CN116113700A - 用于glut1表达的腺相关病毒载体及其用途 - Google Patents
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Abstract
本文提供的是使用重组腺相关病毒(rAAV)病毒体作为表达GLUT1蛋白或其功能变体的载体,用于GLUT1缺乏综合征和相关病症的基因疗法。rAAV病毒体可以使用内皮特异性启动子,例如FLT‑1或Tie‑1启动子。衣壳可以是AAV6、AA8、AAV9、AAVrh.74或AAVrh.10衣壳或其功能变体。可以使用其它启动子或衣壳。进一步提供的是例如通过大脑内和/或静脉内的rAAV病毒体的治疗方法,以及其它组合物和方法。
Description
相关申请的交叉引用
本申请要求于2021年8月5日提交的美国申请号63/061,726的优先权,所述美国申请的内容通过引用以其整体并入本文。
关于序列表的声明
与本申请相关的序列表以文本格式代替纸质副本提供,并且在此通过引用并入说明书内。含有序列表的文本文件的名称是ROPA_018_01WO_ST25.txt。文本文件为约190KB,于2021年8月3日创建,并且经由EFS-Web以电子方式提交。
背景技术
编码葡萄糖转运蛋白1(GLUT1)的SLC2A1基因中的突变与称为GLUT1缺乏综合征(GLUT1 DS)的神经发育障碍相关。GLUT1 DS是一种常染色体显性遗传病症,其经常呈现为散发性疾病,具有产生单倍体不足并赋予有症状的杂合性的新生突变。
GLUT1是一种胰岛素不依赖性葡萄糖转运蛋白。患有典型GLUT1 DS也称为De Vivo病的患者具有低脑葡萄糖水平,并且显示出通过以下表征的表型:早发性癫痫发作(中位12个月)、发育迟缓、获得性小头畸形(头部生长减慢)、复杂运动障碍(痉挛状态、共济失调、肌张力障碍);阵发性眼头运动;以及脑脊液糖分过少(hypoglycorrhachia)或脑脊液(CSF)中的低葡萄糖浓度。该疾病的临床过程揭示了早期治疗的重要性。Alter等人J.ChildNeurol.30(2):160-169(2015)。GLUT1已牵涉内皮细胞的功能,包括血管生成和血脑屏障(BBB)的维持。然而,单倍体不足小鼠模型中的研究已提供了关于GLUT1在维持BBB的物理完整性中的作用的相矛盾的证据。尽管GLUT1的内皮细胞谱系特异性敲除减少内皮能量可用性并减少增殖而不影响迁移,从而延迟发育性血管生成(Veys等人,Circ.Res.2020;127:466-482),但特异性地在内皮细胞中恢复GLUT1表达的效应尚未进行测试。
关于该疾病的治疗策略在Tang等人Ann.Clin.Trans.Neurol.2019;6(9):1923-1932中进行综述。目前的护理标准是生酮饮食,其提高血液中的酮水平,所述酮取代葡萄糖,以使得它们对于脑可用。用甘油三酯三庚酸甘油酯的治疗已提议作为生酮饮食的替代方案。还已尝试了使用腺相关病毒(AAV)载体的基因疗法。靶向神经元中的GLUT1缺乏,编码处于神经元特异性启动子(例如,突触蛋白)的控制下的GLUT1的AAV9载体已在年幼的产后小鼠模型中进行测试。其它研究采用组成型启动子(例如CMV启动子)或内源性GLUT1基因的启动子。还已测试了各种小分子,包括抗惊厥剂碳酸酐酶抑制剂乙酰唑胺及其它。
虽然GLUT1的单倍体不足阻止脑血管生成,导致相对较小的大脑微血管系统,其可能与内皮尖端细胞的葡萄糖依赖性有关,但Tang等人已观察到内皮细胞中的低GLUT1是否触发这种病理状态仍有待调查。GLUT1蛋白在另外的脑细胞中表达,所述另外的脑细胞包括少突胶质细胞、小胶质细胞和室管膜细胞。
存在通过基因疗法解决GLUT1 DS的多重挑战。需要的载体对CNS的覆盖程度以及达到临床上有意义的效应所需的GLUT1的治疗水平均为高度不可预测的。
存在关于用于GLUT1缺乏综合征的疗法的未满足需求。本文提供的基因疗法解决了这一需求。
发明内容
本发明一般涉及使用编码GLUT1或其功能变体的多核苷酸的基于腺相关病毒(AAV)的递送、用于神经系统疾病或病症的基因疗法。
尽管GLUT1缺乏综合征(DS)是一种神经发育障碍,其临床表现源于适当神经元功能的缺乏,但不受理论束缚,目前的基因疗法可能靶向负责指导中枢神经系统(CNS)中的血管生成和脉管系统发育的内皮细胞。将AAV直接递送至发育中的中枢神经系统CNS脉管系统,伴随内皮尖端细胞中的后续GLUT1蛋白表达,可以在血管生成和神经发育的关键窗口期间促进整个CNS的血管生长和形成。
在一个方面,本公开内容提供了表达盒,其包含可操作地连接至启动子的编码GLUT1或其功能变体的多核苷酸序列。
在一些实施方案中,启动子是内皮启动子,任选地Tie-1启动子、Tie-2(TEK)启动子、FLT-1启动子、FLK-1(KDR)启动子、ICAM-2启动子、VE-钙粘蛋白(CDH5)启动子、VWF启动子、ENG启动子、PDGFB启动子、ESM1启动子、APLN启动子或封闭蛋白-5(Ple261)启动子,条件是内皮启动子不是Glut1启动子。
在一些实施方案中,启动子是FLT-1启动子。
在一些实施方案中,FLT-1启动子是人FLT-1(hFLT-1)启动子。
在一些实施方案中,hFLT-1启动子与SEQ ID NO:1具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在一些实施方案中,启动子是Tie-1启动子。
在一些实施方案中,Tie-1启动子是人Tie-1(hTie-1)启动子。
在一些实施方案中,hTie-1启动子与SEQ ID NO:2具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在一些实施方案中,启动子是血管内皮-钙粘蛋白(VE-钙粘蛋白)启动子。
在一些实施方案中,VE-钙粘蛋白启动子是人VE-钙粘蛋白(hVE-钙粘蛋白)启动子。
在一些实施方案中,hVE-钙粘蛋白启动子与SEQ ID NO:3具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在一些实施方案中,启动子是泛在启动子。
在一些实施方案中,启动子是CMV启动子。
在一些实施方案中,启动子是CAG启动子。
在一些实施方案中,表达盒包含polyA信号,任选地人生长激素(hGH)polyA。
在一些实施方案中,表达盒包含土拨鼠肝炎病毒转录后调控元件(WPRE),任选地WPRE(x)。
在一些实施方案中,表达盒包含3'非翻译区(3’UTR),其包含与SEQ ID NO:4具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性的序列。
在一些实施方案中,编码GLUT1的多核苷酸序列是SLC2A1多核苷酸。
在一些实施方案中,SLC2A1多核苷酸是人SLC2A1多核苷酸。
在一些实施方案中,编码GLUT1的多核苷酸序列与SEQ ID NO:5具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在一些实施方案中,表达盒侧接5'和3'反向末端重复序列(ITR),任选地AAV2ITR。
在一些实施方案中,表达盒与SEQ ID NO:8-16、SEQ ID NO:97、SEQ ID NO:99和SEQ ID NO:101中的任何一个具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在另一个方面,本公开内容提供了基因治疗载体,其包含本公开内容的表达盒中的任何一种。
在一些实施方案中,基因治疗载体是重组腺相关病毒(rAAV)载体。
在一些实施方案中,rAAV载体是AAV6、AAV8、AAV9或AAVrh.74、AAVrh.10载体或其功能变体。
在一些实施方案中,rAAV载体不是AAV2载体。
在一些实施方案中,rAAV载体包含衣壳蛋白,其与SEQ ID NO:76-82中的任何一个具有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的同一性。
在另一个方面,本公开内容提供了治疗和/或预防有此需要的受试者中的疾病或病症的方法,其包括向受试者施用本公开内容的载体中的任何一种。
在一些实施方案中,疾病或病症是神经系统病症。
在一些实施方案中,疾病或病症是葡萄糖转运蛋白1缺乏综合征(GLUT1 DS)或DeVivo病。
在一些实施方案中,载体通过脑室内(ICV)注射进行施用。
在一些实施方案中,施用导致脑中的编码GLUT1的多核苷酸序列的表达增加和/或CSF中的葡萄糖水平或乳酸盐水平增加,任选地处于与参考rAAV载体相比增加的水平,其中任选地所述增加是至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或更高的增加。
在一些实施方案中,施用导致脑中的GLUT1蛋白的表达,任选地处于与参考rAAV载体相比增加的水平。
在一些实施方案中,载体以1E11个载体基因组(vg)、1E12 vg、1E13、1E14、2E14或3E14的剂量进行施用。
在另一个方面,本公开内容提供了在细胞中表达GLUT1的方法,其包括使细胞与本公开内容的载体中的任何一种接触。
在一些实施方案中,细胞是内皮细胞。
在一些实施方案中,内皮细胞是体内内皮细胞。
在一些实施方案中,细胞是神经元。
在一些实施方案中,神经元是体内神经元。
在一些实施方案中,方法包括将载体体内施用于受试者。
在一个进一步的方面,本公开内容提供了多核苷酸(例如,载体基因组)、药物组合物、试剂盒及其它组合物和方法。
在下述详细描述中公开了各个其它方面和实施方案。本发明仅受所附权利要求的限制。
附图说明
图1显示了关于载体基因组的各种非限制性实例的载体图解。
图2显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:17。大写部分是表达盒(SEQ ID NO:8)。
图3显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:19。大写部分是表达盒(SEQ ID NO:10)。
图4显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:21。大写部分是表达盒(SEQ ID NO:12)。
图5显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:96。大写部分是表达盒(SEQ ID NO:97)。载体基因组的完整多核苷酸序列的替代方案是SEQ ID NO:23。表达盒的替代方案是SEQ ID NO:14。
图6显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:25。大写部分是表达盒(SEQ ID NO:16)。
图7显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:98。大写部分是表达盒(SEQ ID NO:99)。
图8显示了载体基因组的非限制性实例的载体图解。载体基因组的完整多核苷酸序列是SEQ ID NO:100。大写部分是表达盒(SEQ ID NO:101)。
图9.AAV9介导的hGlut1蛋白在CHO-Lec2细胞中的表达。CHO-Lec2细胞用表达hGlut1转基因蛋白的AAV9载体进行转导,所述hGlut1转基因蛋白由几种内皮特异性启动子(即,hFLT1、mTie1或hGlut1)之一或泛在CMV启动子驱动。[SLC2A1=GLUT1基因]。
图10A-10C.在人脑微血管内皮细胞(hCMEC/d3s)的转染之后,转基因蛋白(Glut1-GFP)的表达。
图10A.在用含有驱动Glut1-GFP转基因表达的几种内皮细胞启动子之一的构建体转染之后72小时的GFP荧光。
图10B.在用含有两种泛在启动子(CMV或CAG)之一的构建体,不含Glut1的对照载体(CMV-GFP)转染或无转染(无NFX)之后72小时的GFP荧光。使用Operetta CLSTM 获得的图像。
图10C.含有目的启动子(hFLT1、mTie、hTie或hGlut1)和GLUT1(SLC2A1)基因(T2A连接的GFP)和侧接AAV2反向末端重复序列(ITR)的调控元件的表达盒的图解。
图11A-11C.在人GLUT1(SLC2A1)的表达之后,在hCMEC/d3细胞中的2-脱氧-D-葡萄糖(葡萄糖)摄取。用质粒转染人脑微血管内皮细胞(hCMEC/d3s),所述质粒表达CAG-GFP(阴性对照)、或者由几种内皮特异性启动子(即,hFLT1、mTie1或hGlut1)之一或泛在CMV启动子驱动的hGLUT1-t2A-eGFP转基因。使用基于发光的试剂盒在培养基中使用0.5mM 2-脱氧-D-葡萄糖(2-DG)来测量葡萄糖摄取。使用相衬成像通过总细胞使葡萄糖摄取标准化[误差条代表S.E.M;n=6个重复/条件]。
图11A.在第一个实验中,在转染后72小时测量葡萄糖(2-DG)摄取。
图11B.在第二个实验中,在转染后72小时测量葡萄糖(2-DG)摄取。
图11C.在转染后96小时测量葡萄糖(2-DG)摄取。
图12A-12B.在人GLUT1(SLC2A1)的表达之后,在hCMEC/d3细胞中的2-脱氧-D-葡萄糖(葡萄糖)摄取。用质粒转染人脑微血管内皮细胞(hCMEC/d3s),所述质粒表达由几种内皮特异性启动子(即,hFLT1、mTie1或hGlut1)之一或泛在CMV启动子驱动的hGLUT1-t2A-eGFP转基因。未转染的hCMEC/d3充当对照(CON)。使用基于发光的试剂盒在培养基中使用不同浓度(0mM、0.1mM、0.5mM或1.0mM)的2-脱氧-D-葡萄糖来测量葡萄糖摄取。根据制造商的建议执行的,通过使用RealTime-Glo MT Cell Viability Assay的多重分析,在每个细胞的基础上对葡萄糖摄取进行标准化。
图12A.显示了在72小时时间点,在人Glut1(SLC2A1)的表达之后,在hCMEC/d3细胞中的葡萄糖摄取。
图12B.显示了在96小时时间点,在人Glut1(SLC2A1)的表达之后,在hCMEC/d3细胞中的葡萄糖摄取。
图13.在AAV9介导的hGLUT1(SLC2A1)在hCMEC/d3细胞中的表达之后,2-脱氧-D-葡萄糖(葡萄糖)摄取。用AAV9载体(3x 105个载体基因组/细胞)转导人脑微血管内皮细胞(hCMEC/d3s),所述AAV9载体表达CAG-GFP(阴性对照)、或者由几种内皮特异性启动子(即,hFLT1、mTie1或hGlut1)之一或泛在CMV启动子驱动的hGLUT1转基因。使用基于发光的Glucose Uptake-Glo试剂盒在转导后72小时测量葡萄糖(2-DG)摄取,并且使用RealTime-Glo MT Cell Viability Assay对每个细胞进行标准化[误差条代表S.E.M;n=4个重复/条件]。
具体实施方式
定义
章节标题仅用于组构目的,并且不应解释为将所述的主题限制于特定方面或实施方案。
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在本说明书中,除非另有说明,否则任何浓度范围、百分比范围、比率范围或整数范围应理解为包括在所叙述范围内的任何整数的值,并在适当时包括其分数(例如,整数的十分之一和百分之一)。当紧接在数目或数字之前时,术语“约”意指该数目或数字范围加或减10%。应该理解,除非另有说明,否则如本文使用的,术语“一个”和“一种”指所列举的组分中的“一个或多个/一种或多种”。替代项(例如“或”)的使用应该理解为意指替代项中的任一个、两个或其任何组合。术语“和/或”应该理解为意指替代项中的任一个或两个。如本文使用的,术语“包括”和“包含”同义使用。
如本文使用的,关于多肽或多核苷酸序列,术语“同一性”和“相同的”指在该“查询”序列与“主题”序列的比对,例如由BLAST算法生成的比对中的精确匹配残基的百分比。除非另有说明,否则在主题序列的全长上计算同一性。因此,如果在将查询序列与主题序列比对时,查询序列与主题序列“具有至少x%的同一性”,则主题序列中至少x%(向下四舍五入)的残基被比对为与查询序列中的对应残基精确匹配。在主题序列具有可变位置(例如,表示为X的残基)的情况下,与查询序列中的任何残基的比对计数为匹配。
如本文使用的,“AAV载体”或“rAAV载体”指包含一种或多种目的多核苷酸(或转基因)的重组载体,所述目的多核苷酸侧接AAV末端重复序列(ITR)。当存在于已用编码且表达rep和cap基因产物的质粒转染的宿主细胞中时,此类AAV载体可以被复制并包装成感染性病毒颗粒。可替代地,可以使用已稳定改造为表达rep和cap基因的宿主细胞,将AAV载体包装到感染性颗粒内。
如本文使用的,“AAV病毒体”或“AAV病毒颗粒”或“AAV载体颗粒”指由至少一种AAV衣壳蛋白和衣壳化多核苷酸AAV载体构成的病毒颗粒。如本文使用的,如果颗粒包含异源多核苷酸(即,除野生型AAV基因组外的多核苷酸,例如待递送至哺乳动物细胞的转基因),则它通常被称为“AAV载体颗粒”或简称为“AAV载体”。因此,AAV载体颗粒的产生必然包括AAV载体的产生,因为此类载体包含在AAV载体颗粒内。
如本文使用的,“启动子”指能够促进从真核细胞中的多核苷酸开始RNA转录的多核苷酸序列。
如本文使用的,“载体基因组”指由载体(例如,rAAV病毒体)包装的多核苷酸序列,包括侧接序列(在AAV中,反向末端重复序列)。术语“表达盒”和“多核苷酸盒”指侧接ITR序列之间的载体基因组的一部分。“表达盒”暗示载体基因组包含可操作地连接至驱动表达的元件(例如,启动子),编码基因产物的至少一种基因。
如本文使用的,术语“有需要的患者”或“有需要的受试者”指处于疾病、病症或状况的风险中或者患有疾病、病症或状况的患者或受试者,所述疾病、病症或状况顺应用本文公开的重组基因治疗载体或基因编辑系统的治疗或改善。有需要的患者或受试者可以是例如诊断有与中枢神经系统相关的病症的患者或受试者。受试者可能具有SLC2A1基因中的突变或者SLC2A1基因或基因调控序列的全部或部分的缺失,其导致GLUT1蛋白的异常表达。“受试者”和“患者”在本文中可互换使用。通过本文所述方法治疗的受试者可以是新生儿、婴儿、青少年或成人。
如本文使用的,术语“变体”或“功能变体”可互换地指与亲本蛋白质相比具有一种或多种氨基酸取代、插入或缺失的蛋白质,其保留亲本蛋白质的一种或多种所需活性。
如本文使用的,“遗传破坏”指基因的部分或完全的功能缺失或异常活性。例如,受试者可能遭受SLC2A1基因的表达或功能中的遗传破坏,其降低受试者的至少一些细胞(例如,内皮细胞和/或神经元)中的GLUT1蛋白的表达或者导致其丧失或异常功能。
如本文使用的,“治疗”指改善疾病或病症的一种或多种症状。术语“预防”指延迟或中断疾病或病症的一种或多种症状的发作,或者减缓SLC2A1相关的神经系统疾病或病症,例如GLUT1缺乏综合征(GLUT1 DS)的进展。
GLUT1蛋白或多核苷酸
本公开内容考虑了与葡萄糖转运蛋白1(GLUT1)蛋白相关的组合物和使用方法。已知SLC2A1中的各种突变与GLUT1 DS相关。已观察到遗传突变和新生突变两者。在一些情况下,杂合错义突变足以引起疾病。
GLUT1的多肽序列如下:
MEPSSKKLTGRLMLAVGGAVLGSLQFGYNTGVINAPQKVIEEFYNQ
TWVHRYGESILPTTLTTLWSLSVAIFSVGGMIGSFSVGLFVNRFGRRNSM
LMMNLLAFVSAVLMGFSKLGKSFEMLILGRFIIGVYCGLTTGFVPMYVG
EVSPTALRGALGTLHQLGIVVGILIAQVFGLDSIMGNKDLWPLLLSIIFIPA
LLQCIVLPFCPESPRFLLINRNEENRAKSVLKKLRGTADVTHDLQEMKEES
RQMMREKKVTILELFRSPAYRQPILIAVVLQLSQQLSGINAVFYYSTSIFE
KAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAI
LMTIALALLEQLPWMSYLSIVAIFGFVAFFEVGPGPIPWFIVAELFSQGPRP
AAIAVAGFSNWTSNFIVGMCFQYVEQLCGPYVFIIFTVLLVLFFIFTYFKV
PETKGRTFDEIASGFRQGGASQSDKTPEELFHPLGADSQV
(SEQ ID NO:26)。
在一些实施方案中,GLUT1蛋白包含与SEQ ID NO:26至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多肽序列)。
在一些实施方案中,本公开内容提供了重组腺相关病毒(rAAV)病毒体,其包含衣壳和载体基因组,其中所述载体基因组包含可操作地连接至启动子的编码GLUT1蛋白或其功能变体的多核苷酸序列。在一些实施方案中,本公开内容提供了重组腺相关病毒(rAAV)病毒体,其包含衣壳和载体基因组,其中所述载体基因组包含可操作地连接至启动子的编码GLUT1蛋白的多核苷酸序列。编码GLUT1蛋白的多核苷酸可以包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
ATGGAGCCCAGCAGCAAGAAGCTGACGGGTCGCCTCATGCTGGCCGTGGGAGGAGCAGTGCTTGGCTCCCTGCAGTTTGGCTACAACACTGGAGTCATCAATGCCCCCCAGAAGGTGATCGAGGAGTTCTACAACCAGACATGGGTCCACCGCTATGGGGAGAGCATCCTGCCCACCACGCTCACCACGCTCTGGTCCCTCTCAGTGGCCATCTTTTCTGTTGGGGGCATGATTGGCTCCTTCTCTGTGGGCCTTTTCGTTAACCGCTTTGGCCGGCGGAATTCAATGCTGATGATGAACCTGCTGGCCTTCGTGTCCGCCGTGCTCATGGGCTTCTCGAAACTGGGCAAGTCCTTTGAGATGCTGATCCTGGGCCGCTTCATCATCGGTGTGTACTGCGGCCTGACCACAGGCTTCGTGCCCATGTATGTGGGTGAAGTGTCACCCACAGCCCTTCGTGGGGCCCTGGGCACCCTGCACCAGCTGGGCATCGTCGTCGGCATCCTCATCGCCCAGGTGTTCGGCCTGGACTCCATCATGGGCAACAAGGACCTGTGGCCCCTGCTGCTGAGCATCATCTTCATCCCGGCCCTGCTGCAGTGCATCGTGCTGCCCTTCTGCCCCGAGAGTCCCCGCTTCCTGCTCATCAACCGCAACGAGGAGAACCG GGCCAAGAGTGTGCTAAAGAAGCTGCGCGGGACAGCTGACGTGACCCATGACCTGCAGGAGATGAAGGAAGAGAGTCGGCAGATGATGCGGGAGAAGAAGGTCACCATCCTGGAGCTGTTCCGCTCCCCCGCCTACCGCCAGCCCATCCTCATCGCTGTGGTGCTGCAGCTGTCCCAGCAGCTGTCTGGCATCAACGCTGTCTTCTATTACTCCACGAGCATCTTCGAGAAGGCGGGGGTGCAGCAGCCTGTGTATGCCACCATTGGCTCCGGTATCGTCAACACGGCCTTCACTGTCGTGTCGCTGTTTGTGGTGGAGCGAGCAGGCCGGCGGACCCTGCACCTCATAGGCCTCGCTGGCATGGCGGGTTGTGCCATACTCATGACCATCGCGCTAGCACTGCTGGAGCAGCTACCCTGGATGTCCTATCTGAGCATCGTGGCCATCTTTGGCTTTGTGGCCTTCTTTGAAGTGGGTCCTGGCCCCATCCCATGGTTCATCGTGGCTGAACTCTTCAGCCAGGGTCCACGTCCAGCTGCCATTGCCGTTGCAGGCTTCTCCAACTGGACCTCAAATTTCATTGTGGGCATGTGCTTCCAGTATGTGGAGCAACTGTGTGGTCCCTACGTCTTCATCATCTTCACTGTGCTCCTGGTTCTGTTCTTCATCTTCACCTACTTCAAAGTTCCTGAGACTAAAGGCCGGACCTTCGATGAGATCGCTTCCGGCTTCCGGCAGGGGGGAGCCAGCCAAAGTGACAAGACACCCGAGGAGCTGTTCCATCCCCTGGGGGCTGATTCCCAAGTG
(SEQ ID NO:5)。
在一些实施方案中,编码GLUT1蛋白的多核苷酸序列是密码子优化的序列。编码GLUT1蛋白的多核苷酸可以包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
ATGGAACCATCATCCAAAAAGCTGACCGGACGACTGATGCTTGCAGTTGGCGGTGCGGTCTTGGGGAGCCTGCAGTTTGGGTACAATACTGGCGTAATCAATGCCCCGCAGAAGGTTATTGAAGAATTTTACAATCAAACGTGGGTACATCGCTACGGTGAATCCATTCTTCCTACAACTCTGACCACACTCTGGAGCCTTTCTGTAGCGATTTTTTCCGTCGGGGGCATGATAGGATCATTTTCCGTCGGTCTTTTTGTGAACCGCTTTGGCCGGAGAAATTCCATGCTGATGATGAATCTTCTCGCTTTCGTGAGTGCCGTCCTCATGGGATTTAGTAAACTGGGTAAATCTTTCGAGATGTTGATACTGGGGAGATTTATTATCGGCGTGTATTGTGGTTTGACCACGGGCTTTGTACCAATGTATGTTGGCGAGGTTTCTCCGACAGCATTGAGAGGTGCACTCGGGACCTTGCACCAGTTGGGCATCGTAGTAGGAATCCTTATAGCGCAAGTTTTCGGGCTCGATTCCATCATGGGGAACAAAGATCTCTGGCCATTGCTCCTCTCAATAATTTTTATACCGGCATTGCTTCAGTGTATTGTTCTTCCTTTTTGCC CAGAGTCCCCTAGGTTCCTGCTCATAAACAGGAATGAGGAGAATCGCGCTAAGTCCGTGTTGAAAAAACTTAGGGGAACTGCAGACGTTACTCACGATTTGCAAGAGATGAAGGAGGAATCTAGGCAAATGATGCGCGAGAAGAAGGTTACCATACTCGAACTCTTCCGCTCCCCCGCGTACAGGCAGCCCATTCTTATCGCGGTCGTCTTGCAGTTGTCACAACAGTTGAGTGGGATTAATGCAGTTTTCTATTATAGCACGTCCATATTTGAAAAAGCAGGCGTCCAACAACCTGTCTATGCAACTATAGGCTCAGGCATTGTAAACACAGCGTTTACTGTAGTATCACTGTTTGTCGTTGAGCGGGCTGGTCGAAGGACCTTGCACCTCATAGGACTGGCGGGCATGGCGGGCTGTGCGATTCTTATGACAATTGCGCTCGCGCTGTTGGAACAGCTTCCGTGGATGTCCTATCTCTCTATAGTAGCAATATTTGGATTTGTTGCATTTTTTGAAGTTGGGCCCGGACCTATCCCCTGGTTCATCGTCGCGGAGCTCTTTTCCCAAGGCCCAAGACCGGCTGCCATTGCTGTTGCAGGCTTCTCAAACTGGACGAGTAATTTCATAGTAGGTATGTGTTTCCAGTATGTTGAACAGCTCTGTGGGCCCTATGTCTTTATCATCTTTACTGTGTTGCTCGTGTTGTTCTTTATCTTCACTTATTTCAAAGTACCCGAGACAAAGGGCAGGACGTTTGACGAGATTGCATCTGGTTTTAGACAAGGAGGTGCCTCACAGAGTGATAAAACCCCGGAGGAATTGTTTCATCCGCTGGGAGCCGACTCACAGGTC
(SEQ ID NO:27)
任选地,编码载体基因组的多核苷酸序列可以包含Kozak序列,包括但不限于GCCACCATGG(SEQ ID NO:28)。Kozak序列可能与编码GLUT1蛋白或其功能变体的多核苷酸序列重叠。例如,载体基因组可以包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列(其中Kozak是加下划线的):
gccaccATGGAGCCCAGCAGCAAGAAGCTGACGGGTCGCCTCATGCTGGCCGTGGGAGGAGCAGTGCTTGGCTCCCTGCAGTTTGGCTACAACACTGGAGTCATCAATGCCCCCCAGAAGGTGATCGAGGAGTTCTACAACCAGACATGGGTCCACCGCTATGGGGAGAGCATCCTGCCCACCACGCTCACCACGCTCTGGTCCCTCTCAGTGGCCATCTTTTCTGTTGGGGGCATGATTGGCTCCTTCTCTGTGGGCCTTTTCGTTAACCGCTTTGGCCGGCGGAATTCAATGCTGATGATGAACCTGCTGGCCTTCGTGTCCGCCGTGCTCATGGGCTTCTCGAAACTGGGCAAGTCCTTTGAGATGCTGATCCTGGGCCGCTTCATCATCGGTGTGTACTGCGGCCTGACCACAGGCTTCGTGCCCATGTATGTGGGTGAAGTGTCACCCACAGCCCTTCGTGGGGCCCTGGGC ACCCTGCACCAGCTGGGCATCGTCGTCGGCATCCTCATCGCCCAGGTGTTCGGCCTGGACTCCATCATGGGCAACAAGGACCTGTGGCCCCTGCTGCTGAGCATCATCTTCATCCCGGCCCTGCTGCAGTGCATCGTGCTGCCCTTCTGCCCCGAGAGTCCCCGCTTCCTGCTCATCAACCGCAACGAGGAGAACCGGGCCAAGAGTGTGCTAAAGAAGCTGCGCGGGACAGCTGACGTGACCCATGACCTGCAGGAGATGAAGGAAGAGAGTCGGCAGATGATGCGGGAGAAGAAGGTCACCATCCTGGAGCTGTTCCGCTCCCCCGCCTACCGCCAGCCCATCCTCATCGCTGTGGTGCTGCAGCTGTCCCAGCAGCTGTCTGGCATCAACGCTGTCTTCTATTACTCCACGAGCATCTTCGAGAAGGCGGGGGTGCAGCAGCCTGTGTATGCCACCATTGGCTCCGGTATCGTCAACACGGCCTTCACTGTCGTGTCGCTGTTTGTGGTGGAGCGAGCAGGCCGGCGGACCCTGCACCTCATAGGCCTCGCTGGCATGGCGGGTTGTGCCATACTCATGACCATCGCGCTAGCACTGCTGGAGCAGCTACCCTGGATGTCCTATCTGAGCATCGTGGCCATCTTTGGCTTTGTGGCCTTCTTTGAAGTGGGTCCTGGCCCCATCCCATGGTTCATCGTGGCTGAACTCTTCAGCCAGGGTCCACGTCCAGCTGCCATTGCCGTTGCAGGCTTCTCCAACTGGACCTCAAATTTCATTGTGGGCATGTGCTTCCAGTATGTGGAGCAACTGTGTGGTCCCTACGTCTTCATCATCTTCACTGTGCTCCTGGTTCTGTTCTTCATCTTCACCTACTTCAAAGTTCCTGAGACTAAAGGCCGGACCTTCGATGAGATCGCTTCCGGCTTCCGGCAGGGGGGAGCCAGCCAAAGTGACAAGACACCCGAGGAGCTGTTCCATCCCCTGGGGGCTGATTCCCAAGTG
(SEQ ID NO:29)。
在一些实施方案中,Kozak序列是替代的Kozak序列,其包含以下中的任何一种或由其组成:
(gcc)gccRccAUGG(SEQ ID NO:30);
AGNNAUGN;
ANNAUGG;
ACCAUGG;和
GACACCAUGG(SEQ ID NO:31)。
在一些实施方案中,载体基因组不包含Kozak序列。
载体基因组
本公开内容的AAV病毒体包含载体基因组。载体基因组可以包含表达盒(或用于不需要表达多核苷酸序列的基因编辑应用的多核苷酸盒)。可以使用任何合适的反向末端重复序列(ITR)。ITR可以来自与衣壳相同的血清型或不同的血清型(例如,可以使用AAV2ITR)。
在一些实施方案中,5’ITR包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCT
(SEQ ID NO:32)
在一些实施方案中,5’ITR包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
GCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTA
(SEQ ID NO:6)
在一些实施方案中,5’ITR包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTGTAGTTAATGATTAACCCGCCATGCTACTTATCTACGTA
(SEQ ID NO:33)
在一些实施方案中,3’ITR包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG
(SEQ ID NO:34)
在一些实施方案中,3’ITR包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
TACGTAGATAAGTAGCATGGCGGGTTAATCATTAACTACAAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGC
(SEQ ID NO:7)
在一些实施方案中,载体基因组包含例如与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的一个或多个填充序列:
GCGGCAATTCAGTCGATAACTATAACGGTCCTAAGGTAGCGATTTAAATACGCGCTCTCTTAAGGTAGCCCCGGGACGCGTCAATTGACTACAAACCGAGTATCTGCAGAGGGCCCTGCGTATG(SEQ ID NO:35);
CTTCTGAGGCGGAAAGAACCAGATCCTCTCTTAAGGTAGCATCGAGATTTAAATTAGGGATAACAGGGTAATGGCGCGGGCCGC(SEQ ID NO:36);或
GTTACCCAGGCTGGAGTGCAGTGGCACATTTCTGCTCACTGCAACCTCCTCCTCCCTGGGTTC(SEQID NO:37)。
启动子
在一些实施方案中,编码GLUT1蛋白或其功能变体的多核苷酸序列可操作地连接至启动子。
本公开内容考虑了各种启动子的使用。可用于本公开内容的实施方案中的启动子包括但不限于巨细胞病毒(CMV)启动子、磷酸甘油酸激酶(PGK)启动子、或由CMV增强子和鸡β-肌动蛋白启动子和兔β-球蛋白基因(CAG)的一部分构成的启动子序列。在一些情况下,启动子可以是合成启动子。示例性合成启动子由Schlabach等人PNAS USA.107(6):2538–43(2010)提供。在一些实施方案中,启动子包含与以下至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列:
ACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCGG
(SEQ ID NO:38)
在一些实施方案中,编码GLUT1蛋白或其功能变体的多核苷酸序列可操作地连接至诱导型启动子。诱导型启动子可以被配置成响应于药剂的添加或累积或者响应于药剂的去除、降解或稀释而使多核苷酸序列转录表达或不转录表达。药剂可以是药物。药剂可以是四环素或其衍生物之一,包括但不限于强力霉素。在一些情况下,诱导型启动子是tet-on启动子、tet-off启动子、化学调节启动子、物理调节启动子(即,响应光的存在或不存在或者低温或高温的启动子)。诱导型启动子包括重金属离子诱导型启动子(例如小鼠乳腺肿瘤病毒(mMTV)启动子或各种生长激素启动子),以及在T7 RNA聚合酶的存在下具有活性的来自T7噬菌体的启动子。该诱导型启动子列表是非限制性的。
在一些情况下,启动子是组织特异性启动子,例如与非神经元细胞中相比,能够在神经元中驱动表达至更大程度的启动子。在一些实施方案中,组织特异性启动子是神经元特异性启动子。在一些实施方案中,组织特异性启动子选自任何各种神经元特异性启动子,包括但不限于hSYN1(人突触蛋白)、INA(α-中连蛋白(internexin))、NES(巢蛋白)、TH(酪氨酸羟化酶)、FOXA2(叉头框A2)、CaMKII(钙调蛋白依赖性蛋白激酶II)和NSE(神经元特异性烯醇化酶)。在一些情况下,启动子是泛在启动子。“泛在启动子”指在实验或临床条件下并非组织特异性的启动子。在一些情况下,泛在启动子是CMV、CAG、UBC、PGK、EF1-α、GAPDH、SV40、HBV、鸡β-肌动蛋白和人β-肌动蛋白启动子中的任何一种。
在一些实施方案中,启动子序列选自表3。在一些实施方案中,启动子包含与SEQID NOS 1-3和39-51中的任何一个至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。
表3
在一个优选的实施方案中,载体基因组包含与SEQ ID NO:1至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。在一个优选的实施方案中,载体基因组包含与SEQ ID NO:2至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。在一个优选的实施方案中,载体基因组包含与SEQ ID NO:3至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。
