcgt gttctcaaag ggcttccaaa tagcatggtg 1020
gccttggatg cccagggaag cctcagagtt gcttatctcc ctctagacag aaggggaatc 1080
tcggtcaaga gggagaggtc gccctgttca aggccaccca gccagctcat ggcggtaatg 1140
ggacaaggct ggccagccat cccaccctca gaagggaccc ggtggggcag gtgatctcag 1200
aggaggctca cttctgggtc tcacattctt ggatccggtt ccaggcctcg gccctaaata 1260
gtctccctgg gctttcaaga gaaccacatg agaaaggagg attcgggctc tgagcagttt 1320
caccacccac cccccagtct gcaaatcctg acccgtgggt ccacctgccc caaaggcgga 1380
cgcaggacag tagaagggaa cagagaacac ataaacacag agagggccac agcggctccc 1440
acagtcaccg ccaccttcct ggcggggatg ggtggggcgt ctgagtttgg ttcccagcaa 1500
atccctctga gccgcccttg cgggctcgcc tcaggagcag gggagcaaga ggtgggagga 1560
ggaggtctaa gtcccaggcc caattaagag atcaggtagt gtagggtttg ggagctttta 1620
aggtgaagag gcccgggctg atcccacagg ccagtataaa gcgccgtgac cctcaggtga 1680
tgcgccaggg ccggctgccg tcggggacag ggctttccat agcc 1724
<210> 14
<211> 234
<212> DNA
<213> 人工序列(artificial Sequence)
<220>
<223> 最小M-视蛋白启动子(minimal M-opsin promoter region)
<400> 14
ccagcaaatc cctctgagcc gcccccgggg gctcgcctca ggagcaagga agcaaggggt 60
gggaggagga ggtctaagtc ccaggcccaa ttaagagatc agatggtgta ggatttggga 120
gcttttaagg tgaagaggcc cgggctgatc ccactggccg gtataaagca ccgtgaccct 180
caggtgacgc accagggccg gctgccgtcg gggacagggc tttccatagc ccag 234
<210> 15
<211> 1958
<212> DNA
<213> 人工序列(artificial Sequence)
<220>
<223> pMNTC表达盒(pMNTC expression cassette)
<400> 15
cctacagcag ccagggtgag attatgaggc tgagctgaga atatcaagac tgtaccgagt 60
agggggcctt ggcaagtgtg gagagcccgg cagctggggc agagggcgga gtacggtgtg 120
cgtttacgga cctcttcaaa cgaggtagga aggtcagaag tcaaaaaggg aacaaatgat 180
gtttaaccac acaaaaatga aaatccaatg gttggatatc cattccaaat acacaaaggc 240
aacggataag tgatccgggc caggcacaga aggccatgca cccgtaggat tgcactcaga 300
gctcccaaat gcataggaat agaagggtgg gtgcaggagg ctgaggggtg gggaaagggc 360
atgggtgttt catgaggaca gagcttccgt ttcatgcaat gaaaagagtt tggagacgga 420
tggtggtgac tggactatac acttacacac ggtagcgatg gtacactttg tattatgtat 480
attttaccac gatcttttta aagtgtcaaa ggcaaatggc caaatggttc cttgtcctat 540
agctgtagca gccatcggct gttagtgaca aagcccctga gtcaagatga cagcagcccc 600
cataactcct aatcggctct cccgcgtgga gtcatttagg agtagtcgca ttagagacaa 660
gtccaacatc taatcttcca ccctggccag ggccccagct ggcagcgagg gtgggagact 720
ccgggcagag cagagggcgc tgacattggg gcccggcctg gcttgggtcc ctctggcctt 780
tccccagggg ccctctttcc ttggggcttt cttgggccgc cactgctccc gctcctctcc 840
ccccatccca ccccctcacc ccctcgttct tcatatcctt ctctagtgct ccctccactt 900
tcatccaccc ttctgcaaga gtgtgggacc acaaatgagt tttcacctgg cctggggaca 960
cacgtgcccc cacaggtgct gagtgacttt ctaggacagt aatctgcttt aggctaaaat 1020
gggacttgat cttctgttag ccctaatcat caattagcag agccggtgaa ggtgcagaac 1080
ctaccgcctt tccaggcctc ctcccacctc tgccacctcc actctccttc ctgggatgtg 1140
ggggctggca cacgtgtggc ccagggcatt ggtgggattg cactgagctg ggtcattagc 1200
gtaatcctgg acaagggcag acagggcgag cggagggcca gctccggggc tcaggcaagg 1260
ctgggggctt cccccagaca ccccactcct cctctgctgg acccccactt catagggcac 1320
ttcgtgttct caaagggctt ccaaatagca tggtggcctt ggatgcccag ggaagcctca 1380
gagttgctta tctccctcta gacagaaggg gaatctcggt caagagggag aggtcgccct 1440
gttcaaggcc acccagccag ctcatggcgg taatgggaca aggctggcca gccatcccac 1500
cctcagaagg gacccggtgg ggcaggtgat ctcagaggag gctcacttct gggtctcaca 1560
ttcttccagc aaatccctct gagccgcccc cgggggctcg cctcaggagc aaggaagcaa 1620
ggggtgggag gaggaggtct aagtcccagg cccaattaag agatcagatg gtgtaggatt 1680
tgggagcttt taaggtgaag aggcccgggc tgatcccact ggccggtata aagcaccgtg 1740
accctcaggt gacgcaccag ggccggctgc cgtcggggac agggctttcc atagcccagg 1800
taagtatcaa ggttacaaga caggtttaag gagaccaata gaaactgggc ttgtcgagac 1860
agagaagact cttgcgtttc tgataggcac ctattggtct tactgacatc cactttgcct 1920
ttctctccac aggcccagag aggagacagg ccgccacc 1958
<210> 16
<211> 6493
<212> DNA
<213> 人工序列(artificial)
<220>
<223> 质粒(plasmid)
<400> 16
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120
actccatcac taggggttcc ttctagacaa ctttgtatag aaaagttggg aggctgaggg 180
gtggggaaag ggcatgggtg tttcatgagg acagagcttc cgtttcatgc aatgaaaaga 240
gtttggagac ggatggtggt gactggacta tacacttaca cacggtagcg atggtacact 300
ttgtattatg tatattttac cacgatcttt ttaaagtgtc aaaggcaaat ggccaaatgg 360
ttccttgtcc tatagctgta gcagccatcg gctgttagtg acaaagcccc tgagtcaaga 420
tgacagcagc ccccataact cctaatcggc tctcccgcgt ggagtcattt aggagtagtc 480
gcattagaga caagtccaac atctaatctt ccaccctggc cagggcccca gctggcagcg 540
agggtgggag actccgggca gagcagaggg cgctgacatt ggggcccggc ctggcttggg 600
tccctctggc ctttccccag gggccctctt tccttggggc tttcttgggc cgccactgct 660
cccgctcctc tccccccatc ccaccccctc accccctcgt tcttcatatc cttctctagt 720
gctccctcca ctttcatcca cccttctgca agagtgtggg accacaaatg agttttcacc 780
tggcctgggg acacacgtgc ccccacaggt gctgagtgac tttctaggac agtaatctgc 840
tttaggctaa aatgggactt gatcttctgt tagccctaat catcaattag cagagccggt 900
gaaggtgcag aacctaccgc ctttccaggc ctcctcccac ctctgccacc tccactctcc 960
ttcctgggat gtgggggctg gcacacgtgt ggcccagggc attggtggga ttgcactgag 1020
ctgggtcatt agcgtaatcc tggacaaggg cagacagggc gagcggaggg ccagctccgg 1080
ggctcaggca aggctggggg cttcccccag acaccccact cctcctctgc tggaccccca 1140
cttcataggg cacttcgtgt tctcaaaggg cttccaaata gcatggtggc cttggatgcc 1200
cagggaagcc tcagagttgc ttatctccct ctagacagaa ggggaatctc ggtcaagagg 1260
gagaggtcgc cctgttcaag gccacccagc cagctcatgg cggtaatggg acaaggctgg 1320
ccagccatcc caccctcaga agggacccgg tggggcaggt gatctcagag gaggctcact 1380
tctgggtctc acattcttgg atccggttcc aggcctcggc cctaaatagt ctccctgggc 1440
tttcaagaga accacatgag aaaggaggat tcgggctctg agcagtttca ccacccaccc 1500
cccagtctgc aaatcctgac ccgtgggtcc acctgcccca aaggcggacg caggacagta 1560
gaagggaaca gagaacacat aaacacagag agggccacag cggctcccac agtcaccgcc 1620
accttcctgg cggggatggg tggggcgtct gagtttggtt cccagcaaat ccctctgagc 1680
cgcccttgcg ggctcgcctc aggagcaggg gagcaagagg tgggaggagg aggtctaagt 1740
cccaggccca attaagagat caggtagtgt agggtttggg agcttttaag gtgaagaggc 1800
ccgggctgat cccacaggcc agtataaagc gccgtgaccc tcaggtgatg cgccagggcc 1860
ggctgccgtc ggggacaggg ctttccatag ccactagtgt aagtttagtc tttttgtctt 1920
ttatttcagg tcccggatcc ggtggtggtg caaatcaaag aactgctcct cagtggatgt 1980
tgcctttact tctagcaagt ttgtacaaaa aagcaggctg ccaccatgag cgccctgaga 2040
agaaagttcg gcgacgacta ccaggtggtc accacaagca gctctggctc tggactgcag 2100
cctcaaggac ctggacagga tcctcagcag cagctggtgc ccaagaagaa acggcagaga 2160
ttcgtggaca agaacggccg gtgcaatgtg cagcacggca atctgggcag cgagacaagc 2220
agatacctga gcgacctgtt caccacactg gtggacctga agtggcggtg gaacctgttc 2280
atcttcatcc tgacctacac cgtggcctgg ctgttcatgg ccagcatgtg gtgggttatc 2340
gcctacacca gaggcgacct gaacaaggcc catgtgggca actacacccc ttgcgtggcc 2400
aacgtgtaca acttccctag cgccttcctg ttcagcatcg agacagaggc cacaatcggc 2460
tacggctacc ggtacatcac cgacaagtgc cccgagggaa ttatcctgtt cctgttccag 2520
tccatcctgg gctctatcgt ggatgccttc ctgatcggct gcatgttcat caagatgagc 2580
cagcctaaga agcgggccga gacactgatg tttagcgagc acgccgtgat cagcatgcgc 2640
gacggaaaac tgaccctgat gttcagagtg ggcaacctgc ggaacagcca catggtgtca 2700
gcccagatca gatgcaagct gctgaagtcc agacagaccc ctgagggcga gttcctgcct 2760
ctggatcagc tggaactgga cgtgggcttt agcacaggcg ccgatcagct gtttctggtg 2820
tcccctctga ccatctgcca cgtgatcgac gctaagagcc ccttctacga tctgagccag 2880
cggagcatgc agaccgagca gtttgagatc gtggtcatcc tggaaggcat tgtggaaacc 2940
accggcatga cctgccaggc cagaaccagc tacacagagg atgaggtgct gtggggccac 3000
agattcttcc ccgtgatctc tctggaagag ggcttcttca aggtggacta cagccagttc 3060
cacgccacct ttgaggtgcc cacacctcct tacagcgtga aagaacaaga ggaaatgctg 3120
ctgatgagca gccctctgat cgcccctgcc atcaccaaca gcaaagaacg gcacaacagc 3180
gtggaatgcc tggacggcct ggatgacatc accaccaagc tgccttccaa gctgcagaag 3240
atcaccggca gagaggactt ccccaagaaa ctgctgagaa tgagcagcac caccagcgag 3300
aaggcctact ctctgggcga cctgcctatg aagctgcagc ggatctctag cgtgcccggc 3360