启动子的进一步说明性实例是来自猿猴病毒40的SV40晚期启动子、杆状病毒多面体增强子/启动子元件、单纯疱疹病毒胸苷激酶(HSV tk)、来自巨细胞病毒(CMV)的立即早期启动子和各种逆转录病毒启动子包括LTR元件。大量各种其它启动子是本领域已知且一般可用的,并且许多此类启动子的序列可在序列数据库例如GenBank数据库中获得。
其它调控元件
在一些情况下,本公开内容的载体进一步包含选自增强子、内含子、polyA信号、2A肽编码序列、WPRE(土拨鼠肝炎病毒转录后调控元件)和HPRE(乙型肝炎转录后调控元件)的一种或多种调控元件。
在一些实施方案中,载体包含CMV增强子。
在某些实施方案中,载体包含一种或多种增强子。在特定实施方案中,增强子是CMV增强子序列、GAPDH增强子序列、β-肌动蛋白增强子序列或EF1-α增强子序列。前述的序列是本领域已知的。例如,CMV立即早期(IE)增强子的序列是:
CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG
(SEQ ID NO:52)
在某些实施方案中,载体包含一个或多个内含子。在特定实施方案中,内含子是兔球蛋白内含子序列、鸡β-肌动蛋白内含子序列、合成内含子序列或EF1-α内含子序列。
在某些实施方案中,载体包含polyA序列。在特定实施方案中,polyA序列是兔球蛋白polyA序列、人生长激素polyA序列、牛生长激素polyA序列、PGKpolyA序列、SV40polyA序列或TKpolyA序列。在一些实施方案中,poly-A信号可以是牛生长激素多腺苷酸化信号(bGHpA)。
在某些实施方案中,载体包含一种或多种转录物稳定元件。在特定实施方案中,转录物稳定元件是WPRE序列、HPRE序列、支架附着区、3’UTR或5’UTR。在特定实施方案中,载体包含5’UTR和3’UTR两者。
在一些实施方案中,载体包含选自表4的5'非翻译区(UTR)。在一些实施方案中,载体基因组包含与SEQ ID NO 53-61中的任何一个至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。
表4
在一些实施方案中,载体包含选自表5的3'非翻译区。在一些实施方案中,载体基因组包含与SEQ ID NO 62-70中的任何一个至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。
表5
在一些实施方案中,载体包含选自表6的多腺苷酸化(polyA)信号。在一些实施方案中,polyA信号包含与SEQ ID NO 71-75中的任何一个至少75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的多核苷酸序列。
表6
示例性载体基因组在图2-8中进行描绘,并且作为SEQ ID NO:17-25提供。每个序列的大写部分是表达盒(SEQ ID NO:8-16、SEQ ID NO:97、SEQ ID NO:99和SEQ ID NO:101)。在一些实施方案中,载体基因组包含多核苷酸序列、基本上由多核苷酸序列组成或由多核苷酸序列组成,所述多核苷酸序列与SEQ ID NO:8-16、SEQ ID NO:97、SEQ ID NO:99和SEQ ID NO:101中的任何一个具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的同一性,任选地具有或不具有以小写的ITR序列。编码序列是加下划线的。表达盒是大写的。
腺相关病毒载体
腺相关病毒(AAV)是一种复制缺陷型细小病毒,其单链DNA基因组长度为约4.7kb,包括两个~145核苷酸的反向末端重复序列(ITR)。存在AAV的多重已知变体,当按抗原表位分类时,有时也称为血清型。AAV血清型的基因组的核苷酸序列是已知的。例如,AAV-1的完整基因组在GenBank登录号NC_002077中提供;AAV-2的完整基因组在NC_001401和Srivastava等人,J.Virol.,45:555-564(1983)中提供;AAV-3的完整基因组在GenBank登录号NC_1829中提供;AAV-4的完整基因组在GenBank登录号NC_001829中提供;AAV-5基因组在GenBank登录号AF085716中提供;AAV-6的完整基因组在GenBank登录号NC_00 1862中提供;AAV-7和AAV-8基因组的至少一部分分别在GenBank登录号AX753246和AX753249中提供;AAV-9基因组在Gao等人,J.Virol.,78:6381-6388(2004)中提供;AAV-10基因组在Mol.Ther.,13(1):67-76(2006)中提供;并且AAV-11基因组在Virology,330(2):375-383(2004)中提供。AAVrh.74基因组的序列在通过引用并入本文的美国专利9,434,928中提供。指导病毒DNA复制(rep)、衣壳化/包装和宿主细胞染色体整合的顺式作用序列包含在AAVITR内。三种AAV启动子(因其相对图谱定位而命名为p5、p19和p40)驱动编码rep和cap基因的两个AAV内部开放读码框的表达。两个rep启动子(p5和p19)加上单个AAV内含子(在核苷酸2107和2227处)的差异剪接,导致由rep基因产生四种rep蛋白(rep78、rep68、rep52和rep40)。Rep蛋白具有多重酶促性质,其最终负责复制病毒基因组。cap基因由p40启动子表达,并且它编码三种衣壳蛋白VP1、VP2和VP3。选择性剪接和非共有翻译起始位点负责三种相关衣壳蛋白的产生。单个共有多腺苷酸化位点定位于AAV基因组的图谱位置95处。AAV的生命周期和遗传学在Muzyczka,Current Topics in Microbiology and Immunology,158:97-129(1992)中进行综述。
AAV具有使其作为例如在基因治疗中用于将外源DNA递送至细胞的载体有吸引力的独特特征。培养中的细胞的AAV感染是非致细胞病变的,并且人和其它动物的天然感染是隐性和无症状的。此外,AAV感染许多哺乳动物细胞,允许在体内靶向许多不同的组织的可能性。此外,AAV转导缓慢分裂细胞和非分裂细胞,并且可以作为转录活性的核附加体(染色体外元件)对于这些细胞的寿命基本上持续。AAV原病毒基因组作为克隆DNA插入质粒中,其使得重组基因组的构建可行。此外,由于指导AAV复制和基因组衣壳化的信号包含在AAV基因组的ITR内,因此基因组的内部大约4.3kb的一些或全部(编码复制和结构衣壳蛋白,rep-cap)可能由外来DNA替换。为了生成AAV载体,rep和cap蛋白可以是反式提供的。AAV的另一个显著特征在于它是一种极其稳定和强大的病毒。它容易地承受用于灭活腺病毒的条件(56°至65℃数小时),使得AAV的冷藏保存较不关键。AAV甚至可以是冻干的。最后,AAV感染的细胞对重复感染没有抵抗力。
rAAV基因组中的AAV DNA可以来自重组病毒可以由其衍生的任何AAV变体或血清型,包括但不限于AAV变体或血清型AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-11、AAV-12、AAV-13和AAVrh10。假型rAAV的生产公开于例如WO 01/83692。还考虑了其它类型的rAAV变体,例如具有衣壳突变的rAAV。参见例如,Marsic等人,Molecular Therapy,22(11):1900-1909(2014)。各种AAV血清型的基因组的核苷酸序列是本领域已知的。
在一些情况下,rAAV包含自互补的基因组。如本文定义的,包含“自互补”或“双链”基因组的rAAV指这样的rAAV,其已进行改造,使得rAAV的编码区配置为形成分子内双链DNA模板,如McCarty等人Self-complementary recombinant adeno-associated virus(scAAV)vectors promote efficient transduction independently of DNAsynthesis.Gene Therapy.8(16):1248–54(2001)中描述的。在一些情况下,本公开内容考虑了包含自互补基因组的rAAV的使用,因为在感染(此类转导)而不是等待细胞介导的rAAV基因组的第二链合成后,scAAV的两个互补一半将结合,以形成一个双链DNA(dsDNA)单元,其准备好立即复制和转录。应理解,与在rAAV中发现的完全编码容量(4.7-6kb)不同,包含自互补基因组的rAAV只能容纳该量的约一半(≈2.4kb)。
在其它情况下,rAAV载体包含单链基因组。如本文定义的,“单一标准”基因组指并非自互补的基因组。在大多数情况下,非重组AAV具有单链DNA基因组。已存在rAAV应该是scAAV,以实现细胞的有效转导的一些指示。然而,本公开内容考虑了可能具有单链基因组,而不是自互补基因组的rAAV载体,伴随rAAV载体的其它遗传修饰可能有益于在靶细胞中获得最佳基因转录的理解。在一些情况下,本公开内容涉及能够实现向小鼠眼中的前段的有效基因转移的单链rAAV载体。参见Wang等人Single stranded adeno-associated virusachieves efficient gene transfer to anterior segment in the mouse eye.PLoSONE 12(8):e0182473(2017)。
在一些情况下,rAAV载体具有血清型AAV1、AAV2、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAVrh10或AAVrh74。假型rAAV的生产公开于例如WO 01/83692中。还考虑了其它类型的rAAV变体,例如具有衣壳突变的rAAV。参见例如,Marsic等人,Molecular Therapy,22(11):1900-1909(2014)。在一些情况下,rAAV载体具有AAV9血清型。在一些实施方案中,所述rAAV载体具有血清型AAV9并且包含单链基因组。在一些实施方案中,所述rAAV载体具有血清型AAV9并且包含自互补基因组。在一些实施方案中,rAAV载体包含AAV2的反向末端重复(ITR)序列。在一些实施方案中,rAAV载体包含AAV2基因组,使得rAAV载体是AAV-2/9载体、AAV-2/6载体或AAV-2/8载体。
关于大多数已知AAV的全长序列和衣壳基因的序列在美国专利号8,524,446中提供,所述美国专利以其整体并入本文。
AAV载体可以包含野生型AAV序列,或者它们可以包含对野生型AAV序列的一种或多种修饰。在某些实施方案中,AAV载体包含在衣壳蛋白例如VP1、VP2和/或VP3内的一种或多种氨基酸修饰,例如取代、缺失或插入。在特定实施方案中,当向受试者提供AAV载体时,修饰提供了减少的免疫原性。
rAAV的衣壳蛋白可以这样进行修饰,使得rAAV靶向特定目的靶组织,例如内皮细胞或更具体地内皮尖端细胞。在一些实施方案中,将rAAV直接注射到受试者的脑室内间隙内。
在一些实施方案中,rAAV病毒体是AAV2 rAAV病毒体。衣壳可以是AAV2衣壳或其功能变体。在一些实施方案中,AAV2衣壳与例如以下的参考AAV2衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL
(SEQ ID NO:76)
在一些实施方案中,rAAV病毒体是AAV9 rAAV病毒体。衣壳可以是AAV9衣壳或其功能变体。在一些实施方案中,AAV9衣壳与例如以下的参考AAV9衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARG LVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL
(SEQ ID NO:77)
在一些实施方案中,rAAV病毒体是AAV6 rAAV病毒体。衣壳可以是AAV6衣壳或其功能变体。在一些实施方案中,AAV6衣壳与例如以下的参考AAV6衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPAKKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL
(SEQ ID NO:78)
在一些实施方案中,rAAV病毒体是AAVrh.10rAAV病毒体。衣壳可以是AAVrh.10衣壳或其功能变体。在一些实施方案中,AAVrh.10衣壳与例如以下的参考AAVrh.10衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYQFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFSQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTDGTYSEPRPIGTRYLTRNL
(SEQ ID NO:79)
在一些实施方案中,rAAV病毒体是AAV8 rAAV病毒体。衣壳可以是AAV8衣壳或其功能变体。在一些实施方案中,AAV8衣壳与例如以下的参考AAV8衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTGGTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAWTAGTKYHLNGRNSLANPGIAMATHKDDEER FFPSNGILIFGKQNAARDNADYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYLTRNL
(SEQ ID NO:80)
在一些实施方案中,rAAV病毒体是AAVrh.74rAAV病毒体。衣壳可以是AAVrh.74衣壳或其功能变体。在一些实施方案中,AAVrh.74衣壳与例如以下的参考AAVrh.74衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVESPVKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYNFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL
(SEQ ID NO:81)
在一些实施方案中,rAAV病毒体是AAV-PHP.B rAAV病毒体或其神经营养变体,例如但不限于在国际专利公开号WO 2015/038958 A1和WO 2017/100671 A1中公开的那些。例如,AAV衣壳可以包含例如插入编码AAV9的氨基酸588和589的序列之间,来自序列TLAVPFK(SEQ ID NO:83)或KFPVALT(SEQ ID NO:84)的至少4个邻接氨基酸。
衣壳可以是AAV-PHP.B衣壳或其功能变体。在一些实施方案中,AAV-PHP.B衣壳与例如以下的参考AAV-PHP.B衣壳具有至少98%、99%或100%的同一性,
MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQTLAVPFKAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL
(SEQ ID NO:82)
在本公开内容的rAAV病毒体中使用的进一步AAV衣壳包括在专利公开号WO 2009/012176 A2和WO 2015/168666 A2中公开的那些AAV衣壳。
不受理论的束缚,本发明人已确定了AAV9载体或AAVrh.10载体将赋予载体广泛的CNS分布。不受理论的束缚,本发明人已进一步确定了AAV6载体可以提供对于靶向的内皮细胞的一些特异性。可以使用其它载体血清型,包括但不限于AAV8和AAVrh.10。
在一些实施方案中,rAAV载体不是AAV2载体。不受理论的束缚,本发明人已确定了,在一些情况下,AAV2载体的使用导致除内皮细胞之外或代替内皮细胞的神经元细胞的转导。不受理论的束缚,本发明人已进一步确定了,AAV2载体在CNS内的扩散受限于其与硫酸乙酰肝素蛋白多糖(HSPG)受体的相互作用。
药物组合物和试剂盒
在一个方面,本公开内容提供了药物组合物,其包含本公开内容的rAAV病毒体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
为了例如通过注射施用的目的,可以采用各种溶液,例如无菌水溶液。需要时,此类水溶液可以进行缓冲,并且液体稀释剂首先用盐水或葡萄糖致使等渗。作为游离酸(DNA含有酸性磷酸基)或药理学上可接受的盐的rAAV溶液,可以在水中适当地以例如0.001%或0.01%与表面活性剂如Poloxamer 188混合进行制备。rAAV的分散体也可以在甘油、液体聚乙二醇及其混合物和油中进行制备。在普通的贮存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。在这方面,所采用的无菌水性介质都可以通过本领域技术人员众所周知的标准技术容易地获得。
适合于注射使用的药物形式包括但不限于无菌水溶液或分散体,以及用于临时制备无菌可注射溶液或分散体的无菌粉末。在所有情况下,形式都是无菌的,并且必须是流动至存在容易注射性的程度。它在制造和贮存条件下必须是稳定的,并且必须针对微生物如细菌和真菌的污染作用进行防腐。载体可以是溶剂或分散介质,其含有例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等等)、其合适的混合物和植物油。适当的流动性可以例如通过以下得到维持:使用包衣例如卵磷脂、在分散体的情况下维持所需的粒度以及使用表面活性剂。可以通过各种抗菌剂和抗真菌剂来达到微生物作用的预防,所述抗菌剂和抗真菌剂例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等等。在许多情况下,优选包括等渗剂,例如糖或氯化钠。可以通过使用延迟吸收的试剂例如单硬脂酸铝和明胶来达到可注射组合物的延长吸收。
无菌注射液可以通过以下进行制备:将所需量的rAAV掺入根据需要具有上文列举的各种其它成分的适当溶剂中,随后为过滤灭菌。一般地,通过将灭菌的活性成分掺入无菌媒介物内来制备分散体,所述无菌媒介物含有基本分散介质和来自上文列举那些的所需其它成分。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,所述技术由其先前无菌过滤的溶液产生活性成分加上任何另外的所需成分的粉末。
在另一个方面,本公开内容包含试剂盒,其包含本公开内容的rAAV病毒体和使用说明书。
使用方法
在一个方面,本公开内容提供了增加细胞中的GLUT1活性的方法,其包括使细胞与本公开内容的rAAV接触。在另一个方面,本公开内容提供了增加受试者中的GLUT1活性的方法,其包括施用本公开内容的rAAV。在一些实施方案中,细胞和/或受试者在SLC2A1信使RNA或GLUT1蛋白表达水平和/或活性方面是缺陷的,和/或包含在SLC2A1中的功能丧失突变。细胞可以是内皮细胞,例如内皮尖端细胞。
在一些实施方案中,该方法恢复内皮尖端细胞的正常功能。在一些实施方案中,该方法恢复细胞培养物和/或体内的GLUT1转运蛋白表达水平。在一些实施方案中,该方法在细胞培养物中和/或在体内恢复正常的葡萄糖转运和代谢(例如糖酵解、乳酸盐产生)。在一些实施方案中,该方法恢复中枢神经系统(CNS)中的微脉管系统的正常血管生成和/或发育。
治疗方法
在另一个方面,本公开内容提供了治疗有此需要的受试者中的疾病或病症的方法,其包括向受试者施用有效量的本公开内容的rAAV病毒体。在一些实施方案中,疾病或病症是神经系统疾病或病症。在一些实施方案中,受试者遭受SLC2A1表达或功能中的遗传破坏。在一些实施方案中,疾病或病症是GLUT1缺乏综合征(GLUT1 DS)。
AAV介导的GLUT1蛋白向CNS的递送可能增加生命期限,预防、缩减、减轻或减弱神经元变性、早发性癫痫发作、发育迟缓、获得性小头畸形(头部生长减慢)、复杂运动障碍(痉挛状态、共济失调、肌张力障碍)、阵发性眼头运动和/或脑脊液中的低乳酸盐和/或葡萄糖浓度(脑脊液糖分过少)。在一些实施方案中,该方法提供了在疾病过程的早期,例如在新生儿、婴儿或青少年中的治疗。
本文公开的方法可以提供了在脑和/或CNS中的有效生物分布。它们可能导致在所有或相当一部分的内皮细胞(例如,内皮尖端细胞)中的持续表达。值得注意的是,本文公开的方法可以在受试者的发育和衰老自始至终提供了GLUT1蛋白的持久表达。
本发明还考虑了组合疗法。特别考虑了本发明的方法与标准医学治疗(例如,皮质类固醇或局部减压用药)的组合,以及与新型疗法的组合。在一些情况下,受试者可以用类固醇和/或免疫抑制剂的组合进行治疗,以预防或减少对本文所述的rAAV施用的免疫应答。
例如,用于脑室内(ICV)或小脑延髓池内(ICM)注射的rAAV载体的治疗有效量是范围为按脑重量计约1e12 vg/kg至约5e12 vg/kg、或约1e13vg/kg至约5e13 vg/kg、或约1e14vg/kg至约5e14 vg/kg、或约1e15 vg/kg至约5e15 vg/kg的rAAV剂量。本发明还包括包含这些范围的rAAV载体的组合物。
例如,在特定实施方案中,rAAV载体的治疗有效量是约1e10 vg、约2e10 vg、约3e10 vg、约4e10 vg、约5e10 vg、约6e10 vg、约7e10 vg、约8e10 vg、约9e10 vg、约1e12vg、约2e12 vg、约3e12 vg、约4e12 vg、约4e13 vg和约4e14 vg的剂量。本发明还包括包含rAAV载体的这些剂量的组合物。
在一些实施方案中,例如当执行ICV注射时,rAAV载体的治疗有效量是在1e10 vg/半球至2e14 vg/半球、或约1e10 vg/半球、约1e11 vg/半球、约1e12vg/半球、1E13vg/半球、或约1e14vg/半球的范围内的剂量。在一些实施方案中,例如当执行ICM注射时,rAAV载体的治疗有效量是在总计2e10vg至总计2e14vg、或总计约2e10vg、总计约2e11vg、总计约2e12vg、总计约2e13vg、或总计约2e14vg范围内的剂量。
在一些实施方案中,治疗组合物包含多于约1e9、1e10或1e11个rAAV载体基因组/注射的治疗组合物体积。在实施方案的情况下,治疗组合物包含多于大约1e11、1e12、1e13或1e14个rAAV载体基因组/mL。在某些实施方案中,治疗组合物包含少于约1e14、1e13或1e12个rAAV载体基因组/mL。
患者中的功能改善、临床益处或功效的证据可以通过以下进行评价:阵发性眼头运动的分析,癫痫发作频率(全身性强直阵挛和肌阵挛性癫痫发作)减少的替代标记物,脑脊液(CSF)中的乳酸盐和/或葡萄糖浓度,发育迟缓、舞蹈病、肌张力障碍和小头畸形的评价。使用标准疾病评定量表的认知、运动、言语和语言功能测量,所述量表例如哥伦比亚神经系统评分(Columbia Neurological Score)、综合智力评估(Composite IntellectualEstimate)、适应性行为综合(Adaptive Behavior Composite)、语言和非语言认知技能和视觉运动整合、以及六分钟步行测试(Six Minute Walk Test)。认知和发育评价包括Peabody运动发育量表(Peabody Developmental Motor Scales)第2版(PDMS-2),以及适当地应用于儿童的残疾程度的贝利婴儿发展量表(Bayley Scales of InfantDevelopment),第3版。粗大运动功能测量(GFMF-88),残疾量表的儿科评估(PediatricEvaluation of Disability Inventory)(PEDI)。这些或类似的量表,以及患者报告的生活质量结果,例如在3点量表(平均持续时间的减少、不变或增加)上的护理人员对发作持续时间变化的总体印象(Caregiver Global Impression of Change in Seizure Duration)(CGICSD),儿科生活质量量表(PedsQLTM)和文兰适应行为量表第二版(Vineland AdaptiveBehavior Scales-2nd),可能证实了疾病的组分中的改善。与年龄匹配的患者对照数据和来自GLUT1缺乏症患者的历史数据相比,基线和治疗后的脑磁共振成像可能显示了关于患者年龄的脑容量的改善或正常化。
可以观察到临床益处,如寿命增加,符合正常的神经发育里程碑,CSF中的正常化的葡萄糖浓度,阵发性眼头运动的频率或幅度降低,癫痫发作活动(包括肌阵挛、阵挛、全身性强直阵挛和/或癫痫性痉挛)的降低或不存在,复杂运动障碍如痉挛状态、肌张力障碍和/或共济失调的改善或发展缺乏,以及哥伦比亚神经系统评分和/或六分钟步行测试的改善或正常表现。神经保护和/或神经恢复效应的证据可能在所有先前提到的指标和/或通过表征整体脑大小、小头畸形和/或皮质和/或小脑萎缩的缺乏的磁共振成像(MRI)上是显而易见的。
在一些实施方案中,与接触包含内源性Glut1启动子或泛在启动子的载体的细胞或施用所述载体的受试者的细胞相比,该方法导致通过细胞增加的葡萄糖摄取。在一些情况下,增加是至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少40%或至少50%。在一些情况下,增加是至少1.1倍、至少1.2倍、至少1.3倍、至少1.4倍、至少1.5倍、至少1.6倍、至少1.7倍或至少1.8倍。载体可以是本文公开的任何载体。细胞可以是内皮细胞或神经元细胞。例如,该方法可以在体外或体内增加通过人脑微血管内皮细胞的葡萄糖摄取。
组合物的施用
有效剂量的组合物的施用可以是通过本领域标准的途径,其包括但不限于静脉内、大脑内、鞘内、脑池内或脑室内施用。在一些情况下,施用包含静脉内、大脑内、鞘内、脑池内或脑室内注射。施用可以通过鞘内注射来执行,伴随或不伴随特伦德伦伯卧位倾斜式(Trendelenberg tilting)。小脑延髓池内(ICM)递送可以经由在鞘内(IT)间隙处的导管进入来实现。脑室内注射可以经由磁共振成像(MRI)引导的神经外科靶向来实现。
在一些实施方案中,本公开内容提供了本发明的rAAV和组合物的有效剂量的全身施用。例如,全身施用可以是施用到循环系统内,使得影响整个身体。全身施用包括通过注射或输注的静脉内施用。
特别地,本发明的rAAV的施用可以通过使用任何物理方法来实现,所述物理方法将rAAV重组载体转运到动物的靶组织内。施用包括但不限于注射到中枢神经系统(CNS)或脑脊液(CSF)内和/或直接注射到脑内。
在一些实施方案中,本公开内容的方法包括脑室内、小脑延髓池内、鞘内或实质内递送。可以使用专用插管、导管、使用输注泵的注射器/针来执行输注。任选地,注射部位的靶向可以通过MRI引导成像来完成。施用可以包括将有效量的rAAV病毒体或包含rAAV病毒体的药物组合物递送至CNS。这些可以例如经由单侧脑室内注射、双侧脑室内注射、伴随特伦德伦伯卧位倾斜式程序的小脑延髓池内输注、或不伴随特伦德伦伯卧位倾斜式程序的小脑延髓池内输注、伴随特伦德伦伯卧位倾斜式程序的鞘内输注、或不伴随特伦德伦伯卧位倾斜式程序的鞘内输注来实现。本公开内容的组合物可以进一步是静脉内施用的。
对CNS的直接递送可以涉及单侧或双侧靶向脑室内间隙,特定的神经元区域或含有神经元靶的更一般的脑区域。个别患者的脑室内间隙、脑区域和/或神经元靶的选择以及后续AAV的术中递送可以通过使用多种成像技术(MRI、CT、CT联合MRI融合),且采用任何数目的软件规划程序(例如,Stealth System、Clearpoint Neuronavigation System、Brainlab、Neuroinspire等)来完成。脑室内间隙或脑区域靶向和递送可以涉及使用标准立体定向框架(Leksell,CRW)或使用无框架方法,伴随或不伴随术中MRI。AAV的实际递送可能是通过经由针或插管的注射,所述插管具有或不具有衬有防止AAV载体吸附的材料的内腔(例如Smartflow插管、MRI Interventions插管)。递送装置由注射器和自动输注或微量输注泵组成,具有预编程的输注速率和体积。注射器/针组合或仅用于针的引导插管可以与立体定向框架直接接合。输注可以包括恒定流速或变化流速,伴随对流增强的递送。
实施例
实施例1:临床前生物活性和功效
重组AAV病毒颗粒使用图2-8中公开的载体基因组产生。这些在作为GLUT1缺乏病的后果的小鼠疾病模型中进行评估。一种模型采用与转基因动物杂交的flox-ed GLUT1基因,所述转基因动物由组成型启动子或内皮特异性启动子(例如Tie-2)表达Cre/lox。所得到的小鼠在GLUT1基因座处是杂合子无效的,并且显示出模拟人疾病的发育表型。GLUT1 DS的第二种小鼠模型是通过小鼠GLUT-1基因的启动子和外显子1区域的靶向破坏而生成的杂合单倍体不足小鼠(GLUT-1+/-小鼠)。另外的动物模型可能包括其中GLUT1基因具有S324P点突变的GLUT1 DS模型。
基因表达和剂量应答在体外(使用内皮和神经元细胞系)和体内(使用野生型和GLUT1 DS模型小鼠)进行评估。用SLC2A1表达载体转染的培养细胞(人胚肾细胞293,HEK293;人脐静脉内皮细胞,HUVEC;人脑衍生的内皮细胞,bEND3;人脑微血管内皮细胞,HBEC-5i;人脑微血管内皮细胞系,hCMEC/D3(血脑屏障模型);人神经胶质少突胶质细胞杂交细胞,MO3.13;人神经母细胞瘤,SH-SY5Y),通过定量实时PCR分析揭示转导效率,通过ELISA和/或蛋白质印迹法揭示GLUT1水平。AAV载体构建体的概念证明和功效使用GLUT1 DS小鼠通过以下在体内进行揭示:通过免疫标记在CNS中的转基因(GLUT1蛋白)表达、增强的脑毛细血管密度和/或CNS中的血管大小增加,使用正电子发射断层扫描(PET)的脑葡萄糖摄取增加,CSF葡萄糖水平或乳酸盐水平和/或CSF/血糖比率的增加,CSF乳酸盐水平的增加,以及相对于GLUT1 DS突变型小鼠对照,使用标准测定例如转棒和/或垂直杆测定的运动表现改善。在同时采用单独和/或组合的这些施用途径,通过静脉内注射或直接注射到脑室内间隙的AAV载体构建体递送之后,使用GLUT1 DS小鼠模型的体内基因表达和功效将是显而易见的。
实施例2:使用内皮启动子的GLUT1表达的体外评估
使用人脑微血管内皮细胞(hCMEC/D3)在体外评估基因表达。评估了通过用AAV9载体转染的hCMEC/D3细胞的Glut1表达,所述AAV9载体编码处于hFLT1、mTIE1、hGlut1或CMV启动子(在图10C中进行图解)的控制下的SLC2A1(图9)。来自内皮启动子(hFLT1和mTIE1)的表达与来自Glut1启动子的表达是可比较的,并且远低于来自CMV启动子的表达。通过免疫荧光法显微镜检查观察到这些构建体之间的表达水平的相似模式(图10A和图10B)。
令人惊讶的是,与对照Glut1启动子相比,通过用在内皮启动子的控制下的基因转染或转导的人脑微血管内皮细胞的2-脱氧-D-葡萄糖(2-DG)摄取更大,其中hFLT-1启动子证实了最高水平的2-DG(葡萄糖)摄取(图11A-11C、图12和图13)。跨越一系列2-DG浓度(图12A;0、0.1、0.5和1mM)以及在转染之后的不同时间点(图12B),也观察到关于hFLT-1启动子构建体的更大2-DG(葡萄糖)摄取的这种发现,并且在一些情况下,发现与用CMV启动子观察到的可比较或略微更大(图11A-11C;图12A、12B;图13)。
图9在人脑微血管内皮细胞(hCMEC/d3s)的转染之后,转基因蛋白(Glut1-GFP)的表达。
图10A.在用含有驱动Glut1-GFP转基因表达的几种内皮细胞启动子之一的构建体转染之后72小时的GFP荧光。
图10B.在用含有两种泛在启动子(CMV或CAG)之一的构建体,不含Glut1的对照载体(CMV-GFP)转染或无转染(无NFX)之后72小时的GFP荧光。使用Operetta CLSTM 获得的图像。
图10C.含有目的启动子(hFLT1、mTie、hTie或hGlut1)和GLUT1(SLC2A1)基因(T2A连接的GFP)和侧接AAV2反向末端重复序列(ITR)的调控元件的表达盒的图解。
图11A-11C.在人GLUT1(SLC2A1)的表达之后,在hCMEC/d3细胞中的2-脱氧-D-葡萄糖(葡萄糖)摄取。用质粒转染人脑微血管内皮细胞(hCMEC/d3s),所述质粒表达CAG-GFP(CON;阴性对照)、或者由几种内皮特异性启动子(即,hFLT1、mTie、hTie或hGlut1)之一或者泛在CMV或CAG启动子驱动的hGLUT1-t2A-eGFP转基因。使用基于发光的试剂盒在培养基中使用0.5mM 2-脱氧葡萄糖(2-DG)来测量葡萄糖摄取。使用相衬成像通过总细胞使葡萄糖(2-DG)摄取标准化[误差条代表S.E.M;n=6个重复/条件]。
图11A.在第一个实验中,在转染后72小时测量葡萄糖(2-DG)摄取。
图11B.在第二个实验中,在转染后72小时测量葡萄糖(2-DG)摄取。
图11C.在转染后96小时测量葡萄糖(2-DG)摄取。
图12A.显示了在72小时时间点,在人Glut1(SLC2A1)的表达之后,在hCMEC/D3细胞中的葡萄糖(2-DG)摄取。
图12B.显示了在96小时时间点,在人Glut1(SLC2A1)的表达之后,在hCMEC/D3细胞中的葡萄糖(2-DG)摄取。
图13.在AAV9介导的hGLUT1(SLC2A1)在hCMEC/D3细胞中的表达之后,2-脱氧-D-葡萄糖(葡萄糖)摄取。用AAV9载体(3x 105个载体基因组/细胞)转导人脑微血管内皮细胞(hCMEC/d3s),所述AAV9载体表达CAG-GFP(阴性对照)、或者由几种内皮特异性启动子(即,hFLT1、mTie1或hGlut1)之一或泛在CMV启动子驱动的hGLUT1转基因。使用基于发光的Glucose Uptake-Glo试剂盒在转导后72小时测量葡萄糖(2-DG)摄取,并且使用RealTime-Glo MT Cell Viability Assay对每个细胞进行标准化[误差条代表S.E.M;n=4个重复/条件]。
实施例3:在GLUT1缺乏症的动物模型中,使用内皮启动子的AAV9介导的GLUT1表达的体内评估
执行一系列实验,评估AAV9介导的Glut1转运蛋白表达在GLUT1缺乏综合征(DS)的小鼠模型中的体内效应。该模型采用这样的小鼠,其由于小鼠GLUT-1基因的启动子和外显子1区域的靶向破坏而是杂合单倍体不足的(GLUT-1+/-小鼠),并且展示了人GLUT DS的特有特征,例如癫痫发作活动、脑脊液糖分过少、小脑畸形和运动功能损害(Wang等人,HumMol Gen,2006;Tang等人,Nat Comm,2016)。AAV9构建体将在不同剂量和不同施用途径(静脉内或脑室内)下进行评估,其中GLUT1转基因的表达由泛在启动子(CMV)或几种内皮细胞启动子(hFLT-1、mTie、hGlut1)之一驱动。将评估使用AAV9载体的递送之后内皮细胞启动子介导的GLUT1转基因表达可以预防或减轻该小鼠模型中的功能和病理缺陷的程度。通过与未治疗的GLUT-1+/-对照小鼠的比较,揭示了当施用于杂合单倍体不足小鼠时,AAV9介导的Glut1蛋白表达的潜在有益效应,并且由以下组成:改善或正常化的体重增加、在运动测试时(例如转棒、垂直杆测定)的行为表现、CSF葡萄糖水平、脑重量、以及脑微血管系统的完整性和大小(例如脑毛细血管密度、血管大小、血管分支点的数目)。
序列表
<110> Spacecraft Seven, LLC
<120> 用于GLUT1表达的腺相关病毒载体及其用途
<130> ROPA-018/01WO 329592-2262
<150> US 63/061,726
<151> 2020-08-05
<160> 102
<170> PatentIn 3.5版
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cccatgtatg tgggtgaagt gtcacccaca gcccttcgtg gggccctggg caccctgcac 480
cagctgggca tcgtcgtcgg catcctcatc gcccaggtgt tcggcctgga ctccatcatg 540
ggcaacaagg acctgtggcc cctgctgctg agcatcatct tcatcccggc cctgctgcag 600
tgcatcgtgc tgcccttctg ccccgagagt ccccgcttcc tgctcatcaa ccgcaacgag 660
gagaaccggg ccaagagtgt gctaaagaag ctgcgcggga cagctgacgt gacccatgac 720
ctgcaggaga tgaaggaaga gagtcggcag atgatgcggg agaagaaggt caccatcctg 780
gagctgttcc gctcccccgc ctaccgccag cccatcctca tcgctgtggt gctgcagctg 840
tcccagcagc tgtctggcat caacgctgtc ttctattact ccacgagcat cttcgagaag 900
gcgggggtgc agcagcctgt gtatgccacc attggctccg gtatcgtcaa cacggccttc 960
actgtcgtgt cgctgtttgt ggtggagcga gcaggccggc ggaccctgca cctcataggc 1020
ctcgctggca tggcgggttg tgccatactc atgaccatcg cgctagcact gctggagcag 1080
ctaccctgga tgtcctatct gagcatcgtg gccatctttg gctttgtggc cttctttgaa 1140
gtgggtcctg gccccatccc atggttcatc gtggctgaac tcttcagcca gggtccacgt 1200
ccagctgcca ttgccgttgc aggcttctcc aactggacct caaatttcat tgtgggcatg 1260
tgcttccagt atgtggagca actgtgtggt ccctacgtct tcatcatctt cactgtgctc 1320
ctggttctgt tcttcatctt cacctacttc aaagttcctg agactaaagg ccggaccttc 1380
gatgagatcg cttccggctt ccggcagggg ggagccagcc aaagtgacaa gacacccgag 1440