aactctgagg aaaagctggt ttccaagacc accaagatgc tgagcgatcc catgagccag 3420
tccgtggctg atctgccacc taaactgcag aaaatggctg gcggagccgc cagaatggaa 3480
ggcaatctgc ctgccaaact gcgcaagatg aactccgacc ggttcaccta gacccagctt 3540
tcttgtacaa agtgggaatt cctagagctc gctgatcagc ctcgactgtg ccttctagtt 3600
gccagccatc tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc 3660
ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt 3720
ctattctggg gggtggggtg gggcaggaca gcaaggggga ggattgggaa gagaatagca 3780
ggcatgctgg ggagggccgc aggaacccct agtgatggag ttggccactc cctctctgcg 3840
cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg 3900
ggcggcctca gtgagcgagc gagcgcgcag ctgcctgcag gggcgcctga tgcggtattt 3960
tctccttacg catctgtgcg gtatttcaca ccgcatacgt caaagcaacc atagtacgcg 4020
ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt gaccgctaca 4080
cttgccagcg ccttagcgcc cgctcctttc gctttcttcc cttcctttct cgccacgttc 4140
gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg atttagtgct 4200
ttacggcacc tcgaccccaa aaaacttgat ttgggtgatg gttcacgtag tgggccatcg 4260
ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa tagtggactc 4320
ttgttccaaa ctggaacaac actcaactct atctcgggct attcttttga tttataaggg 4380
attttgccga tttcggtcta ttggttaaaa aatgagctga tttaacaaaa atttaacgcg 4440
aattttaaca aaatattaac gtttacaatt ttatggtgca ctctcagtac aatctgctct 4500
gatgccgcat agttaagcca gccccgacac ccgccaacac ccgctgacgc gccctgacgg 4560
gcttgtctgc tcccggcatc cgcttacaga caagctgtga ccgtctccgg gagctgcatg 4620
tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac gaaagggcct cgtgatacgc 4680
ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg tggcactttt 4740
cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat 4800
ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg 4860
agccatattc aacgggaaac gtcttgctct aggccgcgat taaattccaa catggatgct 4920
gatttatatg ggtataaatg ggctcgcgat aatgtcgggc aatcaggtgc gacaatctat 4980
cgattgtatg ggaagcccga tgcgccagag ttgtttctga aacatggcaa aggtagcgtt 5040
gccaatgatg ttacagatga gatggtcaga ctaaactggc tgacggaatt tatgcctctt 5100
ccgaccatca agcattttat ccgtactcct gatgatgcat ggttactcac cactgcgatc 5160
cccgggaaaa cagcattcca ggtattagaa gaatatcctg attcaggtga aaatattgtt 5220
gatgcgctgg cagtgttcct gcgccggttg cattcgattc ctgtttgtaa ttgtcctttt 5280
aacagcgatc gcgtatttcg tctcgctcag gcgcaatcac gaatgaataa cggtttggtt 5340
gatgcgagtg attttgatga cgagcgtaat ggctggcctg ttgaacaagt ctggaaagaa 5400
atgcataaac ttttgccatt ctcaccggat tcagtcgtca ctcatggtga tttctcactt 5460
gataacctta tttttgacga ggggaaatta ataggttgta ttgatgttgg acgagtcgga 5520
atcgcagacc gataccagga tcttgccatc ctatggaact gcctcggtga gttttctcct 5580
tcattacaga aacggctttt tcaaaaatat ggtattgata atcctgatat gaataaattg 5640
cagtttcatt tgatgctcga tgagtttttc taactgtcag accaagttta ctcatatata 5700
ctttagattg atttaaaact tcatttttaa tttaaaagga tctaggtgaa gatccttttt 5760
gataatctca tgaccaaaat cccttaacgt gagttttcgt tccactgagc gtcagacccc 5820
gtagaaaaga tcaaaggatc ttcttgagat cctttttttc tgcgcgtaat ctgctgcttg 5880
caaacaaaaa aaccaccgct accagcggtg gtttgtttgc cggatcaaga gctaccaact 5940
ctttttccga aggtaactgg cttcagcaga gcgcagatac caaatactgt tcttctagtg 6000
tagccgtagt taggccacca cttcaagaac tctgtagcac cgcctacata cctcgctctg 6060
ctaatcctgt taccagtggc tgctgccagt ggcgataagt cgtgtcttac cgggttggac 6120
tcaagacgat agttaccgga taaggcgcag cggtcgggct gaacgggggg ttcgtgcaca 6180
cagcccagct tggagcgaac gacctacacc gaactgagat acctacagcg tgagctatga 6240
gaaagcgcca cgcttcccga agggagaaag gcggacaggt atccggtaag cggcagggtc 6300
ggaacaggag agcgcacgag ggagcttcca gggggaaacg cctggtatct ttatagtcct 6360
gtcgggtttc gccacctctg acttgagcgt cgatttttgt gatgctcgtc aggggggcgg 6420
agcctatgga aaaacgccag caacgcggcc tttttacggt tcctggcctt ttgctggcct 6480
tttgctcaca tgt 6493
<210> 17
<211> 7084
<212> DNA
<213> 人工序列(artificial)
<220>
<223> 质粒(plasmid)
<400> 17
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120
actccatcac taggggttcc ttctagacaa ctttgtatag aaaagttggg aggctgaggg 180
gtggggaaag ggcatgggtg tttcatgagg acagagcttc cgtttcatgc aatgaaaaga 240
gtttggagac ggatggtggt gactggacta tacacttaca cacggtagcg atggtacact 300
ttgtattatg tatattttac cacgatcttt ttaaagtgtc aaaggcaaat ggccaaatgg 360
ttccttgtcc tatagctgta gcagccatcg gctgttagtg acaaagcccc tgagtcaaga 420
tgacagcagc ccccataact cctaatcggc tctcccgcgt ggagtcattt aggagtagtc 480
gcattagaga caagtccaac atctaatctt ccaccctggc cagggcccca gctggcagcg 540
agggtgggag actccgggca gagcagaggg cgctgacatt ggggcccggc ctggcttggg 600
tccctctggc ctttccccag gggccctctt tccttggggc tttcttgggc cgccactgct 660
cccgctcctc tccccccatc ccaccccctc accccctcgt tcttcatatc cttctctagt 720
gctccctcca ctttcatcca cccttctgca agagtgtggg accacaaatg agttttcacc 780
tggcctgggg acacacgtgc ccccacaggt gctgagtgac tttctaggac agtaatctgc 840
tttaggctaa aatgggactt gatcttctgt tagccctaat catcaattag cagagccggt 900
gaaggtgcag aacctaccgc ctttccaggc ctcctcccac ctctgccacc tccactctcc 960
ttcctgggat gtgggggctg gcacacgtgt ggcccagggc attggtggga ttgcactgag 1020
ctgggtcatt agcgtaatcc tggacaaggg cagacagggc gagcggaggg ccagctccgg 1080
ggctcaggca aggctggggg cttcccccag acaccccact cctcctctgc tggaccccca 1140
cttcataggg cacttcgtgt tctcaaaggg cttccaaata gcatggtggc cttggatgcc 1200
cagggaagcc tcagagttgc ttatctccct ctagacagaa ggggaatctc ggtcaagagg 1260
gagaggtcgc cctgttcaag gccacccagc cagctcatgg cggtaatggg acaaggctgg 1320
ccagccatcc caccctcaga agggacccgg tggggcaggt gatctcagag gaggctcact 1380
tctgggtctc acattcttgg atccggttcc aggcctcggc cctaaatagt ctccctgggc 1440
tttcaagaga accacatgag aaaggaggat tcgggctctg agcagtttca ccacccaccc 1500
cccagtctgc aaatcctgac ccgtgggtcc acctgcccca aaggcggacg caggacagta 1560
gaagggaaca gagaacacat aaacacagag agggccacag cggctcccac agtcaccgcc 1620
accttcctgg cggggatggg tggggcgtct gagtttggtt cccagcaaat ccctctgagc 1680
cgcccttgcg ggctcgcctc aggagcaggg gagcaagagg tgggaggagg aggtctaagt 1740
cccaggccca attaagagat caggtagtgt agggtttggg agcttttaag gtgaagaggc 1800
ccgggctgat cccacaggcc agtataaagc gccgtgaccc tcaggtgatg cgccagggcc 1860
ggctgccgtc ggggacaggg ctttccatag ccactagtgt aagtttagtc tttttgtctt 1920
ttatttcagg tcccggatcc ggtggtggtg caaatcaaag aactgctcct cagtggatgt 1980
tgcctttact tctagcaagt ttgtacaaaa aagcaggctg ccaccatgag cgccctgaga 2040
agaaagttcg gcgacgacta ccaggtggtc accacaagca gctctggctc tggactgcag 2100
cctcaaggac ctggacagga tcctcagcag cagctggtgc ccaagaagaa acggcagaga 2160
ttcgtggaca agaacggccg gtgcaatgtg cagcacggca atctgggcag cgagacaagc 2220
agatacctga gcgacctgtt caccacactg gtggacctga agtggcggtg gaacctgttc 2280
atcttcatcc tgacctacac cgtggcctgg ctgttcatgg ccagcatgtg gtgggttatc 2340
gcctacacca gaggcgacct gaacaaggcc catgtgggca actacacccc ttgcgtggcc 2400
aacgtgtaca acttccctag cgccttcctg ttcagcatcg agacagaggc cacaatcggc 2460
tacggctacc ggtacatcac cgacaagtgc cccgagggaa ttatcctgtt cctgttccag 2520
tccatcctgg gctctatcgt ggatgccttc ctgatcggct gcatgttcat caagatgagc 2580
cagcctaaga agcgggccga gacactgatg tttagcgagc acgccgtgat cagcatgcgc 2640
gacggaaaac tgaccctgat gttcagagtg ggcaacctgc ggaacagcca catggtgtca 2700
gcccagatca gatgcaagct gctgaagtcc agacagaccc ctgagggcga gttcctgcct 2760
ctggatcagc tggaactgga cgtgggcttt agcacaggcg ccgatcagct gtttctggtg 2820
tcccctctga ccatctgcca cgtgatcgac gctaagagcc ccttctacga tctgagccag 2880
cggagcatgc agaccgagca gtttgagatc gtggtcatcc tggaaggcat tgtggaaacc 2940
accggcatga cctgccaggc cagaaccagc tacacagagg atgaggtgct gtggggccac 3000
agattcttcc ccgtgatctc tctggaagag ggcttcttca aggtggacta cagccagttc 3060
cacgccacct ttgaggtgcc cacacctcct tacagcgtga aagaacaaga ggaaatgctg 3120
ctgatgagca gccctctgat cgcccctgcc atcaccaaca gcaaagaacg gcacaacagc 3180
gtggaatgcc tggacggcct ggatgacatc accaccaagc tgccttccaa gctgcagaag 3240
atcaccggca gagaggactt ccccaagaaa ctgctgagaa tgagcagcac caccagcgag 3300
aaggcctact ctctgggcga cctgcctatg aagctgcagc ggatctctag cgtgcccggc 3360