gagctgttcc atcccctggg ggctgattcc caagtg 1476
<210> 6
<211> 168
<212> DNA
<213> 腺相关病毒2
<400> 6
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgta 168
<210> 7
<211> 168
<212> DNA
<213> 腺相关病毒2
<400> 7
tacgtagata agtagcatgg cgggttaatc attaactaca aggaacccct agtgatggag 60
ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 120
cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgc 168
<210> 8
<211> 2963
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 8
ctctggagac gcgttacata cgttacataa cttacggtaa atggcccgcc tggctgaccg 60
cccaacgacc cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata 120
gggactttcc attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta 180
catcaagtgt atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc 240
gcctggcatt atgcccagta catgacctta tgggactttc ctacttggca gtacatctac 300
gtattagtca tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga 360
tagcggtttg actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg 420
ttttggcacc aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg 480
caaatgggcg gtaggcgtgt acggtgggag gtctatataa gcagagctcg tttagtgaac 540
cgtcagatcg cctggagacg ccatccacgc tgttttgacc tccatagaag acaccgggac 600
cgatccagcc tccgcggatg gagcccagca gcaagaagct gacgggtcgc ctcatgctgg 660
ccgtgggagg agcagtgctt ggctccctgc agtttggcta caacactgga gtcatcaatg 720
ccccccagaa ggtgatcgag gagttctaca accagacatg ggtccaccgc tatggggaga 780
gcatcctgcc caccacgctc accacgctct ggtccctctc agtggccatc ttttctgttg 840
ggggcatgat tggctccttc tctgtgggcc ttttcgttaa ccgctttggc cggcggaatt 900
caatgctgat gatgaacctg ctggccttcg tgtccgccgt gctcatgggc ttctcgaaac 960
tgggcaagtc ctttgagatg ctgatcctgg gccgcttcat catcggtgtg tactgcggcc 1020
tgaccacagg cttcgtgccc atgtatgtgg gtgaagtgtc acccacagcc cttcgtgggg 1080
ccctgggcac cctgcaccag ctgggcatcg tcgtcggcat cctcatcgcc caggtgttcg 1140
gcctggactc catcatgggc aacaaggacc tgtggcccct gctgctgagc atcatcttca 1200
tcccggccct gctgcagtgc atcgtgctgc ccttctgccc cgagagtccc cgcttcctgc 1260
tcatcaaccg caacgaggag aaccgggcca agagtgtgct aaagaagctg cgcgggacag 1320
ctgacgtgac ccatgacctg caggagatga aggaagagag tcggcagatg atgcgggaga 1380
agaaggtcac catcctggag ctgttccgct cccccgccta ccgccagccc atcctcatcg 1440
ctgtggtgct gcagctgtcc cagcagctgt ctggcatcaa cgctgtcttc tattactcca 1500
cgagcatctt cgagaaggcg ggggtgcagc agcctgtgta tgccaccatt ggctccggta 1560
tcgtcaacac ggccttcact gtcgtgtcgc tgtttgtggt ggagcgagca ggccggcgga 1620
ccctgcacct cataggcctc gctggcatgg cgggttgtgc catactcatg accatcgcgc 1680
tagcactgct ggagcagcta ccctggatgt cctatctgag catcgtggcc atctttggct 1740
ttgtggcctt ctttgaagtg ggtcctggcc ccatcccatg gttcatcgtg gctgaactct 1800
tcagccaggg tccacgtcca gctgccattg ccgttgcagg cttctccaac tggacctcaa 1860
atttcattgt gggcatgtgc ttccagtatg tggagcaact gtgtggtccc tacgtcttca 1920
tcatcttcac tgtgctcctg gttctgttct tcatcttcac ctacttcaaa gttcctgaga 1980
ctaaaggccg gaccttcgat gagatcgctt ccggcttccg gcagggggga gccagccaaa 2040
gtgacaagac acccgaggag ctgttccatc ccctgggggc tgattcccaa gtgtgataat 2100
ggatcaacct ctggattaca aaatttgtga aagattgact ggtattctta actatgttgc 2160
tccttttacg ctatgtggat acgctgcttt aatgcctttg tatcatgcta ttgcttcccg 2220
tatggctttc attttctcct ccttgtataa atcctggttg ctgtctcttt atgaggagtt 2280
gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg tttgctgacg caacccccac 2340
tggttggggc attgccacca cctgtcagct cctttccggg actttcgctt tccccctccc 2400
tattgccacg gcggaactca tcgccgcctg ccttgcccgc tgctggacag gggctcggct 2460
gttgggcact gacaattccg tggtgttgtc ggggaaatca tcgtcctttc cttggctgct 2520
cgcctgtgtt gccacctgga ttctgcgcgg gacgtccttc tgctacgtcc cttcggccct 2580
caatccagcg gaccttcctt cccgcggcct gctgccggct ctgcggcctc ttccgcgtct 2640
tcgccttcgc cctcagacga gtcggatctc cctttgggcc gcctccccgc atcattgcct 2700
gcccgggtgg catccctgtg acccctcccc agtgcctctc ctggccctgg aagttgccac 2760
tccagtgccc accagccttg tcctaataaa attaagttgc atcattttgt ctgactaggt 2820
gtccttctat aatattatgg ggtggagggg ggtggtatgg agcaaggggc ccaagttggg 2880
aagaaacctg tagggcctgc gttacccagg ctggagtgca gtggcacatt tctgctcact 2940
gcaacctcct cctccctggg ttc 2963
<210> 9
<400> 9
000
<210> 10
<211> 3414
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 10
ctctggagac gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac 60
ccccgcccat tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc 120
cattgacgtc aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg 180
tatcatatgc caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat 240
tatgcccagt acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc 300
atcgctatta ccatggtcga ggtgagcccc acgttctgct tcactctccc catctccccc 360
ccctccccac ccccaatttt gtatttattt attttttaat tattttgtgc agcgatgggg 420
gcgggggggg ggggggcgcg cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc 480
gaggcggaga ggtgcggcgg cagccaatca gagcggcgcg ctccgaaagt ttccttttat 540
ggcgaggcgg cggcggcggc ggccctataa aaagcgaagc gcgcggcggg cgggagtcgc 600
tgcgcgctgc cttcgccccg tgccccgctc cgccgccgcc tcgcgccgcc cgccccggct 660
ctgactgacc gcgttactcc cacaggtgag cgggcgggac ggcccttctc ctccgggctg 720
taattagcgc ttggtttaat gacggcttgt ttcttttctg tggctgcgtg aaagccttga 780
ggggctccgg gagggccctt tgtgcggggg gagcggctcg gggggtgcgt gcgtgtgtgt 840
gtgcgtgggg agcgccgcgt gcggctccgc gctgcccggc ggctgtgagc gctgcgggcg 900
cggcgcgggg ctttgtgcgc tccgcagtgt gcgcgagggg agcgcggccg ggggcggtgc 960
cccgcggtgc ggggggggct gcgaggggaa caaaggctgc gtgcggggtg tgtgcgtggg 1020
ggggtgagca gggggtgtgg gcgcgtcggt cgggctgcaa ccccccctgc acccccctcc 1080
ccgagttgct gagcacggcc cggcttcggg tgcggggctc cgtacggggc gtggcgcggg 1140
gctcgccgtg ccgggcgggg ggtggcggca ggtgggggtg ccgggcgggg cggggccgcc 1200
tcgggccggg gagggctcgg gggaggggcg cggcggcccc cggagcgccg gcggctgtcg 1260
aggcgcggcg agccgcagcc attgcctttt atggtaatcg tgcgagaggg cgcagggact 1320
tcctttgtcc caaatctgtg cggagccgaa atctgggagg cgccgccgca ccccctctag 1380
cgggcgcggg gcgaagcggt gcggcgccgg caggaaggaa atgggcgggg agggccttcg 1440
tgcgtcgccg cgccgccgtc cccttctccc tctccagcct cggggctgtc cgcgggggga 1500
cggctgcctt cgggggggac ggggcagggc ggggttcggc ttctggcgtg tgaccggcgg 1560
ctctagagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc tcctgggcaa 1620
cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttcatggagc ccagcagcaa 1680
gaagctgacg ggtcgcctca tgctggccgt gggaggagca gtgcttggct ccctgcagtt 1740
tggctacaac actggagtca tcaatgcccc ccagaaggtg atcgaggagt tctacaacca 1800
gacatgggtc caccgctatg gggagagcat cctgcccacc acgctcacca cgctctggtc 1860
cctctcagtg gccatctttt ctgttggggg catgattggc tccttctctg tgggcctttt 1920
cgttaaccgc tttggccggc ggaattcaat gctgatgatg aacctgctgg ccttcgtgtc 1980
cgccgtgctc atgggcttct cgaaactggg caagtccttt gagatgctga tcctgggccg 2040
cttcatcatc ggtgtgtact gcggcctgac cacaggcttc gtgcccatgt atgtgggtga 2100
agtgtcaccc acagcccttc gtggggccct gggcaccctg caccagctgg gcatcgtcgt 2160
cggcatcctc atcgcccagg tgttcggcct ggactccatc atgggcaaca aggacctgtg 2220
gcccctgctg ctgagcatca tcttcatccc ggccctgctg cagtgcatcg tgctgccctt 2280
ctgccccgag agtccccgct tcctgctcat caaccgcaac gaggagaacc gggccaagag 2340
tgtgctaaag aagctgcgcg ggacagctga cgtgacccat gacctgcagg agatgaagga 2400
agagagtcgg cagatgatgc gggagaagaa ggtcaccatc ctggagctgt tccgctcccc 2460
cgcctaccgc cagcccatcc tcatcgctgt ggtgctgcag ctgtcccagc agctgtctgg 2520
catcaacgct gtcttctatt actccacgag catcttcgag aaggcggggg tgcagcagcc 2580
tgtgtatgcc accattggct ccggtatcgt caacacggcc ttcactgtcg tgtcgctgtt 2640
tgtggtggag cgagcaggcc ggcggaccct gcacctcata ggcctcgctg gcatggcggg 2700
ttgtgccata ctcatgacca tcgcgctagc actgctggag cagctaccct ggatgtccta 2760
tctgagcatc gtggccatct ttggctttgt ggccttcttt gaagtgggtc ctggccccat 2820
cccatggttc atcgtggctg aactcttcag ccagggtcca cgtccagctg ccattgccgt 2880
tgcaggcttc tccaactgga cctcaaattt cattgtgggc atgtgcttcc agtatgtgga 2940
gcaactgtgt ggtccctacg tcttcatcat cttcactgtg ctcctggttc tgttcttcat 3000
cttcacctac ttcaaagttc ctgagactaa aggccggacc ttcgatgaga tcgcttccgg 3060
cttccggcag gggggagcca gccaaagtga caagacaccc gaggagctgt tccatcccct 3120
gggggctgat tcccaagtgt gatcattgcc tgcccgggtg gcatccctgt gacccctccc 3180
cagtgcctct cctggccctg gaagttgcca ctccagtgcc caccagcctt gtcctaataa 3240
aattaagttg catcattttg tctgactagg tgtccttcta taatattatg gggtggaggg 3300
gggtggtatg gagcaagggg cccaagttgg gaagaaacct gtagggcctg cgttacccag 3360
gctggagtgc agtggcacat ttctgctcac tgcaacctcc tcctccctgg gttc 3414
<210> 11
<400> 11
000
<210> 12
<211> 3409
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 12
ctctggagac gcgttacata tttgcttcta ggaagcagaa gactgaggaa atgacttggg 60
cgggtgcatc aatgcggcca aaaaagacac ggacacgctc ccctgggacc tgagctggtt 120
cgcagtcttc ccaaaggtgc caagcaagcg tcagttcccc tcaggcgctc caggttcagt 180
gccttgtgcc gagggtctcc ggtgccttcc tagacttctc gggacagtct gaaggggtca 240
ggagcggcgg gacagcgcgg gaagagcagg caaggggaga cagccggact gcgcctcagt 300
cctccgtgcc aagaacaccg tcgcggaggc gcggccagct tcccttggat cggactttcc 360
gcccctaggg ccaggcggcg gagcttcagc cttgtccctt ccccagtttc gggcggcccc 420
cagagctgag taagccgggt ggagggagtc tgcaaggatt tcctgagcgc gatgggcagg 480
aggaggggca agggcaagag ggcgcggagc aaagaccctg aacctgccgg ggccgcgctc 540
ccgggcccgc gtcgccagca cctccccacg cgcgctcggc cccgggccac ccgccctcgt 600
cggcccccgc ccctctccgt agccgcaggg aagcgagcct gggaggaaga agagggtagg 660
tggggaggcg gatgaggggt gggggacccc ttgacgtcac cagaaggagg tgccggggta 720
ggaagtgggc tggggaaagg ttataaatcg cccccgccct cggctgctct tcatcgaggt 780
ccgcgggagg ctcggagcgc gccaggcgga cactcctctc ggctcctccc cggcagcggc 840
ggcggctcgg agcgggctcc ggggctcggg tgcagcggcc agcgggcgcc tggcggcgag 900
gattacccgg ggaagtggtt gtctcctggc tggagccgcg agacgggcgc tcagggcgcg 960
gggccggcgg cggcgaacaa gaggacggac tctggcggcc gggtcgttgg ccgcggggag 1020
cgcgggcacc gggcgagcag gccgcgtcgc gctcaccgcc accatggagc ccagcagcaa 1080
gaagctgacg ggtcgcctca tgctggccgt gggaggagca gtgcttggct ccctgcagtt 1140
tggctacaac actggagtca tcaatgcccc ccagaaggtg atcgaggagt tctacaacca 1200
gacatgggtc caccgctatg gggagagcat cctgcccacc acgctcacca cgctctggtc 1260
cctctcagtg gccatctttt ctgttggggg catgattggc tccttctctg tgggcctttt 1320
cgttaaccgc tttggccggc ggaattcaat gctgatgatg aacctgctgg ccttcgtgtc 1380
cgccgtgctc atgggcttct cgaaactggg caagtccttt gagatgctga tcctgggccg 1440
cttcatcatc ggtgtgtact gcggcctgac cacaggcttc gtgcccatgt atgtgggtga 1500
agtgtcaccc acagcccttc gtggggccct gggcaccctg caccagctgg gcatcgtcgt 1560
cggcatcctc atcgcccagg tgttcggcct ggactccatc atgggcaaca aggacctgtg 1620
gcccctgctg ctgagcatca tcttcatccc ggccctgctg cagtgcatcg tgctgccctt 1680
ctgccccgag agtccccgct tcctgctcat caaccgcaac gaggagaacc gggccaagag 1740
tgtgctaaag aagctgcgcg ggacagctga cgtgacccat gacctgcagg agatgaagga 1800
agagagtcgg cagatgatgc gggagaagaa ggtcaccatc ctggagctgt tccgctcccc 1860
cgcctaccgc cagcccatcc tcatcgctgt ggtgctgcag ctgtcccagc agctgtctgg 1920
catcaacgct gtcttctatt actccacgag catcttcgag aaggcggggg tgcagcagcc 1980
tgtgtatgcc accattggct ccggtatcgt caacacggcc ttcactgtcg tgtcgctgtt 2040
tgtggtggag cgagcaggcc ggcggaccct gcacctcata ggcctcgctg gcatggcggg 2100
ttgtgccata ctcatgacca tcgcgctagc actgctggag cagctaccct ggatgtccta 2160
tctgagcatc gtggccatct ttggctttgt ggccttcttt gaagtgggtc ctggccccat 2220
cccatggttc atcgtggctg aactcttcag ccagggtcca cgtccagctg ccattgccgt 2280
tgcaggcttc tccaactgga cctcaaattt cattgtgggc atgtgcttcc agtatgtgga 2340
gcaactgtgt ggtccctacg tcttcatcat cttcactgtg ctcctggttc tgttcttcat 2400
cttcacctac ttcaaagttc ctgagactaa aggccggacc ttcgatgaga tcgcttccgg 2460
cttccggcag gggggagcca gccaaagtga caagacaccc gaggagctgt tccatcccct 2520
gggggctgat tcccaagtgt gataatggat caacctctgg attacaaaat ttgtgaaaga 2580
ttgactggta ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg 2640
cctttgtatc atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc 2700
tggttgctgt ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc 2760
actgtgtttg ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt 2820
tccgggactt tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt 2880
gcccgctgct ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg 2940
aaatcatcgt cctttccttg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg 3000
tccttctgct acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg 3060
ccggctctgc ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt 3120
tgggccgcct ccccgcatca ttgcctgccc gggtggcatc cctgtgaccc ctccccagtg 3180
cctctcctgg ccctggaagt tgccactcca gtgcccacca gccttgtcct aataaaatta 3240
agttgcatca ttttgtctga ctaggtgtcc ttctataata ttatggggtg gaggggggtg 3300
gtatggagca aggggcccaa gttgggaaga aacctgtagg gcctgcgtta cccaggctgg 3360
agtgcagtgg cacatttctg ctcactgcaa cctcctcctc cctgggttc 3409
<210> 13
<400> 13
000
<210> 14
<211> 3980
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 14
ctctggagac gcgttacata agctcctccc agcctcaggc ccaggaatgg gaatctctgt 60
gggtcacaca tcagtaggga ggtctttccc gatccttttc tatgctactc caggagtcaa 120
agcgtctcct gggacttttc agggcgcttc agaagagccc tgggcctaaa ccagctcaac 180
caagctgcag ggacccagcc tcctgagaaa agtgaatgtg agcccggtgc attcagagga 240
gaatgaagcc ttcacccaga acacactctg ggaagatgtc ccaggcccag ggggagggtt 300
tgtactacca gacctaagtc acctaaactg acaccaagtc tcatccatcc caaccattcc 360
attccgggtc agaggggtca tcgatttaac cagcaaggct gcccatccaa cggttgctcc 420
ctctgctccc tggaagggcc tcctcgtggg cgttctgtac ctacaggtct tgttccgttc 480
tgggaactgc cagtggtggc aagaggtgga gcaacgggtg ccagggcagg gagaggtgag 540
tctgggaggg aagcagaggc aagatccatg gggctttaga gactttgcca aagcagtgcg 600
actgctccca ggttgttgtc agccgtcaag agtgagtgca cctccctggg cagacttctg 660
ctgccccagt gcccaggaat aggcaggggt ttgccgcaaa atgaatgaca cctggcagac 720
aataagctga agctttcatt agcagcttaa gctgaggact atctatgcaa ccgatactcc 780
ctgtgtgctc cccgggactg cttaatgtga gcccttgtgg agcgattggc accaagaaag 840
caaggactaa gtcagaagtt caagtcccag ccttgccaca gcctcagggt gccctcgagc 900
acagcaagcc tcagttttcc catctgtaca atgagagagg tacacaaggt agactcgaag 960
gctctttgtt gccagggccc tgtgttcctt tgagtgtatg tgcttctcag gcccacagag 1020
gtcctttgtg tttcgtatgt gaactgctct ctaggaaacc catgtaactg tctgtgtcct 1080
ggggcacata catgaggact catgtgggcc gtattgtgtg tttgtgccgg ggggagggga 1140
gaccccagaa caatgtcccc caccccaccc ccctcctcaa taggcggaag ccactggctt 1200
cctccctttc ctgcctcctg cctcctttgt gccagcaaga ctgagtactg gagagagaca 1260
ggggatggga aaaatcagtc cagctgtccc caggtctgcc cttaccataa ccttcccccc 1320
acctcaagtg actcctccca ggccacaccc atccccagcc ttgtgggggc cagattgggg 1380
ggcctagagg ctcaaaggca gaatgagtcc tcccaccccc taccctgcca cccctcccac 1440
ccaagccacc tcatttcctc ttcctcccca gcaccgaccc acactgacca acacaggctg 1500
agcagtcagg cccacagcat ctgaccccag gcccagctcg tcctggctgg cctgggtcgg 1560
cctctggagt atggtctggc gggtgccccc tttcttgctc cccatcctct tcttggcttc 1620
tcatgtgggc caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg 1680
tgggaggagc agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc 1740
cccagaaggt gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca 1800
tcctgcccac cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg 1860
gcatgattgg ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa 1920
tgctgatgat gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg 1980
gcaagtcctt tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga 2040
ccacaggctt cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc 2100
tgggcaccct gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc 2160
tggactccat catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc 2220
cggccctgct gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca 2280
tcaaccgcaa cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg 2340
acgtgaccca tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga 2400
aggtcaccat cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg 2460
tggtgctgca gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga 2520
gcatcttcga gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg 2580
tcaacacggc cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc 2640
tgcacctcat aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag 2700
cactgctgga gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg 2760
tggccttctt tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca 2820
gccagggtcc acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt 2880
tcattgtggg catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca 2940
tcttcactgt gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta 3000
aaggccggac cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg 3060
acaagacacc cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgataatgga 3120
tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc 3180
ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat 3240
ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg 3300
gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg 3360
ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat 3420
tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt 3480
gggcactgac aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc 3540
ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa 3600
tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg 3660
ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgcatc attgcctgcc 3720
cgggtggcat ccctgtgacc cctccccagt gcctctcctg gccctggaag ttgccactcc 3780
agtgcccacc agccttgtcc taataaaatt aagttgcatc attttgtctg actaggtgtc 3840
cttctataat attatggggt ggaggggggt ggtatggagc aaggggccca agttgggaag 3900
aaacctgtag ggcctgcgtt acccaggctg gagtgcagtg gcacatttct gctcactgca 3960
acctcctcct ccctgggttc 3980
<210> 15
<400> 15
000
<210> 16
<211> 4380
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 16
ctctggagac gcgttacata ctagtagcag aaacaaggtc ctctggaaga gcaactgatg 60
ctcttaggta ctgaagcatc atcctgcccc agagaccact cgcatatgaa gcacacatat 120
tcagtctgcc ttacttgtgt taatgattgc cagtgtccct ctgacctcct agccctgaaa 180
agtgtggcct gaaggtcatt tcagagacgg ggagagctgc tcagagaagc caatcggcga 240
gtctaggaca cacagacagg atctagtccc agagttcgct agcctaggtg agcgtcccct 300
ggccccttat accacttcct tctccagctt gcatctaatc tgctctggca gaccatcgtg 360
tttcctgtct tcctggcagc ctccagcacg ctcagtgcta ctccctgcgc atgcgccctc 420
ctcccagtac cttctctgac tccagtgggc ttggagtgcg aggaggaagg gtgaggaagg 480
ggtgaaatca ggtattggat ccacaggggg tctgaagagc actagcctgg ccttttggga 540
ctgaacttct gctatgaaga cctccactgc catccctgga gtccggggca catccaaggc 600
ttgctgtcca tcgtttactg tttacagatg acaacaatga ctgtgttcgg ggcagaaata 660
tccaccaggg ctagagtaca aaaggagttt gcattgatgg ccggacaggc cctgtccctg 720
gcagcctgcc agcgctgagt atgagaccca gcgggaagtg ctaccctggc agacgtgtcc 780
actgagtaca cagaccacca aggcaggcag ctctcgggga agctgtctat gctgggccag 840
cccaccttga gggcagggaa cagaacagat tgtggcagag aggaaaatgt ggagcttctg 900
tttgttcaca gacacacgca ctcgcccacg cacgcacgca cgcacgcacg cacgcacgaa 960
tgcacgcacg cagtagttga atgctatgga ttccgctcag agctgagaac agccccagcg 1020
acagttccct ggcctctctc cttactctga tgtcctcatc tgtcttcaca tggtctcagg 1080
acgctaatac tccatcctaa tgtacactcc tttccctggg cctccgttcc agttcagttc 1140
tcagaggacc tggagggagt gattggctac accaactttg ctttcgttca ccaagcccat 1200
gtctctactt gggtgtctaa tgggcatctc caacattacc taccccaaac agaaaaccct 1260
ttcttccccc caaccacacc ccaccctacc cccacagtat tttctccatg cccggaaaga 1320
tctgctctct tatggtccct ctttgcctca ctgaaaagca ggacaagttg gggacttccc 1380
aaacttttat gcatgaagaa acccaggcaa tttgccaaaa ggtacactct gggggtctgt 1440
catttactct gagccagaac cctgaaattt ttactaaccc atcacataat gaatgaagag 1500
aatctttttc tttttttttt tttttctttt tttttggttt ttcgagacag ggtttctctg 1560
tatagccctg gctatcctgg aacacactct gtagaccagg ctggcctcga actcagaaat 1620
ccacctgcct ctgcctcccg agtgctggga ttaaaggcgt gcgccaccac gcctggctga 1680
atgaagagaa tcttgacctc atctccccag cctcttggtc ctgagggacc ctggtctacc 1740
tactgctttg ctgtcttctt agctcttctt acttttttgc tgactcagac ctatggctat 1800
ctccattata cagatgagga gactgaggca tggatccctg gttggtccat ggtcacgtga 1860
agcccatcac ccagtatttg taaagtgaga tgggccaggc tggtaccttg gaactgaaac 1920
tcacactgcc ctacctggaa gaatctgaca ggcaaaatct gctgctgaaa gtgattgtct 1980
gtcacgtttc tcagctgccc gactctgaga actccacagc cccctttcgt tccaccatac 2040
tacagagtcg ccacggaaag ccggctctgt ggagaagctg aggtagctgg gtttctgtct 2100
gggttactct gtccagcgag gaaacaagta ccttagaccc actaagcctc tgctttctga 2160
actgtaaagt gggggatatg acacctgcct cccagggatg gctgaatgct ctggcagaag 2220
cttagagccc ccacagctac ccctaggctc acagctcctc cgatgagacc tagaattgag 2280
gtatgagttg aataccccag gcaggtccaa ggcttccacg ggcccaggct gaccaagctg 2340
aggccgccca ccgtagggct tgcctatctg caggcagctc acaaaggaac aataacagga 2400
aaccatcccg aggggaagtg ggccagggcc agttggaaaa cctgcctccc tcccagcctg 2460
ggtgtggctc ccctctcccc tcctgaggca atcaactgtg ctctccacaa agctcggccc 2520
tggacagact gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 2580
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 2640
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 2700
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 2760
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 2820
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 2880
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 2940
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 3000
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 3060
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 3120
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 3180
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 3240
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 3300
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 3360
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 3420
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 3480
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 3540
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 3600
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 3660
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 3720
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 3780
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 3840
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 3900
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 3960
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgagctgg 4020
agcctcggta gccgttcctc ctgcccgctg ggcctcccaa cgggccctcc tcccctcctt 4080
gcaccggccc ttcctggtct ttgaataaac attgcctgcc cgggtggcat ccctgtgacc 4140
cctccccagt gcctctcctg gccctggaag ttgccactcc agtgcccacc agccttgtcc 4200
taataaaatt aagttgcatc attttgtctg actaggtgtc cttctataat attatggggt 4260
ggaggggggt ggtatggagc aaggggccca agttgggaag aaacctgtag ggcctgcgtt 4320
acccaggctg gagtgcagtg gcacatttct gctcactgca acctcctcct ccctgggttc 4380
<210> 17
<211> 3299
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 17
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatacg ttacataact tacggtaaat ggcccgcctg gctgaccgcc caacgacccc 240
cgcccattga cgtcaataat gacgtatgtt cccatagtaa cgccaatagg gactttccat 300
tgacgtcaat gggtggagta tttacggtaa actgcccact tggcagtaca tcaagtgtat 360
catatgccaa gtacgccccc tattgacgtc aatgacggta aatggcccgc ctggcattat 420
gcccagtaca tgaccttatg ggactttcct acttggcagt acatctacgt attagtcatc 480
gctattacca tggtgatgcg gttttggcag tacatcaatg ggcgtggata gcggtttgac 540
tcacggggat ttccaagtct ccaccccatt gacgtcaatg ggagtttgtt ttggcaccaa 600
aatcaacggg actttccaaa atgtcgtaac aactccgccc cattgacgca aatgggcggt 660
aggcgtgtac ggtgggaggt ctatataagc agagctcgtt tagtgaaccg tcagatcgcc 720
tggagacgcc atccacgctg ttttgacctc catagaagac accgggaccg atccagcctc 780
cgcggatgga gcccagcagc aagaagctga cgggtcgcct catgctggcc gtgggaggag 840
cagtgcttgg ctccctgcag tttggctaca acactggagt catcaatgcc ccccagaagg 900
tgatcgagga gttctacaac cagacatggg tccaccgcta tggggagagc atcctgccca 960
ccacgctcac cacgctctgg tccctctcag tggccatctt ttctgttggg ggcatgattg 1020
gctccttctc tgtgggcctt ttcgttaacc gctttggccg gcggaattca atgctgatga 1080
tgaacctgct ggccttcgtg tccgccgtgc tcatgggctt ctcgaaactg ggcaagtcct 1140
ttgagatgct gatcctgggc cgcttcatca tcggtgtgta ctgcggcctg accacaggct 1200
tcgtgcccat gtatgtgggt gaagtgtcac ccacagccct tcgtggggcc ctgggcaccc 1260
tgcaccagct gggcatcgtc gtcggcatcc tcatcgccca ggtgttcggc ctggactcca 1320
tcatgggcaa caaggacctg tggcccctgc tgctgagcat catcttcatc ccggccctgc 1380
tgcagtgcat cgtgctgccc ttctgccccg agagtccccg cttcctgctc atcaaccgca 1440
acgaggagaa ccgggccaag agtgtgctaa agaagctgcg cgggacagct gacgtgaccc 1500
atgacctgca ggagatgaag gaagagagtc ggcagatgat gcgggagaag aaggtcacca 1560
tcctggagct gttccgctcc cccgcctacc gccagcccat cctcatcgct gtggtgctgc 1620
agctgtccca gcagctgtct ggcatcaacg ctgtcttcta ttactccacg agcatcttcg 1680
agaaggcggg ggtgcagcag cctgtgtatg ccaccattgg ctccggtatc gtcaacacgg 1740
ccttcactgt cgtgtcgctg tttgtggtgg agcgagcagg ccggcggacc ctgcacctca 1800
taggcctcgc tggcatggcg ggttgtgcca tactcatgac catcgcgcta gcactgctgg 1860
agcagctacc ctggatgtcc tatctgagca tcgtggccat ctttggcttt gtggccttct 1920
ttgaagtggg tcctggcccc atcccatggt tcatcgtggc tgaactcttc agccagggtc 1980
cacgtccagc tgccattgcc gttgcaggct tctccaactg gacctcaaat ttcattgtgg 2040
gcatgtgctt ccagtatgtg gagcaactgt gtggtcccta cgtcttcatc atcttcactg 2100
tgctcctggt tctgttcttc atcttcacct acttcaaagt tcctgagact aaaggccgga 2160
ccttcgatga gatcgcttcc ggcttccggc aggggggagc cagccaaagt gacaagacac 2220
ccgaggagct gttccatccc ctgggggctg attcccaagt gtgataatgg atcaacctct 2280
ggattacaaa atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct 2340
atgtggatac gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat 2400
tttctcctcc ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt 2460
caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat 2520
tgccaccacc tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc 2580
ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga 2640
caattccgtg gtgttgtcgg ggaaatcatc gtcctttcct tggctgctcg cctgtgttgc 2700
cacctggatt ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga 2760
ccttccttcc cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc 2820
tcagacgagt cggatctccc tttgggccgc ctccccgcat cattgcctgc ccgggtggca 2880
tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc cagtgcccac 2940
cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt ccttctataa 3000
tattatgggg tggagggggg tggtatggag caaggggccc aagttgggaa gaaacctgta 3060
gggcctgcgt tacccaggct ggagtgcagt ggcacatttc tgctcactgc aacctcctcc 3120
tccctgggtt ctacgtagat aagtagcatg gcgggttaat cattaactac aaggaacccc 3180
tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag gccgggcgac 3240
caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgc 3299
<210> 18
<400> 18
000
<210> 19
<211> 3750
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 19
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg 240
acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa 300
tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca 360
agtacgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac 420
atgaccttat gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc 480
atggtcgagg tgagccccac gttctgcttc actctcccca tctccccccc ctccccaccc 540
ccaattttgt atttatttat tttttaatta ttttgtgcag cgatgggggc gggggggggg 600
ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg 660
tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg cgaggcggcg 720
gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg ggagtcgctg cgcgctgcct 780
tcgccccgtg ccccgctccg ccgccgcctc gcgccgcccg ccccggctct gactgaccgc 840
gttactccca caggtgagcg ggcgggacgg cccttctcct ccgggctgta attagcgctt 900
ggtttaatga cggcttgttt cttttctgtg gctgcgtgaa agccttgagg ggctccggga 960
gggccctttg tgcgggggga gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag 1020
cgccgcgtgc ggctccgcgc tgcccggcgg ctgtgagcgc tgcgggcgcg gcgcggggct 1080
ttgtgcgctc cgcagtgtgc gcgaggggag cgcggccggg ggcggtgccc cgcggtgcgg 1140
ggggggctgc gaggggaaca aaggctgcgt gcggggtgtg tgcgtggggg ggtgagcagg 1200
gggtgtgggc gcgtcggtcg ggctgcaacc ccccctgcac ccccctcccc gagttgctga 1260
gcacggcccg gcttcgggtg cggggctccg tacggggcgt ggcgcggggc tcgccgtgcc 1320
gggcgggggg tggcggcagg tgggggtgcc gggcggggcg gggccgcctc gggccgggga 1380
gggctcgggg gaggggcgcg gcggcccccg gagcgccggc ggctgtcgag gcgcggcgag 1440
ccgcagccat tgccttttat ggtaatcgtg cgagagggcg cagggacttc ctttgtccca 1500
aatctgtgcg gagccgaaat ctgggaggcg ccgccgcacc ccctctagcg ggcgcggggc 1560
gaagcggtgc ggcgccggca ggaaggaaat gggcggggag ggccttcgtg cgtcgccgcg 1620
ccgccgtccc cttctccctc tccagcctcg gggctgtccg cggggggacg gctgccttcg 1680
ggggggacgg ggcagggcgg ggttcggctt ctggcgtgtg accggcggct ctagagcctc 1740
tgctaaccat gttcatgcct tcttcttttt cctacagctc ctgggcaacg tgctggttat 1800
tgtgctgtct catcattttg gcaaagaatt catggagccc agcagcaaga agctgacggg 1860
tcgcctcatg ctggccgtgg gaggagcagt gcttggctcc ctgcagtttg gctacaacac 1920
tggagtcatc aatgcccccc agaaggtgat cgaggagttc tacaaccaga catgggtcca 1980
ccgctatggg gagagcatcc tgcccaccac gctcaccacg ctctggtccc tctcagtggc 2040
catcttttct gttgggggca tgattggctc cttctctgtg ggccttttcg ttaaccgctt 2100
tggccggcgg aattcaatgc tgatgatgaa cctgctggcc ttcgtgtccg ccgtgctcat 2160
gggcttctcg aaactgggca agtcctttga gatgctgatc ctgggccgct tcatcatcgg 2220
tgtgtactgc ggcctgacca caggcttcgt gcccatgtat gtgggtgaag tgtcacccac 2280
agcccttcgt ggggccctgg gcaccctgca ccagctgggc atcgtcgtcg gcatcctcat 2340
cgcccaggtg ttcggcctgg actccatcat gggcaacaag gacctgtggc ccctgctgct 2400
gagcatcatc ttcatcccgg ccctgctgca gtgcatcgtg ctgcccttct gccccgagag 2460
tccccgcttc ctgctcatca accgcaacga ggagaaccgg gccaagagtg tgctaaagaa 2520
gctgcgcggg acagctgacg tgacccatga cctgcaggag atgaaggaag agagtcggca 2580
gatgatgcgg gagaagaagg tcaccatcct ggagctgttc cgctcccccg cctaccgcca 2640
gcccatcctc atcgctgtgg tgctgcagct gtcccagcag ctgtctggca tcaacgctgt 2700
cttctattac tccacgagca tcttcgagaa ggcgggggtg cagcagcctg tgtatgccac 2760
cattggctcc ggtatcgtca acacggcctt cactgtcgtg tcgctgtttg tggtggagcg 2820
agcaggccgg cggaccctgc acctcatagg cctcgctggc atggcgggtt gtgccatact 2880
catgaccatc gcgctagcac tgctggagca gctaccctgg atgtcctatc tgagcatcgt 2940
ggccatcttt ggctttgtgg ccttctttga agtgggtcct ggccccatcc catggttcat 3000
cgtggctgaa ctcttcagcc agggtccacg tccagctgcc attgccgttg caggcttctc 3060
caactggacc tcaaatttca ttgtgggcat gtgcttccag tatgtggagc aactgtgtgg 3120
tccctacgtc ttcatcatct tcactgtgct cctggttctg ttcttcatct tcacctactt 3180
caaagttcct gagactaaag gccggacctt cgatgagatc gcttccggct tccggcaggg 3240
gggagccagc caaagtgaca agacacccga ggagctgttc catcccctgg gggctgattc 3300
ccaagtgtga tcattgcctg cccgggtggc atccctgtga cccctcccca gtgcctctcc 3360
tggccctgga agttgccact ccagtgccca ccagccttgt cctaataaaa ttaagttgca 3420
tcattttgtc tgactaggtg tccttctata atattatggg gtggaggggg gtggtatgga 3480
gcaaggggcc caagttggga agaaacctgt agggcctgcg ttacccaggc tggagtgcag 3540
tggcacattt ctgctcactg caacctcctc ctccctgggt tctacgtaga taagtagcat 3600
ggcgggttaa tcattaacta caaggaaccc ctagtgatgg agttggccac tccctctctg 3660
cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc 3720
cgggcggcct cagtgagcga gcgagcgcgc 3750
<210> 20
<400> 20
000
<210> 21
<211> 3745
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 21
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatatt tgcttctagg aagcagaaga ctgaggaaat gacttgggcg ggtgcatcaa 240
tgcggccaaa aaagacacgg acacgctccc ctgggacctg agctggttcg cagtcttccc 300
aaaggtgcca agcaagcgtc agttcccctc aggcgctcca ggttcagtgc cttgtgccga 360
gggtctccgg tgccttccta gacttctcgg gacagtctga aggggtcagg agcggcggga 420
cagcgcggga agagcaggca aggggagaca gccggactgc gcctcagtcc tccgtgccaa 480
gaacaccgtc gcggaggcgc ggccagcttc ccttggatcg gactttccgc ccctagggcc 540
aggcggcgga gcttcagcct tgtcccttcc ccagtttcgg gcggccccca gagctgagta 600
agccgggtgg agggagtctg caaggatttc ctgagcgcga tgggcaggag gaggggcaag 660
ggcaagaggg cgcggagcaa agaccctgaa cctgccgggg ccgcgctccc gggcccgcgt 720
cgccagcacc tccccacgcg cgctcggccc cgggccaccc gccctcgtcg gcccccgccc 780
ctctccgtag ccgcagggaa gcgagcctgg gaggaagaag agggtaggtg gggaggcgga 840
tgaggggtgg gggacccctt gacgtcacca gaaggaggtg ccggggtagg aagtgggctg 900
gggaaaggtt ataaatcgcc cccgccctcg gctgctcttc atcgaggtcc gcgggaggct 960
cggagcgcgc caggcggaca ctcctctcgg ctcctccccg gcagcggcgg cggctcggag 1020
cgggctccgg ggctcgggtg cagcggccag cgggcgcctg gcggcgagga ttacccgggg 1080
aagtggttgt ctcctggctg gagccgcgag acgggcgctc agggcgcggg gccggcggcg 1140
gcgaacaaga ggacggactc tggcggccgg gtcgttggcc gcggggagcg cgggcaccgg 1200
gcgagcaggc cgcgtcgcgc tcaccgccac catggagccc agcagcaaga agctgacggg 1260
tcgcctcatg ctggccgtgg gaggagcagt gcttggctcc ctgcagtttg gctacaacac 1320
tggagtcatc aatgcccccc agaaggtgat cgaggagttc tacaaccaga catgggtcca 1380
ccgctatggg gagagcatcc tgcccaccac gctcaccacg ctctggtccc tctcagtggc 1440
catcttttct gttgggggca tgattggctc cttctctgtg ggccttttcg ttaaccgctt 1500
tggccggcgg aattcaatgc tgatgatgaa cctgctggcc ttcgtgtccg ccgtgctcat 1560
gggcttctcg aaactgggca agtcctttga gatgctgatc ctgggccgct tcatcatcgg 1620
tgtgtactgc ggcctgacca caggcttcgt gcccatgtat gtgggtgaag tgtcacccac 1680
agcccttcgt ggggccctgg gcaccctgca ccagctgggc atcgtcgtcg gcatcctcat 1740
cgcccaggtg ttcggcctgg actccatcat gggcaacaag gacctgtggc ccctgctgct 1800
gagcatcatc ttcatcccgg ccctgctgca gtgcatcgtg ctgcccttct gccccgagag 1860
tccccgcttc ctgctcatca accgcaacga ggagaaccgg gccaagagtg tgctaaagaa 1920
gctgcgcggg acagctgacg tgacccatga cctgcaggag atgaaggaag agagtcggca 1980
gatgatgcgg gagaagaagg tcaccatcct ggagctgttc cgctcccccg cctaccgcca 2040
gcccatcctc atcgctgtgg tgctgcagct gtcccagcag ctgtctggca tcaacgctgt 2100
cttctattac tccacgagca tcttcgagaa ggcgggggtg cagcagcctg tgtatgccac 2160
cattggctcc ggtatcgtca acacggcctt cactgtcgtg tcgctgtttg tggtggagcg 2220
agcaggccgg cggaccctgc acctcatagg cctcgctggc atggcgggtt gtgccatact 2280
catgaccatc gcgctagcac tgctggagca gctaccctgg atgtcctatc tgagcatcgt 2340
ggccatcttt ggctttgtgg ccttctttga agtgggtcct ggccccatcc catggttcat 2400
cgtggctgaa ctcttcagcc agggtccacg tccagctgcc attgccgttg caggcttctc 2460
caactggacc tcaaatttca ttgtgggcat gtgcttccag tatgtggagc aactgtgtgg 2520
tccctacgtc ttcatcatct tcactgtgct cctggttctg ttcttcatct tcacctactt 2580
caaagttcct gagactaaag gccggacctt cgatgagatc gcttccggct tccggcaggg 2640
gggagccagc caaagtgaca agacacccga ggagctgttc catcccctgg gggctgattc 2700
ccaagtgtga taatggatca acctctggat tacaaaattt gtgaaagatt gactggtatt 2760
cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 2820
gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 2880
ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 2940
gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 3000
gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 3060
acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcggggaa atcatcgtcc 3120
tttccttggc tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac 3180
gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 3240
cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 3300
ccgcatcatt gcctgcccgg gtggcatccc tgtgacccct ccccagtgcc tctcctggcc 3360
ctggaagttg ccactccagt gcccaccagc cttgtcctaa taaaattaag ttgcatcatt 3420
ttgtctgact aggtgtcctt ctataatatt atggggtgga ggggggtggt atggagcaag 3480
gggcccaagt tgggaagaaa cctgtagggc ctgcgttacc caggctggag tgcagtggca 3540
catttctgct cactgcaacc tcctcctccc tgggttctac gtagataagt agcatggcgg 3600
gttaatcatt aactacaagg aacccctagt gatggagttg gccactccct ctctgcgcgc 3660
tcgctcgctc actgaggccg ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc 3720
ggcctcagtg agcgagcgag cgcgc 3745
<210> 22
<400> 22
000
<210> 23
<211> 4316
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 23
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataag ctcctcccag cctcaggccc aggaatggga atctctgtgg gtcacacatc 240
agtagggagg tctttcccga tccttttcta tgctactcca ggagtcaaag cgtctcctgg 300
gacttttcag ggcgcttcag aagagccctg ggcctaaacc agctcaacca agctgcaggg 360
acccagcctc ctgagaaaag tgaatgtgag cccggtgcat tcagaggaga atgaagcctt 420
cacccagaac acactctggg aagatgtccc aggcccaggg ggagggtttg tactaccaga 480
cctaagtcac ctaaactgac accaagtctc atccatccca accattccat tccgggtcag 540
aggggtcatc gatttaacca gcaaggctgc ccatccaacg gttgctccct ctgctccctg 600
gaagggcctc ctcgtgggcg ttctgtacct acaggtcttg ttccgttctg ggaactgcca 660
gtggtggcaa gaggtggagc aacgggtgcc agggcaggga gaggtgagtc tgggagggaa 720
gcagaggcaa gatccatggg gctttagaga ctttgccaaa gcagtgcgac tgctcccagg 780
ttgttgtcag ccgtcaagag tgagtgcacc tccctgggca gacttctgct gccccagtgc 840
ccaggaatag gcaggggttt gccgcaaaat gaatgacacc tggcagacaa taagctgaag 900
ctttcattag cagcttaagc tgaggactat ctatgcaacc gatactccct gtgtgctccc 960
cgggactgct taatgtgagc ccttgtggag cgattggcac caagaaagca aggactaagt 1020
cagaagttca agtcccagcc ttgccacagc ctcagggtgc cctcgagcac agcaagcctc 1080
agttttccca tctgtacaat gagagaggta cacaaggtag actcgaaggc tctttgttgc 1140
cagggccctg tgttcctttg agtgtatgtg cttctcaggc ccacagaggt cctttgtgtt 1200
tcgtatgtga actgctctct aggaaaccca tgtaactgtc tgtgtcctgg ggcacataca 1260
tgaggactca tgtgggccgt attgtgtgtt tgtgccgggg ggaggggaga ccccagaaca 1320
atgtccccca ccccaccccc ctcctcaata ggcggaagcc actggcttcc tccctttcct 1380
gcctcctgcc tcctttgtgc cagcaagact gagtactgga gagagacagg ggatgggaaa 1440
aatcagtcca gctgtcccca ggtctgccct taccataacc ttccccccac ctcaagtgac 1500
tcctcccagg ccacacccat ccccagcctt gtgggggcca gattgggggg cctagaggct 1560
caaaggcaga atgagtcctc ccacccccta ccctgccacc cctcccaccc aagccacctc 1620
atttcctctt cctccccagc accgacccac actgaccaac acaggctgag cagtcaggcc 1680
cacagcatct gaccccaggc ccagctcgtc ctggctggcc tgggtcggcc tctggagtat 1740
ggtctggcgg gtgccccctt tcttgctccc catcctcttc ttggcttctc atgtgggcca 1800
ccatggagcc cagcagcaag aagctgacgg gtcgcctcat gctggccgtg ggaggagcag 1860
tgcttggctc cctgcagttt ggctacaaca ctggagtcat caatgccccc cagaaggtga 1920
tcgaggagtt ctacaaccag acatgggtcc accgctatgg ggagagcatc ctgcccacca 1980
cgctcaccac gctctggtcc ctctcagtgg ccatcttttc tgttgggggc atgattggct 2040
ccttctctgt gggccttttc gttaaccgct ttggccggcg gaattcaatg ctgatgatga 2100
acctgctggc cttcgtgtcc gccgtgctca tgggcttctc gaaactgggc aagtcctttg 2160
agatgctgat cctgggccgc ttcatcatcg gtgtgtactg cggcctgacc acaggcttcg 2220
tgcccatgta tgtgggtgaa gtgtcaccca cagcccttcg tggggccctg ggcaccctgc 2280
accagctggg catcgtcgtc ggcatcctca tcgcccaggt gttcggcctg gactccatca 2340
tgggcaacaa ggacctgtgg cccctgctgc tgagcatcat cttcatcccg gccctgctgc 2400
agtgcatcgt gctgcccttc tgccccgaga gtccccgctt cctgctcatc aaccgcaacg 2460
aggagaaccg ggccaagagt gtgctaaaga agctgcgcgg gacagctgac gtgacccatg 2520
acctgcagga gatgaaggaa gagagtcggc agatgatgcg ggagaagaag gtcaccatcc 2580
tggagctgtt ccgctccccc gcctaccgcc agcccatcct catcgctgtg gtgctgcagc 2640
tgtcccagca gctgtctggc atcaacgctg tcttctatta ctccacgagc atcttcgaga 2700
aggcgggggt gcagcagcct gtgtatgcca ccattggctc cggtatcgtc aacacggcct 2760
tcactgtcgt gtcgctgttt gtggtggagc gagcaggccg gcggaccctg cacctcatag 2820
gcctcgctgg catggcgggt tgtgccatac tcatgaccat cgcgctagca ctgctggagc 2880
agctaccctg gatgtcctat ctgagcatcg tggccatctt tggctttgtg gccttctttg 2940
aagtgggtcc tggccccatc ccatggttca tcgtggctga actcttcagc cagggtccac 3000
gtccagctgc cattgccgtt gcaggcttct ccaactggac ctcaaatttc attgtgggca 3060
tgtgcttcca gtatgtggag caactgtgtg gtccctacgt cttcatcatc ttcactgtgc 3120
tcctggttct gttcttcatc ttcacctact tcaaagttcc tgagactaaa ggccggacct 3180
tcgatgagat cgcttccggc ttccggcagg ggggagccag ccaaagtgac aagacacccg 3240
aggagctgtt ccatcccctg ggggctgatt cccaagtgtg ataatggatc aacctctgga 3300
ttacaaaatt tgtgaaagat tgactggtat tcttaactat gttgctcctt ttacgctatg 3360
tggatacgct gctttaatgc ctttgtatca tgctattgct tcccgtatgg ctttcatttt 3420
ctcctccttg tataaatcct ggttgctgtc tctttatgag gagttgtggc ccgttgtcag 3480
gcaacgtggc gtggtgtgca ctgtgtttgc tgacgcaacc cccactggtt ggggcattgc 3540
caccacctgt cagctccttt ccgggacttt cgctttcccc ctccctattg ccacggcgga 3600
actcatcgcc gcctgccttg cccgctgctg gacaggggct cggctgttgg gcactgacaa 3660
ttccgtggtg ttgtcgggga aatcatcgtc ctttccttgg ctgctcgcct gtgttgccac 3720
ctggattctg cgcgggacgt ccttctgcta cgtcccttcg gccctcaatc cagcggacct 3780
tccttcccgc ggcctgctgc cggctctgcg gcctcttccg cgtcttcgcc ttcgccctca 3840
gacgagtcgg atctcccttt gggccgcctc cccgcatcat tgcctgcccg ggtggcatcc 3900
ctgtgacccc tccccagtgc ctctcctggc cctggaagtt gccactccag tgcccaccag 3960
ccttgtccta ataaaattaa gttgcatcat tttgtctgac taggtgtcct tctataatat 4020
tatggggtgg aggggggtgg tatggagcaa ggggcccaag ttgggaagaa acctgtaggg 4080
cctgcgttac ccaggctgga gtgcagtggc acatttctgc tcactgcaac ctcctcctcc 4140
ctgggttcta cgtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4200
tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4260
aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgc 4316
<210> 24
<400> 24
000
<210> 25
<211> 4716
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 25
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacatact agtagcagaa acaaggtcct ctggaagagc aactgatgct cttaggtact 240
gaagcatcat cctgccccag agaccactcg catatgaagc acacatattc agtctgcctt 300
acttgtgtta atgattgcca gtgtccctct gacctcctag ccctgaaaag tgtggcctga 360
aggtcatttc agagacgggg agagctgctc agagaagcca atcggcgagt ctaggacaca 420
cagacaggat ctagtcccag agttcgctag cctaggtgag cgtcccctgg ccccttatac 480
cacttccttc tccagcttgc atctaatctg ctctggcaga ccatcgtgtt tcctgtcttc 540
ctggcagcct ccagcacgct cagtgctact ccctgcgcat gcgccctcct cccagtacct 600
tctctgactc cagtgggctt ggagtgcgag gaggaagggt gaggaagggg tgaaatcagg 660
tattggatcc acagggggtc tgaagagcac tagcctggcc ttttgggact gaacttctgc 720
tatgaagacc tccactgcca tccctggagt ccggggcaca tccaaggctt gctgtccatc 780
gtttactgtt tacagatgac aacaatgact gtgttcgggg cagaaatatc caccagggct 840
agagtacaaa aggagtttgc attgatggcc ggacaggccc tgtccctggc agcctgccag 900
cgctgagtat gagacccagc gggaagtgct accctggcag acgtgtccac tgagtacaca 960
gaccaccaag gcaggcagct ctcggggaag ctgtctatgc tgggccagcc caccttgagg 1020
gcagggaaca gaacagattg tggcagagag gaaaatgtgg agcttctgtt tgttcacaga 1080
cacacgcact cgcccacgca cgcacgcacg cacgcacgca cgcacgaatg cacgcacgca 1140
gtagttgaat gctatggatt ccgctcagag ctgagaacag ccccagcgac agttccctgg 1200
cctctctcct tactctgatg tcctcatctg tcttcacatg gtctcaggac gctaatactc 1260
catcctaatg tacactcctt tccctgggcc tccgttccag ttcagttctc agaggacctg 1320
gagggagtga ttggctacac caactttgct ttcgttcacc aagcccatgt ctctacttgg 1380
gtgtctaatg ggcatctcca acattaccta ccccaaacag aaaacccttt cttcccccca 1440
accacacccc accctacccc cacagtattt tctccatgcc cggaaagatc tgctctctta 1500
tggtccctct ttgcctcact gaaaagcagg acaagttggg gacttcccaa acttttatgc 1560
atgaagaaac ccaggcaatt tgccaaaagg tacactctgg gggtctgtca tttactctga 1620
gccagaaccc tgaaattttt actaacccat cacataatga atgaagagaa tctttttctt 1680
tttttttttt tttctttttt tttggttttt cgagacaggg tttctctgta tagccctggc 1740
tatcctggaa cacactctgt agaccaggct ggcctcgaac tcagaaatcc acctgcctct 1800
gcctcccgag tgctgggatt aaaggcgtgc gccaccacgc ctggctgaat gaagagaatc 1860
ttgacctcat ctccccagcc tcttggtcct gagggaccct ggtctaccta ctgctttgct 1920
gtcttcttag ctcttcttac ttttttgctg actcagacct atggctatct ccattataca 1980
gatgaggaga ctgaggcatg gatccctggt tggtccatgg tcacgtgaag cccatcaccc 2040
agtatttgta aagtgagatg ggccaggctg gtaccttgga actgaaactc acactgccct 2100
acctggaaga atctgacagg caaaatctgc tgctgaaagt gattgtctgt cacgtttctc 2160
agctgcccga ctctgagaac tccacagccc cctttcgttc caccatacta cagagtcgcc 2220
acggaaagcc ggctctgtgg agaagctgag gtagctgggt ttctgtctgg gttactctgt 2280
ccagcgagga aacaagtacc ttagacccac taagcctctg ctttctgaac tgtaaagtgg 2340
gggatatgac acctgcctcc cagggatggc tgaatgctct ggcagaagct tagagccccc 2400
acagctaccc ctaggctcac agctcctccg atgagaccta gaattgaggt atgagttgaa 2460
taccccaggc aggtccaagg cttccacggg cccaggctga ccaagctgag gccgcccacc 2520
gtagggcttg cctatctgca ggcagctcac aaaggaacaa taacaggaaa ccatcccgag 2580
gggaagtggg ccagggccag ttggaaaacc tgcctccctc ccagcctggg tgtggctccc 2640
ctctcccctc ctgaggcaat caactgtgct ctccacaaag ctcggccctg gacagactgc 2700
caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg tgggaggagc 2760
agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc cccagaaggt 2820
gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca tcctgcccac 2880
cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg gcatgattgg 2940
ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa tgctgatgat 3000
gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg gcaagtcctt 3060
tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga ccacaggctt 3120
cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc tgggcaccct 3180
gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc tggactccat 3240
catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc cggccctgct 3300
gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca tcaaccgcaa 3360
cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg acgtgaccca 3420
tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga aggtcaccat 3480
cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg tggtgctgca 3540
gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga gcatcttcga 3600
gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg tcaacacggc 3660
cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc tgcacctcat 3720
aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag cactgctgga 3780
gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg tggccttctt 3840
tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca gccagggtcc 3900
acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt tcattgtggg 3960
catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca tcttcactgt 4020
gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta aaggccggac 4080
cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg acaagacacc 4140
cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgagctggag cctcggtagc 4200
cgttcctcct gcccgctggg cctcccaacg ggccctcctc ccctccttgc accggccctt 4260
cctggtcttt gaataaacat tgcctgcccg ggtggcatcc ctgtgacccc tccccagtgc 4320
ctctcctggc cctggaagtt gccactccag tgcccaccag ccttgtccta ataaaattaa 4380
gttgcatcat tttgtctgac taggtgtcct tctataatat tatggggtgg aggggggtgg 4440
tatggagcaa ggggcccaag ttgggaagaa acctgtaggg cctgcgttac ccaggctgga 4500
gtgcagtggc acatttctgc tcactgcaac ctcctcctcc ctgggttcta cgtagataag 4560
tagcatggcg ggttaatcat taactacaag gaacccctag tgatggagtt ggccactccc 4620
tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc 4680
tttgcccggg cggcctcagt gagcgagcga gcgcgc 4716
<210> 26
<211> 492
<212> PRT
<213> 智人
<400> 26
Met Glu Pro Ser Ser Lys Lys Leu Thr Gly Arg Leu Met Leu Ala Val
1 5 10 15
Gly Gly Ala Val Leu Gly Ser Leu Gln Phe Gly Tyr Asn Thr Gly Val
20 25 30
Ile Asn Ala Pro Gln Lys Val Ile Glu Glu Phe Tyr Asn Gln Thr Trp
35 40 45
Val His Arg Tyr Gly Glu Ser Ile Leu Pro Thr Thr Leu Thr Thr Leu
50 55 60
Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser
65 70 75 80
Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met
85 90 95
Leu Met Met Asn Leu Leu Ala Phe Val Ser Ala Val Leu Met Gly Phe
100 105 110
Ser Lys Leu Gly Lys Ser Phe Glu Met Leu Ile Leu Gly Arg Phe Ile
115 120 125
Ile Gly Val Tyr Cys Gly Leu Thr Thr Gly Phe Val Pro Met Tyr Val
130 135 140
Gly Glu Val Ser Pro Thr Ala Leu Arg Gly Ala Leu Gly Thr Leu His
145 150 155 160
Gln Leu Gly Ile Val Val Gly Ile Leu Ile Ala Gln Val Phe Gly Leu
165 170 175
Asp Ser Ile Met Gly Asn Lys Asp Leu Trp Pro Leu Leu Leu Ser Ile
180 185 190
Ile Phe Ile Pro Ala Leu Leu Gln Cys Ile Val Leu Pro Phe Cys Pro
195 200 205
Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Asn Glu Glu Asn Arg Ala
210 215 220
Lys Ser Val Leu Lys Lys Leu Arg Gly Thr Ala Asp Val Thr His Asp
225 230 235 240
Leu Gln Glu Met Lys Glu Glu Ser Arg Gln Met Met Arg Glu Lys Lys
245 250 255
Val Thr Ile Leu Glu Leu Phe Arg Ser Pro Ala Tyr Arg Gln Pro Ile
260 265 270
Leu Ile Ala Val Val Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn
275 280 285
Ala Val Phe Tyr Tyr Ser Thr Ser Ile Phe Glu Lys Ala Gly Val Gln
290 295 300
Gln Pro Val Tyr Ala Thr Ile Gly Ser Gly Ile Val Asn Thr Ala Phe
305 310 315 320
Thr Val Val Ser Leu Phe Val Val Glu Arg Ala Gly Arg Arg Thr Leu
325 330 335
His Leu Ile Gly Leu Ala Gly Met Ala Gly Cys Ala Ile Leu Met Thr
340 345 350
Ile Ala Leu Ala Leu Leu Glu Gln Leu Pro Trp Met Ser Tyr Leu Ser
355 360 365
Ile Val Ala Ile Phe Gly Phe Val Ala Phe Phe Glu Val Gly Pro Gly
370 375 380
Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg
385 390 395 400
Pro Ala Ala Ile Ala Val Ala Gly Phe Ser Asn Trp Thr Ser Asn Phe
405 410 415
Ile Val Gly Met Cys Phe Gln Tyr Val Glu Gln Leu Cys Gly Pro Tyr
420 425 430
Val Phe Ile Ile Phe Thr Val Leu Leu Val Leu Phe Phe Ile Phe Thr
435 440 445
Tyr Phe Lys Val Pro Glu Thr Lys Gly Arg Thr Phe Asp Glu Ile Ala
450 455 460
Ser Gly Phe Arg Gln Gly Gly Ala Ser Gln Ser Asp Lys Thr Pro Glu
465 470 475 480
Glu Leu Phe His Pro Leu Gly Ala Asp Ser Gln Val
485 490
<210> 27
<211> 1476
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 编码GLUT1的密码子优化的多核苷酸
<400> 27
atggaaccat catccaaaaa gctgaccgga cgactgatgc ttgcagttgg cggtgcggtc 60
ttggggagcc tgcagtttgg gtacaatact ggcgtaatca atgccccgca gaaggttatt 120
gaagaatttt acaatcaaac gtgggtacat cgctacggtg aatccattct tcctacaact 180
ctgaccacac tctggagcct ttctgtagcg attttttccg tcgggggcat gataggatca 240
ttttccgtcg gtctttttgt gaaccgcttt ggccggagaa attccatgct gatgatgaat 300
cttctcgctt tcgtgagtgc cgtcctcatg ggatttagta aactgggtaa atctttcgag 360
atgttgatac tggggagatt tattatcggc gtgtattgtg gtttgaccac gggctttgta 420
ccaatgtatg ttggcgaggt ttctccgaca gcattgagag gtgcactcgg gaccttgcac 480
cagttgggca tcgtagtagg aatccttata gcgcaagttt tcgggctcga ttccatcatg 540
gggaacaaag atctctggcc attgctcctc tcaataattt ttataccggc attgcttcag 600
tgtattgttc ttcctttttg cccagagtcc cctaggttcc tgctcataaa caggaatgag 660
gagaatcgcg ctaagtccgt gttgaaaaaa cttaggggaa ctgcagacgt tactcacgat 720
ttgcaagaga tgaaggagga atctaggcaa atgatgcgcg agaagaaggt taccatactc 780
gaactcttcc gctcccccgc gtacaggcag cccattctta tcgcggtcgt cttgcagttg 840
tcacaacagt tgagtgggat taatgcagtt ttctattata gcacgtccat atttgaaaaa 900
gcaggcgtcc aacaacctgt ctatgcaact ataggctcag gcattgtaaa cacagcgttt 960
actgtagtat cactgtttgt cgttgagcgg gctggtcgaa ggaccttgca cctcatagga 1020
ctggcgggca tggcgggctg tgcgattctt atgacaattg cgctcgcgct gttggaacag 1080
cttccgtgga tgtcctatct ctctatagta gcaatatttg gatttgttgc attttttgaa 1140
gttgggcccg gacctatccc ctggttcatc gtcgcggagc tcttttccca aggcccaaga 1200
ccggctgcca ttgctgttgc aggcttctca aactggacga gtaatttcat agtaggtatg 1260
tgtttccagt atgttgaaca gctctgtggg ccctatgtct ttatcatctt tactgtgttg 1320
ctcgtgttgt tctttatctt cacttatttc aaagtacccg agacaaaggg caggacgttt 1380
gacgagattg catctggttt tagacaagga ggtgcctcac agagtgataa aaccccggag 1440
gaattgtttc atccgctggg agccgactca caggtc 1476
<210> 28
<211> 10
<212> DNA
<213> 人工序列
<220>
<223> Kozak序列基序
<400> 28
gccaccatgg 10
<210> 29
<211> 1482
<212> DNA
<213> 人工序列
<220>
<223> 编码具有Kozak基序的GLUT1的多核苷酸
<400> 29
gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc cgtgggagga 60
gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc cccccagaag 120
gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag catcctgccc 180
accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg gggcatgatt 240
ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc aatgctgatg 300
atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact gggcaagtcc 360
tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct gaccacaggc 420
ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc cctgggcacc 480
ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg cctggactcc 540
atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat cccggccctg 600
ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct catcaaccgc 660
aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc tgacgtgacc 720
catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa gaaggtcacc 780
atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc tgtggtgctg 840
cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac gagcatcttc 900
gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat cgtcaacacg 960
gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac cctgcacctc 1020
ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct agcactgctg 1080
gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt tgtggccttc 1140
tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt cagccagggt 1200
ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa tttcattgtg 1260
ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat catcttcact 1320
gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac taaaggccgg 1380
accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag tgacaagaca 1440
cccgaggagc tgttccatcc cctgggggct gattcccaag tg 1482
<210> 30
<211> 13
<212> DNA
<213> 人工序列
<220>
<223> Kozak序列基序
<400> 30
gccgccrcca ugg 13
<210> 31
<211> 10
<212> DNA
<213> 人工序列
<220>
<223> Kozak序列基序
<400> 31
gacaccaugg 10
<210> 32
<211> 141
<212> DNA
<213> 腺相关病毒
<400> 32
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120
actccatcac taggggttcc t 141
<210> 33
<211> 170
<212> DNA
<213> 腺相关病毒
<400> 33
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta 170
<210> 34
<211> 141
<212> DNA
<213> 腺相关病毒
<400> 34
aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60
ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120
gagcgcgcag ctgcctgcag g 141
<210> 35
<211> 124
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体填充序列
<400> 35
gcggcaattc agtcgataac tataacggtc ctaaggtagc gatttaaata cgcgctctct 60
taaggtagcc ccgggacgcg tcaattgact acaaaccgag tatctgcaga gggccctgcg 120
tatg 124
<210> 36
<211> 84
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体填充序列
<400> 36
cttctgaggc ggaaagaacc agatcctctc ttaaggtagc atcgagattt aaattaggga 60
taacagggta atggcgcggg ccgc 84
<210> 37
<211> 63
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体填充序列
<400> 37
gttacccagg ctggagtgca gtggcacatt tctgctcact gcaacctcct cctccctggg 60
ttc 63
<210> 38
<211> 573
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 部分人β疱疹病毒5中的CAG启动子
<400> 38
acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat 60
aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga 120
gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc 180
ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt 240
atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta ccatggtcga 300
ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt 360
gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg 420
cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg 480
cagccaatca gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc 540
ggccctataa aaagcgaagc gcgcggcggg cgg 573
<210> 39
<211> 253
<212> DNA
<213> 智人
<400> 39
gcccagcacc ccaaggcggc caacgccaaa actctccctc ctcctcttcc tcaatctcgc 60
tctcgctctt tttttttttc gcaaaaggag gggagagggg gtaaaaaaat gctgcactgt 120
gcggcgaagc cggtgagtga gcggcgcggg gccaatcagc gtgcgccgtt ccgaaagttg 180
ccttttatgg ctcgagcggc cgcggcggcg ccctataaaa cccagcggcg cgacgcgcca 240
ccaccgccga gtc 253
<210> 40
<211> 281
<212> DNA
<213> 原鸡
<400> 40
ggtcgaggtg agccccacgt tctgcttcac tctccccatc tcccccccct ccccaccccc 60
aattttgtat ttatttattt tttaattatt ttgtgcagcg atgggggcgg gggggggggg 120
ggcgcgcgcc aggcggggcg gggcggggcg aggggcgggg cggggcgagg cggagaggtg 180
cggcggcagc caatcagagc ggcgcgctcc gaaagtttcc ttttatggcg aggcggcggc 240
ggcggcggcc ctataaaaag cgaagcgcgc ggcgggcggg a 281
<210> 41
<211> 220
<212> DNA
<213> 人β疱疹病毒5
<400> 41
tggtgatgcg gttttggcag tacaccaatg ggcgtggata gcggtttgac tcacggggat 60
ttccaagtct ccaccccatt gacgtcaatg ggagtttgtt ttggcaccaa aatcaacggg 120
actttccaaa atgtcgtaat aaccccgccc cgttgacgca aatgggcggt aggcgtgtac 180
ggtgggaggt ctatataagc agagctcgtt tagtgaaccg 220
<210> 42
<211> 583
<212> DNA
<213> 人β疱疹病毒5
<400> 42
tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata tggagttccg 60
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 120
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 180
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 240
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 300
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 360
catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg 420
atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg 480
ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt 540
acggtgggag gtctatataa gcagagctgg tttagtgaac cgt 583
<210> 43
<211> 508
<212> DNA
<213> 人β疱疹病毒5
<400> 43
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg 360
atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg 420
ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt 480
acggtgggag gtctatataa gcagagct 508
<210> 44
<211> 573
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 部分人β疱疹病毒5中的CAG启动子
<400> 44
acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat tgacgtcaat 60
aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc aatgggtgga 120
gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc 180
ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt acatgacctt 240
atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta ccatggtcga 300
ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt 360
gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg 420
cgccaggcgg ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg 480
cagccaatca gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc 540
ggccctataa aaagcgaagc gcgcggcggg cgg 573
<210> 45
<211> 580
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 部分人β疱疹病毒5中的CAG启动子
<400> 45
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catgtcgagg tgagccccac gttctgcttc actctcccca tctccccccc ctccccaccc 360
ccaattttgt atttatttat tttttaatta ttttgtgcag cgatgggggc gggggggggg 420
ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg 480
tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg cgaggcggcg 540
gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg 580
<210> 46
<211> 455
<212> DNA
<213> 智人
<400> 46
caacctttgg agctaagcca gcaatggtag agggaagatt ctgcacgtcc cttccaggcg 60
gcctccccgt caccaccccc cccaacccgc cccgaccgga gctgagagta attcatacaa 120
aaggactcgc ccctgccttg gggaatccca gggaccgtcg ttaaactccc actaacgtag 180
aacccagaga tcgctgcgtt cccgccccct cacccgcccg ctctcgtcat cactgaggtg 240
gagaatagca tgcgtgaggc tccggtgccc gtcagtgggc agagcgcaca tcgcccacag 300
tccccgagaa gttgggggga ggggtcggca attgaacggg tgcctagaga aggtggcgcg 360
gggtaaactg ggaaagtgat gtcgtgtact ggctccgcct ttttcccgag ggtgggggag 420
aaccgtatat aagtgcagta gtcgccgtga acgtt 455
<210> 47
<211> 401
<212> DNA
<213> 智人
<400> 47
agtgcaagtg ggttttagga ccaggatgag gcggggtggg ggtgcctacc tgacgaccga 60
ccccgaccca ctggacaagc acccaacccc cattccccaa attgcgcatc ccctatcaga 120
gagggggagg ggaaacagga tgcggcgagg cgcgtgcgca ctgccagctt cagcaccgcg 180
gacagtgcct tcgcccccgc ctggcggcgc gcgccaccgc cgcctcagca ctgaaggcgc 240
gctgacgtca ctcgccggtc ccccgcaaac tccccttccc ggccaccttg gtcgcgtccg 300
cgccgccgcc ggcccagccg gaccgcacca cgcgaggcgc gagatagggg ggcacgggcg 360
cgaccatctg cgctgcggcg ccggcgactc agcgctgcct c 401
<210> 48
<211> 448
<212> DNA
<213> 智人
<400> 48
agtgcaagtg ggttttagga ccaggatgag gcggggtggg ggtgcctacc tgacgaccga 60
ccccgaccca ctggacaagc acccaacccc cattccccaa attgcgcatc ccctatcaga 120
gagggggagg ggaaacagga tgcggcgagg cgcgtgcgca ctgccagctt cagcaccgcg 180
gacagtgcct tcgcccccgc ctggcggcgc gcgccaccgc cgcctcagca ctgaaggcgc 240
gctgacgtca ctcgccggtc ccccgcaaac tccccttccc ggccaccttg gtcgcgtccg 300
cgccgccgcc ggcccagccg gaccgcacca cgcgaggcgc gagatagggg ggcacgggcg 360
cgaccatctg cgctgcggcg ccggcgactc agcgctgcct cagtctgcgg tgggcagcgg 420
aggagtcgtg tcgtgcctga gagcgcag 448
<210> 49
<211> 422
<212> DNA
<213> 智人
<400> 49
ctgcagaggg ccctgcgtat gagtgcaagt gggttttagg accaggatga ggcggggtgg 60
gggtgcctac ctgacgaccg accccgaccc actggacaag cacccaaccc ccattcccca 120
aattgcgcat cccctatcag agagggggag gggaaacagg atgcggcgag gcgcgtgcgc 180
actgccagct tcagcaccgc ggacagtgcc ttcgcccccg cctggcggcg cgcgccaccg 240
ccgcctcagc actgaaggcg cgctgacgtc actcgccggt cccccgcaaa ctccccttcc 300
cggccacctt ggtcgcgtcc gcgccgccgc cggcccagcc ggaccgcacc acgcgaggcg 360
cgagataggg gggcacgggc gcgaccatct gcgctgcggc gccggcgact cagcgctgcc 420
tc 422
<210> 50
<211> 281
<212> DNA
<213> 智人
<400> 50
acttgtggac aaagtttgct ctattccacc tcctccaggc cctccttggg tccatcaccc 60
caggggtgct gggtccatcc cacccccagg cccacacagg cttgcagtat tgtgtgcggt 120
atggtcaggg cgtccgagag caggtttcgc agtggaaggc aggcaggtgt tggggaggca 180
gttaccgggg caacgggaac agggcgtttt ggaggtggtt gccatgggga cctggatgct 240
gacgaaggct cgcgaggctg tgagcagcca cagtgccctg c 281
<210> 51
<211> 851
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - eSYN启动子多核苷酸
<400> 51
gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc 60
catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca 120
acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga 180
ctttccattg acgtcaatgg gtggactatt tacggtaaac tgcccacttg gcagtacatc 240
aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct 300
ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat 360
tagtcatcgc tattaccatg gctgcagagg gccctgcgta tgagtgcaag tgggttttag 420
gaccaggatg aggcggggtg ggggtgccta cctgacgacc gaccccgacc cactggacaa 480
gcacccaacc cccattcccc aaattgcgca tcccctatca gagaggggga ggggaaacag 540
gatgcggcga ggcgcgtcgc gactgccagc ttcagcaccg cggacagtgc cttcgccccc 600
gcctggcggc gcgcgccacc gccgcctcag cactgaaggc gcgctgacgt cactcgccgg 660
tcccccgcaa actccccttc ccggccacct tggtcgcgtc cgcgccgccg ccggcccagc 720
cggaccgcac cacgcgaggc gcgagatagg ggggcacggg cgcgaccatc tgcgctgcgg 780
cgccggcgac tcagcgctgc ctcagtctgc ggtgggcagc ggaggagtcg tgtcgtgcct 840
gagagcgcag g 851
<210> 52
<211> 304
<212> DNA
<213> 人β疱疹病毒5
<400> 52
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catg 304
<210> 53
<211> 953
<212> DNA
<213> 智人
<400> 53
cgcgtccgcc cgcgagcaca gagcctcgcc tttgccgatc cgccgcccgt ccacacccgc 60
cgccaggtaa gcccggccag ccgaccgggg catgcggccg cggcccttcg cccgtgcaga 120
gccgccgtct gggccgcagc ggggggcgca tggggcggaa ccggaccgcc gtggggggcg 180
cgggagaagc ccctgggcct ccggagatgg gggacacccc acgccagttc gcaggcgcga 240
ggccgcgctc gggcgggcgc gctccggggg tgccgctctc ggggcggggg caaccggcgg 300
ggtctttgtc tgagccgggc tcttgccaat ggggatcgca cggtgggcgc ggcgtagccc 360
ccgtcaggcc cggtgggggc tggggcgcca tgcgcgtgcg cgctggtcct ttgggcgcta 420
actgcgtgcg cgctgggaat tggcgctaat tgcgcgtgcg cgctgggact caatggcgct 480
aatcgcgcgt gcgttctggg gcccgggcgc ttgcgccact tcctgcccga gccgctggcg 540
cccgagggtg tggccgctgc gtgcgcgcgc gcgacccggt cgctgtttga accgggcgga 600
ggcggggctg gcgcccggtt gggagggggt tggggcctgg cttcctgccg cgcgccgcgg 660
ggacgcctcc gaccagtgtt tgccttttat ggtaataacg cggccggccc ggcttccttt 720
gtccccaatc tgggcgcgcg ccggcgcccc ctggcggcct aaggactcgg cgcgccggaa 780
gtggccaggg cggcagcggc tgctcttggc ggccccgagg tgactatagc cttcttttgt 840
gtcttgatag ttcgccagcc tctgctaacc atgttcatgc cttcttcttt ttcctacagc 900
tcctgggcaa cgtgctggtt attgtgctgt ctcatcattt tggcaaagaa ttc 953
<210> 54
<211> 1068
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 鸡β-肌动蛋白外显子/内含子加上兔球蛋白内含子
<400> 54
gtcgctgcgc gctgccttcg ccccgtgccc cgctccgccg ccgcctcgcg ccgcccgccc 60
cggctctgac tgaccgcgtt actcccacag gtgagcgggc gggacggccc ttctcctccg 120
ggctgtaatt agcgcttggt ttaatgacgg cttgtttctt ttctgtggct gcgtgaaagc 180
cttgaggggc tccgggaggg ccctttgtgc ggggggagcg gctcgggggg tgcgtgcgtg 240
tgtgtgtgcg tggggagcgc cgcgtgcggc tccgcgctgc ccggcggctg tgagcgctgc 300
gggcgcggcg cggggctttg tgcgctccgc agtgtgcgcg aggggagcgc ggccgggggc 360
ggtgccccgc ggtgcggggg gggctgcgag gggaacaaag gctgcgtgcg gggtgtgtgc 420
gtgggggggt gagcaggggg tgtgggcgcg tcggtcgggc tgcaaccccc cctgcacccc 480
cctccccgag ttgctgagca cggcccggct tcgggtgcgg ggctccgtac ggggcgtggc 540
gcggggctcg ccgtgccggg cggggggtgg cggcaggtgg gggtgccggg cggggcgggg 600
ccgcctcggg ccggggaggg ctcgggggag gggcgcggcg gcccccggag cgccggcggc 660
tgtcgaggcg cggcgagccg cagccattgc cttttatggt aatcgtgcga gagggcgcag 720
ggacttcctt tgtcccaaat ctgtgcggag ccgaaatctg ggaggcgccg ccgcaccccc 780
tctagcgggc gcggggcgaa gcggtgcggc gccggcagga aggaaatggg cggggagggc 840
cttcgtgcgt cgccgcgccg ccgtcccctt ctccctctcc agcctcgggg ctgtccgcgg 900
ggggacggct gccttcgggg gggacggggc agggcggggt tcggcttctg gcgtgtgacc 960
ggcggctcta gagcctctgc taaccatgtt catgccttct tctttttcct acagctcctg 1020
ggcaacgtgc tggttattgt gctgtctcat cattttggca aagaattc 1068
<210> 55
<211> 126
<212> DNA
<213> 智人
<400> 55
agtctgcggt gggcagcgga ggagtcgtgt cgtgcctgag agcgcagctg tgctcctggg 60
caccgcgcag tccgcccccg cggctcctgg ccagaccacc cctaggaccc cctgccccaa 120
gtcgca 126
<210> 56
<211> 121
<212> DNA
<213> 人β疱疹病毒5
<400> 56
tcagatcgcc tggagaggcc atccacgctg ttttgacctc catagtggac accgggaccg 60
atccagcctc cgcggccggg aacggtgcat tggaacgcgg attccccgtg ccaagagtga 120
c 121
<210> 57
<211> 512
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 腺病毒衍生的增强子元件
<400> 57
ctcactctct tccgcatcgc tgtctgcgag ggccagctgt tgggctcgcg gttgaggaca 60
aactcttcgc ggtctttcca gtactcttgg atcggaaacc cgtcggcctc cgaacggtac 120
tccgccaccg agggacctga gcgagtccgc atcgaccgga tcggaaaacc tctcgagaaa 180
ggcgtctaac cagtcacagt cgcaaggtag gctgagcacc gtggcgggcg gcagcgggtg 240
gcggtcgggg ttgtttctgg cggaggtgct gctgatgatg taattaaagt aggcggtctt 300
gagacggcgg atggtcgagg tgaggtgtgg caggcttgag atccagctgt tggggtgagt 360
actccctctc aaaagcgggc attacttctg cgctaagatt gtcagtttcc aaaaacgagg 420
aggatttgat attcacctgg cccgatctgg ccatacactt gagtgacaat gacatccact 480
ttgcctttct ctccacaggt gtccactccc ag 512
<210> 58
<211> 956
<212> DNA
<213> 智人
<400> 58
ctttttcgca acgggtttgc cgccagaaca caggtaagtg ccgtgtgtgg ttcccgcggg 60
cctggcctct ttacgggtta tggcccttgc gtgccttgaa ttacttccac ctggctccag 120
tacgtgattc ttgatcccga gctggagcca ggggcgggcc ttgcgcttta ggagcccctt 180
cgcctcgtgc ttgagttgag gcctggcctg ggcgctgggg ccgccgcgtg cgaatctggt 240
ggcaccttcg cgcctgtctc gctgctttcg ataagtctct agccatttaa aatttttgat 300
gacgtgctgc gacgcttttt ttctggcaag atagtcttgt aaatgcgggc caggatctgc 360
acactggtat ttcggttttt gggcccgcgg ccggcgacgg ggcccgtgcg tcccagcgca 420
catgttcggc gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg gggtagtctc 480
aagctggccg gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc ccgccctggg 540
cggcaaggct ggcccggtcg gcaccagttg cgtgagcgga aagatggccg cttcccggcc 600
ctgctccagg gggctcaaaa tggaggacgc ggcgctcggg agagcgggcg ggtgagtcac 660
ccacacaaag gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac tccacggagt 720
accgggcgcc gtccaggcac ctcgattagt tctggagctt ttggagtacg tcgtctttag 780
gttgggggga ggggttttat gcgatggagt ttccccacac tgagtgggtg gagactgaag 840
ttaggccagc ttggcacttg atgtaattct ccttggaatt tggccttttt gagtttggat 900
cttggttcat tctcaagcct cagacagtgg ttcaaagttt ttttcttcca tttcag 956
<210> 59
<211> 939
<212> DNA
<213> 智人
<400> 59
gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta cgggttatgg cccttgcgtg 60
ccttgaatta cttccacctg gctgcagtac gtgattcttg atcccgagct tcgggttgga 120
agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg tgcttgagtt 180
gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct tcgcgcctgt 240
ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc tgcgacgctt 300
tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg tatttcggtt 360
tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc ggcgaggcgg 420
ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg ccggcctgct 480
ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag gctggcccgg 540
tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc agggagctca 600
aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca aaggaaaagg 660
gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc gccgtccagg 720
cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg ggaggggttt 780
tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc agcttggcac 840
ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt cattctcaag 900
cctcagacag tggttcaaag tttttttctt ccatttcag 939
<210> 60
<211> 83
<212> DNA
<213> 智人
<400> 60
tcagaagccc cgggctcgtc agtcaaaccg gttctctgtt tgcactcggc agcacgggca 60
ggcaagtggt ccctaggttc ggg 83
<210> 61
<211> 476
<212> DNA
<213> 智人
<400> 61
gtgagtctat gggacccttg atgttttctt tccccttctt ttctatggtt aagttcatgt 60
cataggaagg ggagaagtaa cagggtacac atattgacca aatcagggta attttgcatt 120
tgtaatttta aaaaatgctt tcttctttta atatactttt ttgtttatct tatttctaat 180
actttcccta atctctttct ttcagggcaa taatgataca atgtatcatg cctctttgca 240
ccattctaaa gaataacagt gataatttct gggttaaggc aatagcaata tttctgcata 300
taaatatttc tgcatataaa ttgtaactga tgtaagaggt ttcatattgc taatagcagc 360
tacaatccag ctaccattct gcttttattt tatggttggg ataaggctgg attattctga 420
gtccaagcta ggcccttttg ctaatcatgt tcatacctct tatcttcctc ccacag 476
<210> 62