aactctgagg aaaagctggt ttccaagacc accaagatgc tgagcgatcc catgagccag 3420
tccgtggctg atctgccacc taaactgcag aaaatggctg gcggagccgc cagaatggaa 3480
ggcaatctgc ctgccaaact gcgcaagatg aactccgacc ggttcaccta gacccagctt 3540
tcttgtacaa agtgggaatt catcaacctc tggattacaa aatttgtgaa agattgactg 3600
atattcttaa ctatgttgct ccttttacgc tgtgtggata tgctgcttta atgcctctgt 3660
atcatgctat tgcttcccgt acggctttcg ttttctcctc cttgtataaa tcctggttgc 3720
tgtctcttta tgaggagttg tggcccgttg tccgtcaacg tggcgtggtg tgctctgtgt 3780
ttatcatcgc aacccccact ggctggggca ttgccaccac ctgtcaactc ctttctggga 3840
ctttcgcttt ccccctcccg atcgccacgg cagaactcat cgccgcctgc cttgcccgct 3900
gctggacagg ggctaggttg ctgggcactg ataattccgt ggtgttgtcg gggaagctga 3960
cgtcctttcc ttggctgctc gcctgtgttg ccaactggat cctgcgcggg acgtccttct 4020
gctacgtccc ttcggctctc aatccagcgg acctcccttc ccgaggcctt ctgccggttc 4080
tgcggcctct cccgcgtctt cgctttcggc ctccgacgag tcggatctcc ctttgggccg 4140
cctccccgcc tgctagagct cgctgatcag cctcgactgt gccttctagt tgccagccat 4200
ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc 4260
tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg 4320
ggggtggggt ggggcaggac agcaaggggg aggattggga agagaatagc aggcatgctg 4380
gggagggccg caggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc 4440
gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc 4500
agtgagcgag cgagcgcgca gctgcctgca ggggcgcctg atgcggtatt ttctccttac 4560
gcatctgtgc ggtatttcac accgcatacg tcaaagcaac catagtacgc gccctgtagc 4620
ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc 4680
gccttagcgc ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt 4740
ccccgtcaag ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac 4800
ctcgacccca aaaaacttga tttgggtgat ggttcacgta gtgggccatc gccctgatag 4860
acggtttttc gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa 4920
actggaacaa cactcaactc tatctcgggc tattcttttg atttataagg gattttgccg 4980
atttcggtct attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac 5040
aaaatattaa cgtttacaat tttatggtgc actctcagta caatctgctc tgatgccgca 5100
tagttaagcc agccccgaca cccgccaaca cccgctgacg cgccctgacg ggcttgtctg 5160
ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat gtgtcagagg 5220
ttttcaccgt catcaccgaa acgcgcgaga cgaaagggcc tcgtgatacg cctattttta 5280
taggttaatg tcatgataat aatggtttct tagacgtcag gtggcacttt tcggggaaat 5340
gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg 5400
agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagccatatt 5460
caacgggaaa cgtcttgctc taggccgcga ttaaattcca acatggatgc tgatttatat 5520
gggtataaat gggctcgcga taatgtcggg caatcaggtg cgacaatcta tcgattgtat 5580
gggaagcccg atgcgccaga gttgtttctg aaacatggca aaggtagcgt tgccaatgat 5640
gttacagatg agatggtcag actaaactgg ctgacggaat ttatgcctct tccgaccatc 5700
aagcatttta tccgtactcc tgatgatgca tggttactca ccactgcgat ccccgggaaa 5760
acagcattcc aggtattaga agaatatcct gattcaggtg aaaatattgt tgatgcgctg 5820
gcagtgttcc tgcgccggtt gcattcgatt cctgtttgta attgtccttt taacagcgat 5880
cgcgtatttc gtctcgctca ggcgcaatca cgaatgaata acggtttggt tgatgcgagt 5940
gattttgatg acgagcgtaa tggctggcct gttgaacaag tctggaaaga aatgcataaa 6000
cttttgccat tctcaccgga ttcagtcgtc actcatggtg atttctcact tgataacctt 6060
atttttgacg aggggaaatt aataggttgt attgatgttg gacgagtcgg aatcgcagac 6120
cgataccagg atcttgccat cctatggaac tgcctcggtg agttttctcc ttcattacag 6180
aaacggcttt ttcaaaaata tggtattgat aatcctgata tgaataaatt gcagtttcat 6240
ttgatgctcg atgagttttt ctaactgtca gaccaagttt actcatatat actttagatt 6300
gatttaaaac ttcattttta atttaaaagg atctaggtga agatcctttt tgataatctc 6360
atgaccaaaa tcccttaacg tgagttttcg ttccactgag cgtcagaccc cgtagaaaag 6420
atcaaaggat cttcttgaga tccttttttt ctgcgcgtaa tctgctgctt gcaaacaaaa 6480
aaaccaccgc taccagcggt ggtttgtttg ccggatcaag agctaccaac tctttttccg 6540
aaggtaactg gcttcagcag agcgcagata ccaaatactg ttcttctagt gtagccgtag 6600