<211> 589
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 突变的土拨鼠肝炎调控元件
<400> 62
aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 60
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 120
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 180
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 240
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 300
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 360
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 420
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 480
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 540
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgc 589
<210> 63
<211> 588
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 突变的土拨鼠肝炎调控元件
<400> 63
tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc 60
ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat 120
ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg 180
gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg 240
ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat 300
tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt 360
gggcactgac aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc 420
ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa 480
tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg 540
ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgca 588
<210> 64
<211> 755
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 突变的土拨鼠肝炎调控元件
<400> 64
ttcctgttaa tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact 60
atgttgctcc ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg 120
cttcccgtat ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg 180
aggagttgtg gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa 240
cccccactgg ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc 300
ccctccctat tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg 360
ctcggctgtt gggcactgac aattccgtgg tgttgtcggg gaagctgacg tcctttccgc 420
ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt 480
cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc 540
cgcctcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgccca 600
tgtatctttt tcacctgtgc cttgtttttg cctgtgttcc gcgtcctact tttcaagcct 660
ccaagctgtg ccttgggcgg ctttggggca tggacataga tccctataaa gaatttggtt 720
catcttatca gttgttgaat tttcttcctt tggac 755
<210> 65
<211> 12
<212> DNA
<213> 人工序列
<220>
<223> CAAX基序
<400> 65
tgtgtgataa tg 12
<210> 66
<211> 810
<212> DNA
<213> 智人
<400> 66
ctgttctcat cacatcatat caaggttata taccatcaat attgccacag atgttactta 60
gccttttaat atttctctaa tttagtgtat atgcaatgat agttctctga tttctgagat 120
tgagtttctc atgtgtaatg attatttaga gtttctcttt catctgttca aatttttgtc 180
tagttttatt ttttactgat ttgtaagact tctttttata atctgcatat tacaattctc 240
tttactgggg tgttgcaaat attttctgtc attctatggc ctgacttttc ttaatggttt 300
tttaatttta aaaataagtc ttaatattca tgcaatctaa ttaacaatct tttctttgtg 360
gttaggactt tgagtcataa gaaatttttc tctacactga agtcatgatg gcatgcttct 420
atattatttt ctaaaagatt taaagttttg ccttctccat ttagacttat aattcactgg 480
aatttttttg tgtgtatggt atgacatatg ggttcccttt tattttttac atataaatat 540
atttccctgt ttttctaaaa aagaaaaaga tcatcatttt cccattgtaa aatgccatat 600
ttttttcata ggtcacttac atatatcaat gggtctgttt ctgagctcta ctctatttta 660
tcagcctcac tgtctatccc cacacatctc atgctttgct ctaaatcttg atatttagtg 720
gaacattctt tcccattttg ttctacaaga atatttttgt tattgtcttt gggctttcta 780
tatacatttt gaaatgaggt tgacaagtta 810
<210> 67
<211> 726
<212> DNA
<213> 乙型肝炎病毒
<400> 67
ataacaggcc tattgattgg aaagtttgtc aacgaattgt gggtcttttg gggtttgctg 60
ccccttttac gcaatgtgga tatcctgctt taatgccttt atatgcatgt atacaagcaa 120
aacaggcttt tactttctcg ccaacttaca aggcctttct cagtaaacag tatatgaccc 180
tttaccccgt tgctcggcaa cggcctggtc tgtgccaagt gtttgctgac gcaaccccca 240
ctggttgggg cttggccata ggccatcagc gcatgcgtgg aacctttgtg tctcctctgc 300
cgatccatac tgcggaactc ctagccgctt gttttgctcg cagcaggtct ggagcaaacc 360
tcatcgggac cgacaattct gtcgtactct cccgcaagta tacatcgttt ccatggctgc 420
taggctgtgc tgccaactgg atcctgcgcg ggacgtcctt tgtttacgtc ccgtcggcgc 480
tgaatcccgc ggacgacccc tcccggggcc gcttggggct ctaccgcccg cttctccgtc 540
tgccgtaccg tccgaccacg gggcgcacct ctctttacgc ggactccccg tctgtgcctt 600
ctcatctgcc ggaccgtgtg cacttcgctt cacctctgca cgtcgcatgg aggccaccgt 660
gaacgcccac cggaacctgc ccaaggtctt gcataagagg actcttggac tttcagcaat 720
gtcatc 726
<210> 68
<211> 755
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - HepB衍生的增强子元件
<400> 68
ttcctgtaaa caggcctatt gattggaaag tttgtcaacg aattgtgggt cttttggggt 60
ttgctgcccc ttttacgcaa tgtggatatc ctgctttaat gcctttatat gcatgtatac 120
aagcaaaaca ggcttttact ttctcgccaa cttacaaggc ctttctcagt aaacagtata 180
tgacccttta ccccgttgct cggcaacggc ctggtctgtg ccaagtgttt gctgacgcaa 240
cccccactgg ttggggcttg gccataggcc atcagcgcat gcgtggaacc tttgtgtctc 300
ctctgccgat ccatactgcg gaactcctag ccgcttgttt tgctcgcagc tggactggag 360
caaacctcat cgggaccgac aattctgtcg tactctcccg caagcactca ccgtttccgc 420
ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt 480
cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc 540
cgcctcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgccca 600
tgtatctttt tcacctgtgc cttgtttttg cctgtgttcc gcgtcctact tttcaagcct 660
ccaagctgtg ccttgggcgg ctttggggca tggacataga tccctataaa gaatttggtt 720
catcttatca gttgttgaat tttcttcctt tggac 755
<210> 69
<211> 94
<212> DNA
<213> 智人
<400> 69
gctggagcct cggtagccgt tcctcctgcc cgctgggcct cccaacgggc cctcctcccc 60
tccttgcacc ggcccttcct ggtctttgaa taaa 94
<210> 70
<211> 596
<212> DNA
<213> 土拨鼠肝炎病毒
<400> 70
attcgagcat cttaccgcca tttattccca tatttgttct gtttttcttg atttgggtat 60
acatttaaat gttaataaaa caaaatggtg gggcaatcat ttacattttt agggatatgt 120
aattactagt tcaggtgtat tgccacaaga caaacatgtt aagaaacttt cccgttattt 180
acgctctgtt cctgttaatc aacctctgga ttacaaaatt tgtgaaagat tgactgatat 240
tcttaactat gttgctcctt ttacgctgtg tggatatgct gctttaatgc ctctgtatca 300
tgctattgct tcccgtacgg ctttcgtttt ctcctccttg tataaatcct ggttgctgtc 360
tctttatgag gagttgtggc ccgttgtccg tcaacgtggc gtggtgtgct ctgtgtttgc 420
tgacgcaacc cccactggct ggggcattgc caccacctgt caactccttt ctgggacttt 480
cgctttcccc ctcccgatcg ccacggcaga actcatcgcc gcctgccttg cccgctgctg 540
gacaggggct aggttgctgg gcactgataa ttccgtggtg ttgtcgggga agggcc 596
<210> 71
<211> 387
<212> DNA
<213> 穴兔
<400> 71
tggctaataa aggaaattta ttttcattgc aatagtgtgt tggaattttt tgtgtctctc 60
actcggaaga acatatggga gggcaaatca tttaaaacat cagaatgagt atttggttta 120
gagtttggca acatatgccc atatgctggc tgccatgaac aaaggttggc tataaagagg 180
tcatcagtat atgaaacagc cccctgctgt ccattcctta ttccatagaa aagccttgac 240
ttgaggttag atttttttta tattttgttt tgtgttattt ttttctttaa catccctaaa 300
attttcctta catgttttac tagccagatt tttcctcctc tcctgactac tcccagtcat 360
agctgtccct cttctcttat ggagatc 387
<210> 72
<211> 251
<212> DNA
<213> 牛
<400> 72
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 60
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 120
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aatacaatag 180
caggcatgct ggggatgcgg tgggctctat gggtacccag gtgctgaaga attgacccgg 240
ttcctcctgg g 251
<210> 73
<211> 251
<212> DNA
<213> 牛
<400> 73
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 60
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 120
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag 180
caggcatgct ggggatgcgg tgggctctat gggtacccag gtgctgaaga attgacccgg 240
ttcctcctgg g 251
<210> 74
<211> 225
<212> DNA
<213> 牛
<400> 74
ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 60
tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 120
tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 180
gggaagacaa tagcaggcat gctggggatg cggtgggctc tatgg 225
<210> 75
<211> 202
<212> DNA
<213> 智人
<400> 75
ctgcccgggt ggcatccctg tgacccctcc ccagtgcctc tcctggccct ggaagttgcc 60
actccagtgc ccaccagcct tgtcctaata aaattaagtt gcatcatttt gtctgactag 120
gtgtccttct ataatattat ggggtggagg ggggtggtat ggagcaaggg gcccaagttg 180
ggaagaaacc tgtagggcct gc 202
<210> 76
<211> 735
<212> PRT
<213> 腺相关病毒2
<400> 76
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> 77
<211> 736
<212> PRT
<213> 腺相关病毒9
<400> 77
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 78
<211> 736
<212> PRT
<213> 腺相关病毒6
<400> 78
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
Phe Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr 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 Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe 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 Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln 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 Asn 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 Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Asp 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 Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Lys Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Leu Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 79
<211> 738
<212> PRT
<213> 非人灵长类动物腺相关病毒
<400> 79
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 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 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 Asn 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
Gln 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
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 Lys 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 Gln Asn Ala 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 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 Asp
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> 80
<211> 738
<212> PRT
<213> 腺相关病毒8
<400> 80
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> 81
<211> 738
<212> PRT
<213> 非人灵长类动物腺相关病毒
<400> 81
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 Asn 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 Ser Pro Val 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 Asn 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
Asn 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
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 Lys 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 Gln Asn Ala 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 Thr Phe Asn 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> 82
<211> 743
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体 - AAV9变体
<400> 82
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Arg Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Thr Leu Ala Val
580 585 590
Pro Phe Lys Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile
595 600 605
Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro
610 615 620
Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro
625 630 635 640
Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile
645 650 655
Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp
660 665 670
Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val
675 680 685
Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro
690 695 700
Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe
705 710 715 720
Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr
725 730 735
Arg Tyr Leu Thr Arg Asn Leu
740
<210> 83
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽插入片段
<400> 83
Thr Leu Ala Val Pro Phe Lys
1 5
<210> 84
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽插入片段
<400> 84
Lys Phe Pro Val Ala Leu Thr
1 5
<210> 85
<211> 940
<212> DNA
<213> 智人
<400> 85
tggagccgcc aaatattttg ggaaatagcg ggaatgttgg cgaactgggc aagtgcgttt 60
tctgattaag agcaaccaga ttcagctttt taaactacaa ttatactggc caaacaaaat 120
acccttatac aaaaaccaaa actactggca ggagtcgctg ccagcttgcg acccggcata 180
cttggctgag tatccgcttc tcccttgtgg ctccaaactg ctgcagattc tcggccactt 240
cagacgcgcg cgatggcgaa gagggtcctg cactttgacg cgcctggtga gggagcgctg 300
ctcttcgcag cgctcctggt gatgctcccc aaatttcggg gaccggcaag cgattaaatc 360
ttggagttgc tcagcgcccg ttaccgagta ctttttattt acaccagaaa caaagttgtt 420
gctctgggat gttctctcct gggcgacttg gggcccagcg cagtccagtt gtgtggggaa 480
atggggagat gtaaatgggc ttggggagct ggagatcgcc gccgggtacc cgggtgaggg 540
gcggggctgg ccgcacggga gagcccctcc tccgctccgg ccccgccccg catggccccg 600
cctccgcgct ctagagtttc ggcaccagct cccaccctgc actgagtccc gggaccccgg 660
gagagcggtc aatgtgtggt cgctgcgttt cctctgcctg cgccgggcat cacttgcgcg 720
ccgcagaaag tccgtctggc agcctggata tcctctccta ccggcacccg cagacgcccc 780
tgcagccgcg gtcggcgccc gggctcccta gccctgtgcg ctcaactgtc ctgcgctgcg 840
gggtgccgcg agttccacct ccgcgcctcc ttctctagac aggcgctggg agaaagaacc 900
ggctcccgag ttctgggcat ttcgcccggc tcgaggtgca 940
<210> 86
<211> 1142
<212> DNA
<213> 小家鼠
<400> 86
aagcttccga ccgttagtca gagaactgta agtgctcaga gcctggctga caatgatctg 60
gaatgaacca gataacaaca taataaaatc tcagtaaaat aatttaacag ttagcttgga 120
agctggtcag ctctggggaa atcagggtaa attgtgctgt catgaactgt cccacactga 180
catcggccaa agtgaatatg aactttggta gatccaatgc ctgttctatt tatttttcca 240
gtgaaaagta ttttgataga gcttttcatt ttgtaaatac actgagttaa ccaaaatatc 300
atggatttcc gtttgttctt aagacatgca actcgtctac ggctatacca ctctgaacgc 360
gcccgatctc ggaagacatg caactcaaat gtaaatacag tagaatatta cttaggtaga 420
aactcctggt gattttaaaa gattggaaaa gaatatgagg aagagttgaa taatgcaaat 480
tctagtgtgt gtgctaccga agtgaacact taatgcacag tctacagact aggacatttt 540
atcgtgtgtt gtaaaattgg gtagaaactt gtgtttgtga aaactgagca ttaaaacctt 600
acagagaccg tttcttgttt acttttgaaa aaaaaaagag tcacgtgagc ctcattttgt 660
atttgtgtgt gtgtgtgtgt gtgtgtctcc cctcctccca gcgtgtgtgt gctgggagga 720
ggggagaccc cagaacaatg tcctgcctcc aaaccttctc aataggcgga agccactggc 780
ttcctccctt tcctgtctcc cgtgctccag caatgcagat ggaagggacc gaagggatgg 840
gagagagagc ccaaccatcc ccagatctgt ccttgtcaca acctgcctcc cacctctaat 900
gccccccctt ccagagactt ccaggccaca cccatcccgg gcttgtgggg gctggacacg 960
ggaggactac aggcgacaac tcttcccacc ctctctccct gccacccctc ctaccctaac 1020
catcatttcc tcttcctccc cagcaccgag gtgcactgag ctggacaggc tgaacactca 1080
gacccacagc aactgacccc gggcccagct ggccttggct ggcccagggc agcttccaga 1140
gt 1142
<210> 87
<211> 2079
<212> DNA
<213> 智人
<400> 87
gctggagtgc agtggcacga tctcggctca ctgcaacctc tgcctcccag gttcaaacaa 60
ttctcctgcc tcagcctcca gagtagctgg ggttacaggt gcacgccagc aagcacagct 120
aaattttgta tttttagtag agatggggtt ttgccatgtt ggccaggctg gtctcaaact 180
cctgacctca ggtgatccac tcccaaagtg ctgggattat aggcgtgagc cactgtgcca 240
ggcccactgt ttttgttttt ttttttcgtg atgacaaatt taaagtcatc tcataggaat 300
agaaaatagc tttttagtag aagctcttgg aatttaaatt gagactgaat ggaaagatga 360
aagaaaataa acttattaac atttaatgag aaccttcaaa gaactaggca tagtaccaaa 420
tggttttata tttttaaacc tcatttattc ctctcaaaac acctgggaag gagatatttt 480
tgccatttca cagctgttga aactgaggct caaaaagact aagtaacttt tctcagctac 540
acatgtggct gagccagtat ttgaacccag ttctgtttgc agacagaacc tgggcttttt 600
cacacctgca aactggaaac attaattggt tcttaagatc atcatcgatg tgataaaacc 660
tgggacagaa attagtcaag actagctgca tctgcctttt cctctggtgg gtaggaaaag 720
gaggagtata atgatttcct caggcatgaa ggtcgatgat gagcaaagtg tatactctct 780
aatctaatgt cataattcat attgtggagt aattatctgg ataagtgtag ggtctctgac 840
ctcattctag atattgtaca ttccatggct attttcattt tggtccatga actctctttg 900
ctctcatgag caccattttt atcccaatct aatcctgtat gtttgtgttt ttacacagat 960
tagtttttaa atgttatata taatttgctt ctgaaacacc attgctcaat gactaccaaa 1020
tctttctcat taccaaaatc cttctatgcc aacttcttca agaaatttga tcacctttag 1080
atgaattgtt aatgaaaatt aaagctatag ccggcaacat gggtatcttt gggctaatgg 1140
ccaaccaaca ggccatctgt gtgaaagaaa acaggctaac aattttggac tctggtctct 1200
tggggctaca ttgagcattg acctcaccgg tgctcactga aattaattgc ttttcaggtt 1260
gtattttctc atcacggaaa ccttcttctc ccaattcaaa ccatgtgggt taaaatgaga 1320
aaacaaaagc caaaacggct tcccacaccc aaaagctcct tctgtcagag atcccagtag 1380
ccccgggaga gctgttagaa gtctgagaag gattggtcat catcgcatac catacatagg 1440
tggagggctt gttattctca gtttcccgcc tatgagagga tacccctatt gtttctgaaa 1500
atgctgaccg ggacccacac ttccaacaaa aattcctctg cccctacagc agcagcaaaa 1560
gcagcagcag aagcaacagc aacagataag tgttttgatg aattgcgaga tggatagggc 1620
ttgagtgccc ccagccctgc tgataccaaa tgcctttaag atacagcctt tcccatccta 1680
atctacaaag gaaacaggaa aaaggaactt aaaactccct gtgctcagac agaaatgaga 1740
ctgttacagc ctgcttctgt gctgttcctt cttgcctcta acttgtaaac aagacgtagt 1800
aggacgatgc taatggaaag tcacaaaccg ctgggttttt gaaaggatcc ttgggacctc 1860
atgcacattt gtggaaactg gatggagaga tttggggaag catggactct ttagccagct 1920
tagttctctg tggagtcagc ttgctccttt ctggtaaggt ttggctttat tttttttaat 1980
ttagtatttt aaaaaacaga gttagtgatt tctgggtgct ctccccaaat ctcatcagtg 2040
ctgatgaaca aggggtggct gtagcaaagg caccatttc 2079
<210> 88
<211> 1559
<212> DNA
<213> 智人
<400> 88
catccatgcc catggcctca gatgccagcc ataagctgtt gggttccaaa cctcgactcc 60
aggctggact cacccctgtc tcccccacca gcctgacacc tccacctggg tatctaacga 120
gcatctcaaa ctcaacctgc ctgagacaga ggaatcacta tcccctcctc ctccaaaaat 180
atccttccat cacactcccc atcttgtgct ctgatttact aaacggccct gggccctctc 240
tttctcaggg tctctgcttg cccagctata taataaaaca agtttgggac ttcccaacca 300