ttaggccacc acttcaagaa ctctgtagca ccgcctacat acctcgctct gctaatcctg 6660
ttaccagtgg ctgctgccag tggcgataag tcgtgtctta ccgggttgga ctcaagacga 6720
tagttaccgg ataaggcgca gcggtcgggc tgaacggggg gttcgtgcac acagcccagc 6780
ttggagcgaa cgacctacac cgaactgaga tacctacagc gtgagctatg agaaagcgcc 6840
acgcttcccg aagggagaaa ggcggacagg tatccggtaa gcggcagggt cggaacagga 6900
gagcgcacga gggagcttcc agggggaaac gcctggtatc tttatagtcc tgtcgggttt 6960
cgccacctct gacttgagcg tcgatttttg tgatgctcgt caggggggcg gagcctatgg 7020
aaaaacgcca gcaacgcggc ctttttacgg ttcctggcct tttgctggcc ttttgctcac 7080
atgt 7084
<210> 18
<211> 7095
<212> DNA
<213> 人工序列(artificial)
<220>
<223> 质粒(plasmid)
<400> 18
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120
actccatcac taggggttcc ttctagacaa ctttgtatag aaaagttggg aggctgaggg 180
gtggggaaag ggcatgggtg tttcatgagg acagagcttc cgtttcatgc aatgaaaaga 240
gtttggagac ggatggtggt gactggacta tacacttaca cacggtagcg atggtacact 300
ttgtattatg tatattttac cacgatcttt ttaaagtgtc aaaggcaaat ggccaaatgg 360
ttccttgtcc tatagctgta gcagccatcg gctgttagtg acaaagcccc tgagtcaaga 420
tgacagcagc ccccataact cctaatcggc tctcccgcgt ggagtcattt aggagtagtc 480
gcattagaga caagtccaac atctaatctt ccaccctggc cagggcccca gctggcagcg 540
agggtgggag actccgggca gagcagaggg cgctgacatt ggggcccggc ctggcttggg 600
tccctctggc ctttccccag gggccctctt tccttggggc tttcttgggc cgccactgct 660
cccgctcctc tccccccatc ccaccccctc accccctcgt tcttcatatc cttctctagt 720
gctccctcca ctttcatcca cccttctgca agagtgtggg accacaaatg agttttcacc 780
tggcctgggg acacacgtgc ccccacaggt gctgagtgac tttctaggac agtaatctgc 840
tttaggctaa aatgggactt gatcttctgt tagccctaat catcaattag cagagccggt 900
gaaggtgcag aacctaccgc ctttccaggc ctcctcccac ctctgccacc tccactctcc 960
ttcctgggat gtgggggctg gcacacgtgt ggcccagggc attggtggga ttgcactgag 1020
ctgggtcatt agcgtaatcc tggacaaggg cagacagggc gagcggaggg ccagctccgg 1080
ggctcaggca aggctggggg cttcccccag acaccccact cctcctctgc tggaccccca 1140
cttcataggg cacttcgtgt tctcaaaggg cttccaaata gcatggtggc cttggatgcc 1200
cagggaagcc tcagagttgc ttatctccct ctagacagaa ggggaatctc ggtcaagagg 1260
gagaggtcgc cctgttcaag gccacccagc cagctcatgg cggtaatggg acaaggctgg 1320
ccagccatcc caccctcaga agggacccgg tggggcaggt gatctcagag gaggctcact 1380
tctgggtctc acattcttgg atccggttcc aggcctcggc cctaaatagt ctccctgggc 1440
tttcaagaga accacatgag aaaggaggat tcgggctctg agcagtttca ccacccaccc 1500
cccagtctgc aaatcctgac ccgtgggtcc acctgcccca aaggcggacg caggacagta 1560
gaagggaaca gagaacacat aaacacagag agggccacag cggctcccac agtcaccgcc 1620
accttcctgg cggggatggg tggggcgtct gagtttggtt cccagcaaat ccctctgagc 1680
cgcccttgcg ggctcgcctc aggagcaggg gagcaagagg tgggaggagg aggtctaagt 1740
cccaggccca attaagagat caggtagtgt agggtttggg agcttttaag gtgaagaggc 1800
ccgggctgat cccacaggcc agtataaagc gccgtgaccc tcaggtgatg cgccagggcc 1860
ggctgccgtc ggggacaggg ctttccatag ccactagtgt aagtttagtc tttttgtctt 1920
ttatttcagg tcccggatcc ggtggtggtg caaatcaaag aactgctcct cagtggatgt 1980
tgcctttact tctagcaagt ttgtacaaaa aagcaggctg ccaccatgag cgccctgaga 2040
agaaagttcg gcgacgacta ccaggtggtc accacaagca gctctggctc tggactgcag 2100
cctcaaggac ctggacagga tcctcagcag cagctggtgc ccaagaagaa acggcagaga 2160
ttcgtggaca agaacggccg gtgcaatgtg cagcacggca atctgggcag cgagacaagc 2220
agatacctga gcgacctgtt caccacactg gtggacctga agtggcggtg gaacctgttc 2280
atcttcatcc tgacctacac cgtggcctgg ctgttcatgg ccagcatgtg gtgggttatc 2340
gcctacacca gaggcgacct gaacaaggcc catgtgggca actacacccc ttgcgtggcc 2400
aacgtgtaca acttccctag cgccttcctg ttcagcatcg agacagaggc cacaatcggc 2460
tacggctacc ggtacatcac cgacaagtgc cccgagggaa ttatcctgtt cctgttccag 2520
tccatcctgg gctctatcgt ggatgccttc ctgatcggct gcatgttcat caagatgagc 2580
cagcctaaga agcgggccga gacactgatg tttagcgagc acgccgtgat cagcatgcgc 2640
gacggaaaac tgaccctgat gttcagagtg ggcaacctgc ggaacagcca catggtgtca 2700
gcccagatca gatgcaagct gctgaagtcc agacagaccc ctgagggcga gttcctgcct 2760
ctggatcagc tggaactgga cgtgggcttt agcacaggcg ccgatcagct gtttctggtg 2820
tcccctctga ccatctgcca cgtgatcgac gctaagagcc ccttctacga tctgagccag 2880
cggagcatgc agaccgagca gtttgagatc gtggtcatcc tggaaggcat tgtggaaacc 2940
accggcatga cctgccaggc cagaaccagc tacacagagg atgaggtgct gtggggccac 3000
agattcttcc ccgtgatctc tctggaagag ggcttcttca aggtggacta cagccagttc 3060
cacgccacct ttgaggtgcc cacacctcct tacagcgtga aagaacaaga ggaaatgctg 3120
ctgatgagca gccctctgat cgcccctgcc atcaccaaca gcaaagaacg gcacaacagc 3180
gtggaatgcc tggacggcct ggatgacatc accaccaagc tgccttccaa gctgcagaag 3240
atcaccggca gagaggactt ccccaagaaa ctgctgagaa tgagcagcac caccagcgag 3300
aaggcctact ctctgggcga cctgcctatg aagctgcagc ggatctctag cgtgcccggc 3360
aactctgagg aaaagctggt ttccaagacc accaagatgc tgagcgatcc catgagccag 3420
tccgtggctg atctgccacc taaactgcag aaaatggctg gcggagccgc cagaatggaa 3480
ggcaatctgc ctgccaaact gcgcaagatg aactccgacc ggttcaccta gacccagctt 3540
tcttgtacaa agtgggaatt cgataatcaa cctctggatt acaaaatttg tgaaagattg 3600
actggtattc ttaactttgt tgctcctttt acgctttgtg gatacgctgc tttattgcct 3660
ttgtatcttg ctattgcttc ccgtttggct ttcattttct cctccttgta taaatcctgg 3720
ttgctgtctc tttttgagga gttgtggccc gttgtcaggc aacgtggcgt ggtgtgcact 3780
gtgtttgctg acgcaacccc cactggttgg ggcattgcca ccacctgtca gctcctttcc 3840
gggactttcg ctttccccct ccctattgcc acggcggaac tcatcgccgc ctgccttgcc 3900
cgctgctgga caggggctcg gctgttgggc actgacaatt ccgtggtgtt gtcggggaaa 3960
tcatcgtcct ttccttggct gctcgcctgt gttgccacct ggattctgcg cgggacgtcc 4020
ttctgctacg tcccttcggc cctcaatcca gcggaccttc cttcccgcgg cctgctgccg 4080
gctctgcggc ctcttccgcg tcttcgcctt cgccctcaga cgagtcggat ctccctttgg 4140
gccgcctccc cgcatcggac tagctagagc tcgctgatca gcctcgactg tgccttctag 4200
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 4260
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 4320
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aagagaatag 4380
caggcatgct ggggagggcc gcaggaaccc ctagtgatgg agttggccac tccctctctg 4440
cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc 4500
cgggcggcct cagtgagcga gcgagcgcgc agctgcctgc aggggcgcct gatgcggtat 4560
tttctcctta cgcatctgtg cggtatttca caccgcatac gtcaaagcaa ccatagtacg 4620
cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta 4680
cacttgccag cgccttagcg cccgctcctt tcgctttctt cccttccttt ctcgccacgt 4740
tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc cgatttagtg 4800
ctttacggca cctcgacccc aaaaaacttg atttgggtga tggttcacgt agtgggccat 4860
cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt aatagtggac 4920
tcttgttcca aactggaaca acactcaact ctatctcggg ctattctttt gatttataag 4980
ggattttgcc gatttcggtc tattggttaa aaaatgagct gatttaacaa aaatttaacg 5040
cgaattttaa caaaatatta acgtttacaa ttttatggtg cactctcagt acaatctgct 5100
ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac gcgccctgac 5160
gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca 5220
tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag acgaaagggc ctcgtgatac 5280
gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt 5340
ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt 5400
atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta 5460
tgagccatat tcaacgggaa acgtcttgct ctaggccgcg attaaattcc aacatggatg 5520
ctgatttata tgggtataaa tgggctcgcg ataatgtcgg gcaatcaggt gcgacaatct 5580
atcgattgta tgggaagccc gatgcgccag agttgtttct gaaacatggc aaaggtagcg 5640
ttgccaatga tgttacagat gagatggtca gactaaactg gctgacggaa tttatgcctc 5700
ttccgaccat caagcatttt atccgtactc ctgatgatgc atggttactc accactgcga 5760
tccccgggaa aacagcattc caggtattag aagaatatcc tgattcaggt gaaaatattg 5820
ttgatgcgct ggcagtgttc ctgcgccggt tgcattcgat tcctgtttgt aattgtcctt 5880
ttaacagcga tcgcgtattt cgtctcgctc aggcgcaatc acgaatgaat aacggtttgg 5940
ttgatgcgag tgattttgat gacgagcgta atggctggcc tgttgaacaa gtctggaaag 6000
aaatgcataa acttttgcca ttctcaccgg attcagtcgt cactcatggt gatttctcac 6060
ttgataacct tatttttgac gaggggaaat taataggttg tattgatgtt ggacgagtcg 6120
gaatcgcaga ccgataccag gatcttgcca tcctatggaa ctgcctcggt gagttttctc 6180
cttcattaca gaaacggctt tttcaaaaat atggtattga taatcctgat atgaataaat 6240
tgcagtttca tttgatgctc gatgagtttt tctaactgtc agaccaagtt tactcatata 6300
tactttagat tgatttaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt 6360
ttgataatct catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc 6420
ccgtagaaaa gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct 6480
tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa 6540
ctctttttcc gaaggtaact ggcttcagca gagcgcagat accaaatact gttcttctag 6600
tgtagccgta gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc 6660
tgctaatcct gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg 6720
actcaagacg atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca 6780
cacagcccag cttggagcga acgacctaca ccgaactgag atacctacag cgtgagctat 6840
gagaaagcgc cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg 6900
tcggaacagg agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc 6960
ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc 7020
ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc 7080
cttttgctca catgt 7095
Claims (26)
1.一种载体,所述载体包含编码G蛋白门控的内向整流钾通道(GIRK1)F137S的亚基1的核苷酸序列。
2.根据权利要求1所述的载体,其中所述载体是选自腺相关病毒(AAV)、腺病毒、慢病毒、SV40病毒载体的病毒。
3.根据权利要求1或2所述的载体,其中所述载体是在VP1衣壳蛋白的GH环中包含7至11个氨基酸长的插入肽的AAV2或AAV9病毒,其中所述插入肽包含氨基酸序列LGETTRP(SEQ IDNO:7)。
4.根据权利要求1至3中任一项所述的载体,其中所述编码G蛋白门控的内向整流钾通道(GIRK1)F137S的亚基1的核苷酸序列处于视锥细胞特异性启动子的控制下。
5.根据权利要求4所述的载体,其中所述视锥细胞特异性启动子是pR1.7或其功能性变体,或者最小M-视蛋白启动子,特别是在pMNTC表达盒中,或者GRK启动子或其截短版本。
6.根据权利要求1至4中任一项所述的载体,其中所述编码GIRK1F137S的核苷酸序列包含序列SEQ ID NO:3。
7.根据前述权利要求中任一项所述的载体,其中所述载体是重组AAV9载体,所述载体包含:
-VP1衣壳蛋白,其中相对于野生型AAV9 VP1衣壳蛋白,在野生型AAV9 VP1衣壳蛋白的氨基酸588和589之间的位置,将7至11个氨基酸长的插入肽插入所述VP1衣壳蛋白的GH环中,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:5);和
-在pR1.7启动子的控制下编码GIRK1 F137S的核苷酸序列。
8.根据前述权利要求中任一项所述的载体,其中所述插入肽包含氨基酸序列AALGETTRPA(SEQ ID NO:10)、LALGETTRPA(SEQ ID NO:11)或GLGETTRPA(SEQ ID NO:12)或由氨基酸序列AALGETTRPA(SEQ ID NO:10)、LALGETTRPA(SEQ ID NO:11)或GLGETTRPA(SEQID NO:12)组成。
9.根据前述权利要求中任一项所述的载体,所述载体还包含编码哺乳动物视锥细胞视蛋白的核苷酸序列。
10.一种药学上可接受的运载体,其包含权利要求1至9中任一项所定义的载体。
11.根据权利要求10所述的药学上可接受的运载体,其还包含含有编码哺乳动物视锥细胞视蛋白的核苷酸序列的载体。
12.根据权利要求10所述的药学上可接受的运载体,其中所述包含编码哺乳动物视锥细胞视蛋白的核苷酸序列的载体:
a)选自腺相关病毒(AAV)、腺病毒、慢病毒和SV40病毒载体;或
b)是在所述VP1衣壳蛋白的GH环中包含7至11个氨基酸长的插入肽的AAV2或AAV9病毒,其中所述插入肽包含氨基酸序列LGETTRP(SEQ ID NO:7);或
c)是重组AAV9载体,其包含:
-VP1衣壳蛋白,其中相对于野生型AAV9 VP1衣壳蛋白,在野生型AAV9 VP1衣壳蛋白的氨基酸588和589之间的位置,将7至11个氨基酸长的插入肽插入所述VP1衣壳蛋白的GH环中,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:7);和
-在pR1.7启动子的控制下编码哺乳动物视锥细胞视蛋白的核苷酸序列。
13.根据权利要求10至12中任一项所述的药学上可接受的运载体,其中所述运载体选自由固体-脂质纳米颗粒、壳聚糖纳米颗粒、脂质体、脂质复合物和阳离子聚合物所组成的组。
14.根据权利要求1至9中任一项所述的载体或根据权利要求10至13中任一项所述的药学上可接受的运载体,其中所述哺乳动物视锥细胞视蛋白是短波长视锥细胞视蛋白(SWO)。
15.一种药物组合物,所述组合物包含根据权利要求1至9和14中任一项所述的载体,或根据权利要求10至14中任一项所述的药学上可接受的运载体,以及药学上可接受的运载体、稀释剂或赋形剂。
16.根据权利要求15所述的药物组合物,所述组合物还包含载体,所述载体包含编码哺乳动物视锥细胞视蛋白的核苷酸序列。
17.根据权利要求1至9和14中任一项所述的载体、根据权利要求10至14中任一项所述的药学上可接受的运载体或根据权利要求15或16所述的药物组合物,其用于治疗视杆-视锥细胞营养不良(RCD)。
18.根据权利要求17所述之用途的载体、药学上可接受的运载体或药物组合物,其中所述载体、药学上可接受的运载体或药物组合物通过在距中央凹一定距离处视网膜下注射来施用。
19.根据权利要求17或18中任一项所述之用途的载体、药学上可接受的运载体或药物组合物,其中所述载体、药学上可接受的运载体或药物组合物通过a)在邻近视网膜动脉的颞上支或颞下支区域;b)在距中央凹中心2-3个视盘直径的距离处;以及c)在由颞视网膜动脉和颞视网膜静脉分支所划定的几何形状中的位置处视网膜下注射来施用。
20.根据权利要求17所述之用途的载体、药学上可接受的运载体或药物组合物,其中所述载体、药学上可接受的运载体或药物组合物通过玻璃体内注射来施用。
21.一种包含编码G蛋白门控的内向整流钾通道(GIRK1)F137S的亚基1的序列的核酸,其用于治疗视杆-视锥细胞营养不良(RCD)。
22.一种包含编码G蛋白门控的内向整流钾通道(GIRK1)F137S的亚基1的异源核酸的视锥前体细胞,其用于治疗视杆-视锥细胞营养不良(RCD)。
23.根据权利要求22所述之用途的视锥前体细胞,其中所述视锥前体细胞由待治疗的RCD受试者获得。
24.根据权利要求22或23所述之用途的视锥前体细胞,其中所述视锥前体细胞是通过对由待治疗的RCD受试者的体细胞获得的诱导性多能干细胞进行分化而获得的。
25.根据权利要求22至24中任一项所述之用途的视锥前体细胞,其中所述视锥前体细胞通过视网膜下腔注射来施用。
26.一种制备包含编码GIRK1 F137S或其功能性衍生物的异源核酸的视锥前体细胞的方法,所述方法包括用根据权利要求1至9和14中任一项所述的病毒载体或根据权利要求10至14中任一项所述的药学上可接受的运载体感染视锥前体细胞。
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