ttcacccatg gaaaaacaga agcaactctt caaaggacag attcccagga tctgccctgg 360
gagattccaa atcagttgat ctggggtgag cccagtcctc tgtagttttt agaagctcct 420
cctatgtctc tcctggtcag cagaatcttg gcccctccct tccccccagc ctcttggttc 480
ttctgggctc tgatccagcc tcagcgtcac tgtcttccac gcccctcttt gattctcgtt 540
tatgtcaaaa gccttgtgag gatgaggctg tgattatccc cattttacag atgaggaaac 600
tgtggctcca ggatgacaca actggccaga ggtcacatca gaagcagagc tgggtcactt 660
gactccaccc aatatcccta aatgcaaaca tcccctacag accgaggctg gcaccttaga 720
gctggagtcc atgcccgctc tgaccaggag aagccaacct ggtcctccag agccaagagc 780
ttctgtccct ttcccatctc ctgaagcctc cctgtcacct ttaaagtcca ttcccacaaa 840
gacatcatgg gatcaccaca gaaaatcaag ctctggggct aggctgaccc cagctagatt 900
tttggctctt ttatacccca gctgggtgga caagcacctt aaacccgctg agcctcagct 960
tcccgggcta taaaatgggg gtgatgacac ctgcctgtag cattccaagg agggttaaat 1020
gtgatgctgc agccaagggt ccccacagcc aggctctttg caggtgctgg gttcagagtc 1080
ccagagctga ggccgggagt aggggttcaa gtggggtgcc ccaggcaggg tccagtgcca 1140
gccctctgtg gagacagcca tccggggccg aggcagccgc ccaccgcagg gcctgcctat 1200
ctgcagccag cccagccctc acaaaggaac aataacagga aaccatccca gggggaagtg 1260
ggccagggcc agctggaaaa cctgaagggg aggcagccag gcctccctcg ccagcggggt 1320
gtggctcccc tccaaagacg gtcggctgac aggctccaca gagctccact cacgctcagc 1380
cctggacgga caggcagtcc aacggaacag aaacatccct cagcccacag gcacggtgag 1440
tgggggctcc cacactcccc tccaccccaa acccgccacc ctgcgcccaa gatgggaggg 1500
tcctcagctt ccccatctgt agaatgggca tcgtcccact cccatgacag agaggctcc 1559
<210> 89
<211> 399
<212> DNA
<213> 智人
<400> 89
gtctcccagg catgactcca acaatgcatc ccatgggatt tggggttccc cagatctggg 60
gcttgtaggc ctgactctcc cctgtgcaca cgtctcatac acgcatgcgt gcacccattg 120
cctgccccgc cccttgcaca gggagtcagc agggaggact gggttatgcc ctgcttatca 180
gcagcttccc agcttcctct gcctggattc ttagaggcct ggggtcctag aacgagctgg 240
tgcacgtggc ttcccaaaga tctctcagat aatgagagga aatgcagtca tcagtttgca 300
gaaggctagg gattctgggc catagctcag acctgcgccc accatctccc tccaggcagc 360
ccttggctgg tccctgcgag cccgtggaga ctgccagtc 399
<210> 90
<211> 735
<212> DNA
<213> 智人
<400> 90
atctttagcc gatccattca accctggcca ggatccaaat ggactgtttt tgtcagggcc 60
aggaccggat ccttcatacc tggggtgcat aggaagtgtt agtactcccc ttcctccaaa 120
cacagcagca aaattggctc aggttgaggt gtttttctca acttccctgg agtccagccc 180
tggaagctgg atcaggaagc tgtgttgttc tactgtgatt ccccctggcc tgtatcagct 240
tgccctgaaa caaccagcat tcctggttat cccacacagg tggggcactc taggaagacc 300
agggatcaag tgtgggggtg tagggatagg gggtgtttgg ggagggcaag gcagttaatt 360
aaggcagctg ccaggaggtc tccctccaaa ctctacaaag ctttatcagc ttggaggtac 420
ttctaatacc atttcctttc attgtttcct tttggtaatt aaaaggaggc caatcccctg 480
ttgtggcagc tcacagctat tgtggtggga aagggagggt ggttggtgga tgtcacagct 540
tgggctttat ctcccccagc agtggggact ccacagcccc tgggctacat aacagcaaga 600
cagtccggag ctgtagcaga cctgattgag cctttgcagc agctgagagc atggcctagg 660
gtgggcggca ccattgtcca gcagctgagt ttcccaggga ccttggagat agccgcagcc 720
ctcatttgca gggga 735
<210> 91
<211> 1132
<212> DNA
<213> 智人
<400> 91
tggcttccgg agggtggcct gggggctggg gtgccaggga caccatcgcc actggtggga 60
gggcagggca cagcccctcc gtgtcccttt gtctctcctg tctgaaggcc agagcaggct 120
gctaggcctg gggccaccac tgcccctggg tgctacaccc agtgtgctgg gtcactggga 180
acttcctgaa gtggtgtcac ctgaactggg cccccaagga tggggtgcgg gcagtaccgc 240
aggaagagga gcagcccctg tgaagattga gaggtctggg aagcccctgc ggcttgggag 300
agtgggggtc gccaggcagg gggaaagccc ctgtgccacc gctttttgcc agagactcag 360
gctccagaga ggcagtgagt ggcatggggg gtgaggctgg ggccctgggc ctgacctcca 420
cacgcctgcc tggcctctct gtttgccatg ggatgagaga gacagtgctg ggactcagag 480
cggggctgga gagtgagagt gcgagaaagg gcctgggtgg ggcttggacc ccggggcggg 540
ctttctggag agccccccta cgagggcctc tacggcggtg acggggtggg gggcttctgc 600
aaaccttggt cagggaagtg gagctggctc gagtggaaga gaccacccgg ctcagtcggg 660
gatgtgggag tggactgggt ggtgcagact gggggtcgag cgccttctga agtgacgggg 720
ccgggacgcg cagggaggcg gcccaagaag cgcgccctag gccagcccag aatgcgctcg 780
gccgcgacta ggacaacggc gggtggggct gggggcggct gccgggcggg gagcggtccc 840
gcgccctcag ctacccctca agagccgttg tttccctaac ttcagctgcc agaggctctg 900
tgattggctg cggcacgatg acccgcgcac ggattggctg cttcgggccg gggggccggg 960
cccgggggac agaatccgcc cccgaacctt caaagagggt accccccggc aggagctggc 1020
agacccagga ggtgcgacag acccgcgggg caaacggact ggggccaaga gccgggagcg 1080
cgggcgcaaa ggcaccaggg cccgcccagg gcgccgcgca gcacggcctt gg 1132
<210> 92
<211> 888
<212> DNA
<213> 智人
<400> 92
cgccttgctg tgccactttg ggacttccct ccctagcctg agcttcagtt ttcctgcctg 60
ttaggcagcc ccatgtcaac tgcacttagt aggccgggtt tgatgcccga caagacgtga 120
agtggtggag gtgggcagga tcccagcgct accatcttct tgaaccagtg atctcaacac 180
atcggatttc tgtttcctca tctgcaaaat gggatcagtg agctcaggtg ggtcacaaat 240
tctacaggaa ctactttagc caagcccggc cccctgaaag ttcccctcgg tgggctgtta 300
gggtgattgt tttcatctgt ggggctccct gatgcgtccc acccaccagc cttggagagg 360
gtgggatggg agggtggggt gcttggggag acaagcctag agcctgggcc ctcccacccc 420
actgcctccc cccatcccag ggccccccac ccagtgacaa agcccgtggc acttcctcta 480
cccggttggc aggcggcctg gcccagcccc ttctctaagg aagcgcattt cctgcctccc 540
tgggccggcc gggctggatg agccgggagc tccctgctgc cggtcatacc acagccttca 600
tctgcgccct ggggccagga ctgctgctgt cactgccatc cattggagcc cagcaccccc 660
tccccgccca tccttcggac agcaactcca gcccagcccc gcgtccctgt gtccacttct 720
cctgacccct cggccgccac cccagaaggc tggagcaggg acgccgtcgc tccggccgcc 780
tgctcccctc gggtccccgt gcgagcccac gccggccccg gtgcccgccc gcagccctgc 840
cactggacac aggataaggc ccagcgcaca ggcccccacg tggacacc 888
<210> 93
<211> 1658
<212> DNA
<213> 智人
<400> 93
gcccaggctg gagtgcagtg gcacagtcac aactcactgc agcctcaaac tcctgggctc 60
aaaacgatcc acagtctcct gagtagctgg gactacagga gcttgttacc acacccagct 120
ccagtttata aattcatctc cagtttataa aggaggaaac cgaggtactg agaggttaaa 180
aaaccttcct gcagacactt gtccagcaag tggccactcc aggatttgga ccaaggtgat 240
gtgtcttcag gctgtgtctc tgccactgtg ccacgctgct gggtggtagg cagcagtggg 300
tgggtgcctg cagtggtctg taaagaccac ctgagatgtc cttcctcctc tgttccaccc 360
tgtccaggtc caagaagaca gtctatgaag agagagcagg tgtgactctc tcagtgtgct 420
cctctgtgag aagcaggctg acatcccaaa gggaagggcg gataacagag acagtgcaag 480
cggaggagat gagggtgcct caaagccggg aggctgggtg atgcaggagc ctgcgtgtcc 540
cgaggggggt gctgggccca gtgtgagtac gtgtgactgt gactgagaca gtgtgactgc 600
tgaaggcagg gacacagcag ctccctgact gggggcagaa ggcgttaact gtgtgaaggc 660
tggttgtggg tgggtgggct ctgggcctcg aacccggggg ctgagggaga tagtaaacag 720
cagggtgact gacgggaaga tcatgttggt agccctgcga agatgctgca gggctgtggg 780
ggtttgtgtg actttgcagt tcaacaaatt caaattcagc caacgctggc agggcctgtt 840
gtgccaggca accagctagg aggaggagac tcggacccag cttgcagctg aagggcgctg 900
gctgccgggt tctgtgggtt caccttgcgg tgtcttccct tgctaacact gagtccttac 960
aatagcccca tctccaggtt gaggctagat ggaggggaca gagggaagtg acttgcccaa 1020
ggtgacccaa gctcccgagt gccagggcag gatctgaatt caggctctca gactgcagag 1080
cctgagtccc tccctgccat gcctgtgcca gggtggaaat gtctggtcct ggaggggagc 1140
gtggactcct ggccttggct ctggagacat ccccctagac cacgtgggct cctaacctgt 1200
ccatggtcac tgtgctgagg ggcgggacgg tgggtcaccc ctagttcttt tttccccagg 1260
gccagattca tggactgaag ggttgctcgg ctctcagaga ccccctaagc gccccgccct 1320
ggccccaagc cctcccccag ctcccgcgtc ccccccctcc tggcgctgac tccgggccag 1380
aagaggaaag gctgtctcca cccacctctc gcactctccc ttctccttta taaaggccgg 1440
aacagctgaa agggtggcaa cttctcctcc tgcagccggg agcggcctgc ctgcctccct 1500
gcgcacccgc agcctccccc gctgcctccc tagggctccc ctccggccgc cagcgcccat 1560
ttttcattcc ctagatagag atactttgcg cgcacacaca tacatacgcg cgcaaaaagg 1620
aaaaaaaaaa aaaaaagccc accctccagc ctcgctgc 1658
<210> 94
<211> 1455
<212> DNA
<213> 智人
<400> 94
acatccaatg cccgctctgc ctcatcttct atgggaaaca agaattttag aggtcaggta 60
gcctaacacc atcaattctc aaaagaggaa gctgaggcca agagaagtcc tgtgaatttc 120
ttacagctca tttgtgacag accaagaatt acccacttta ctgggttgtt atttactaag 180
tgacagtgag tctatatctc ttttgacaag tgaggtgggg gcatggaatt cggcatgtgg 240
ttggtgtaag aactcccctc tctcctcttt aaccttactt aataagaccc tggcacagtt 300
gatattttaa gagggctact ctgttttccc agagggacct aggcacggta accctcttag 360
catgcagacc ttgtttcctg aggggtaatg tttcccttcc ctgtgacttg tttcttgggg 420
gctgtgttct gattttcctg ctgagccact tgttgccttg ggctggctgc cgcgcttggc 480
agtttttagt gagggctctg atagatgcca ggaggtgagg ggaagggctc tgggtggact 540
ccgtcattgg acaagcagac ttagtgatgg atgagccttc ccctgaggaa gttttggatc 600
agaagtccaa ctgataagtt tttccagaat tgagtaaccc agaagcagtg ccgaaaggat 660
cttacctctc ttgtggcttt ttgtattgat tttaaaagaa attctcagag gcagttccac 720
attgtactgg aagcacagct atatccacaa taggcttaga tatatgtaac atgaattgct 780
ttagaaataa catttgagga gaggggtgag aggaaggaag agagggtctt aaaaaatagc 840
cctatcaaaa tattttcttt cttctaagta ttgaaaagac acaatataac cctttcttct 900
ttcaaatgat ctcatagcta tttgttgagg ggaaatacca aatgtttatt attttttttg 960
aagaagcttc ttcggtcctg atgattcatg ttgatatcat tttcctcctg actacagagg 1020
ctctgagaca aagctacacc tcaagtgata tgccagggtc agaacaattc ccgtcctgaa 1080
ggagggtgtg caaccttctt tatccctcct tcacagacgt ccttgagccc ttgagacgga 1140
tgtgagtgag tttttcagtc ctcatgcaaa acaaccatct aaacataaca gatgacatca 1200
gcttgggctt ttcaattcct ggatggcagc agcgtgttaa tccagccttc atcctggatt 1260
tcataaacca aaacaagaga gcctggcagg aggacagcgc tgctgctggg ttgaggaaat 1320
tgatgacggg aaagcatgcg ggcaacccag tgtataaaac tcataaacgt gtaggcagag 1380
gctcagctac cagtttggac ggctgcttcc caccagcaaa gaccacgact ggagagccga 1440
gccggaggca gctgg 1455
<210> 95
<211> 1389
<212> DNA
<213> 智人
<400> 95
tggcacacac gcaccctgtc caatgtatct tttgtgtaaa tctggactta acacttcaag 60
caaactgcct ggcttgctga aaggtggaga cacctttcga ttcagtcttt taatatgtgt 120
tgagtgccac ctatgtgcag agcaagatat tggggacttt ggagagatcc agaagagtga 180
gaagacagta tcctacctta gggggttccc agtccaatga gggaagcagc cccatgcctt 240
gggagctccc aagctataga agcagctaac aatcgagtct ggaaaggcaa acaacttcag 300
gacccgcttc taaagcggaa tcgcaagtac acgcaaaatg aatccagcct tgactgtgtg 360
gagttgggta aaccacctgc ctcttacgtt gatggggaac tagaatgagg acagctccag 420
ggaacaagaa agggtagacc ataggagctg tcccatgtcc caacagtggg gaggagctga 480
tgggcggccc ctgctggatt agtgttatcc tgagaaggct tctggatgcg atgggatttg 540
aggtgctgct gcaaagaatg aattgctcac ggaagggtgg ggtgggggca ttccaggtag 600
agggtgcctc ctgggggatg cagggaacat gaggggcctg ggcaattaat caagccttgg 660
gcacaagcct aggcagtcac ccccaattca aagccagttg aaaatgcaga ggagagagga 720
gggccagtgt ttggttgtct tgaccaaacc cttgaagctg gccagcggca agggcaagga 780
ccagggtcag aggtagaggg cgtgagtgaa ggcaacccag actgagtcct tccctaagcg 840
cccaggtttc ctgacagctg ttaaggaagc aaggtgagaa agggttaagt gtgcccctcc 900
accgccccaa atgcttcctg tgtttgaaat ccttcaggtc tctgcaaacc ctctggcccc 960
cggccaggcg ggcattgtcc ggggagcggt tgtaggttgt cagagaggcc gcgcagcctt 1020
tgttgtgggg ccacctcggg gttccctctc gcgctcacgc tcgggctggg gctgcagagt 1080
gcgtgcctgg aggggggcgg tgcgggaggc tcgctccctc tccctcttcc tgccccccct 1140
ctagccctcc cgatgaccac atgaccaagt gggctcgcgg ccaagccaca agctacaaaa 1200
tgcagcccct ggagtgagcg gggagcattc tctctggcag ccggggtcac gggcagttgc 1260
agccgcggcc gagcagccag ccgctaagaa agagctcgcc gctgccgctc ccggagccgc 1320
cgaggccagc ttcgcggcgc tgccccgcgg cgggagagga ggctgcagaa gagcggaggc 1380
ggccagcgg 1389
<210> 96
<211> 4258
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 96
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataag ctcctcccag cctcaggccc aggaatggga atctctgtgg gtcacacatc 240
agtagggagg tctttcccga tccttttcta tgctactcca ggagtcaaag cgtctcctgg 300
gacttttcag ggcgcttcag aagagccctg ggcctaaacc agctcaacca agctgcaggg 360
acccagcctc ctgagaaaag tgaatgtgag cccggtgcat tcagaggaga atgaagcctt 420
cacccagaac acactctggg aagatgtccc aggcccaggg ggagggtttg tactaccaga 480
cctaagtcac ctaaactgac accaagtctc atccatccca accattccat tccgggtcag 540
aggggtcatc gatttaacca gcaaggctgc ccatccaacg gttgctccct ctgctccctg 600
gaagggcctc ctcgtgggcg ttctgtacct acaggtcttg ttccgttctg ggaactgcca 660
gtggtggcaa gaggtggagc aacgggtgcc agggcaggga gaggtgagtc tgggagggaa 720
gcagaggcaa gatccatggg gctttagaga ctttgccaaa gcagtgcgac tgctcccagg 780
ttgttgtcag ccgtcaagag tgagtgcacc tccctgggca gacttctgct gccccagtgc 840
ccaggaatag gcaggggttt gccgcaaaat gaatgacacc tggcagacaa taagctgaag 900
ctttcattag cagcttaagc tgaggactat ctatgcaacc gatactccct gtgtgctccc 960
cgggactgct taatgtgagc ccttgtggag cgattggcac caagaaagca aggactaagt 1020
cagaagttca agtcccagcc ttgccacagc ctcagggtgc cctcgagcac agcaagcctc 1080
agttttccca tctgtacaat gagagaggta cacaaggtag actcgaaggc tctttgttgc 1140
cagggccctg tgttcctttg agtgtatgtg cttctcaggc ccacagaggt cctttgtgtt 1200
tcgtatgtga actgctctct aggaaaccca tgtaactgtc tgtgtcctgg ggcacataca 1260
tgaggactca tgtgggccgt attgtgtgtt tgtgccgggg ggaggggaga ccccagaaca 1320
atgtccccca ccccaccccc ctcctcaata ggcggaagcc actggcttcc tccctttcct 1380
gcctcctgcc tcctttgtgc cagcaagact gagtactgga gagagacagg ggatgggaaa 1440
aatcagtcca gctgtcccca ggtctgccct taccataacc ttccccccac ctcaagtgac 1500
tcctcccagg ccacacccat ccccagcctt gtgggggcca gattgggggg cctagaggct 1560
caaaggcaga atgagtcctc ccacccccta ccctgccacc cctcccaccc aagccacctc 1620
atttcctctt cctccccagc accgacccac actgaccaac acaggctgag cagtcaggcc 1680
cacagcatct gaccccaggc ccagctcgtc ctggctggcc tgggtcggcc tctggagtgc 1740
caccatggag cccagcagca agaagctgac gggtcgcctc atgctggccg tgggaggagc 1800
agtgcttggc tccctgcagt ttggctacaa cactggagtc atcaatgccc cccagaaggt 1860
gatcgaggag ttctacaacc agacatgggt ccaccgctat ggggagagca tcctgcccac 1920
cacgctcacc acgctctggt ccctctcagt ggccatcttt tctgttgggg gcatgattgg 1980
ctccttctct gtgggccttt tcgttaaccg ctttggccgg cggaattcaa tgctgatgat 2040
gaacctgctg gccttcgtgt ccgccgtgct catgggcttc tcgaaactgg gcaagtcctt 2100
tgagatgctg atcctgggcc gcttcatcat cggtgtgtac tgcggcctga ccacaggctt 2160
cgtgcccatg tatgtgggtg aagtgtcacc cacagccctt cgtggggccc tgggcaccct 2220
gcaccagctg ggcatcgtcg tcggcatcct catcgcccag gtgttcggcc tggactccat 2280
catgggcaac aaggacctgt ggcccctgct gctgagcatc atcttcatcc cggccctgct 2340
gcagtgcatc gtgctgccct tctgccccga gagtccccgc ttcctgctca tcaaccgcaa 2400
cgaggagaac cgggccaaga gtgtgctaaa gaagctgcgc gggacagctg acgtgaccca 2460
tgacctgcag gagatgaagg aagagagtcg gcagatgatg cgggagaaga aggtcaccat 2520
cctggagctg ttccgctccc ccgcctaccg ccagcccatc ctcatcgctg tggtgctgca 2580
gctgtcccag cagctgtctg gcatcaacgc tgtcttctat tactccacga gcatcttcga 2640
gaaggcgggg gtgcagcagc ctgtgtatgc caccattggc tccggtatcg tcaacacggc 2700
cttcactgtc gtgtcgctgt ttgtggtgga gcgagcaggc cggcggaccc tgcacctcat 2760
aggcctcgct ggcatggcgg gttgtgccat actcatgacc atcgcgctag cactgctgga 2820
gcagctaccc tggatgtcct atctgagcat cgtggccatc tttggctttg tggccttctt 2880
tgaagtgggt cctggcccca tcccatggtt catcgtggct gaactcttca gccagggtcc 2940
acgtccagct gccattgccg ttgcaggctt ctccaactgg acctcaaatt tcattgtggg 3000
catgtgcttc cagtatgtgg agcaactgtg tggtccctac gtcttcatca tcttcactgt 3060
gctcctggtt ctgttcttca tcttcaccta cttcaaagtt cctgagacta aaggccggac 3120
cttcgatgag atcgcttccg gcttccggca ggggggagcc agccaaagtg acaagacacc 3180
cgaggagctg ttccatcccc tgggggctga ttcccaagtg tgataatgga tcaacctctg 3240
gattacaaaa tttgtgaaag attgactggt attcttaact atgttgctcc ttttacgcta 3300
tgtggatacg ctgctttaat gcctttgtat catgctattg cttcccgtat ggctttcatt 3360
ttctcctcct tgtataaatc ctggttgctg tctctttatg aggagttgtg gcccgttgtc 3420
aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa cccccactgg ttggggcatt 3480
gccaccacct gtcagctcct ttccgggact ttcgctttcc ccctccctat tgccacggcg 3540
gaactcatcg ccgcctgcct tgcccgctgc tggacagggg ctcggctgtt gggcactgac 3600
aattccgtgg tgttgtcggg gaaatcatcg tcctttcctt ggctgctcgc ctgtgttgcc 3660
acctggattc tgcgcgggac gtccttctgc tacgtccctt cggccctcaa tccagcggac 3720
cttccttccc gcggcctgct gccggctctg cggcctcttc cgcgtcttcg ccttcgccct 3780
cagacgagtc ggatctccct ttgggccgcc tccccgcatc attgcctgcc cgggtggcat 3840
ccctgtgacc cctccccagt gcctctcctg gccctggaag ttgccactcc agtgcccacc 3900
agccttgtcc taataaaatt aagttgcatc attttgtctg actaggtgtc cttctataat 3960
attatggggt ggaggggggt ggtatggagc aaggggccca agttgggaag aaacctgtag 4020
ggcctgcgtt acccaggctg gagtgcagtg gcacatttct gctcactgca acctcctcct 4080
ccctgggttc tacgtagata agtagcatgg cgggttaatc attaactaca aggaacccct 4140
agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc 4200
aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgc 4258
<210> 97
<211> 3922
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 97
ctctggagac gcgttacata agctcctccc agcctcaggc ccaggaatgg gaatctctgt 60
gggtcacaca tcagtaggga ggtctttccc gatccttttc tatgctactc caggagtcaa 120
agcgtctcct gggacttttc agggcgcttc agaagagccc tgggcctaaa ccagctcaac 180
caagctgcag ggacccagcc tcctgagaaa agtgaatgtg agcccggtgc attcagagga 240
gaatgaagcc ttcacccaga acacactctg ggaagatgtc ccaggcccag ggggagggtt 300
tgtactacca gacctaagtc acctaaactg acaccaagtc tcatccatcc caaccattcc 360
attccgggtc agaggggtca tcgatttaac cagcaaggct gcccatccaa cggttgctcc 420
ctctgctccc tggaagggcc tcctcgtggg cgttctgtac ctacaggtct tgttccgttc 480
tgggaactgc cagtggtggc aagaggtgga gcaacgggtg ccagggcagg gagaggtgag 540
tctgggaggg aagcagaggc aagatccatg gggctttaga gactttgcca aagcagtgcg 600
actgctccca ggttgttgtc agccgtcaag agtgagtgca cctccctggg cagacttctg 660
ctgccccagt gcccaggaat aggcaggggt ttgccgcaaa atgaatgaca cctggcagac 720
aataagctga agctttcatt agcagcttaa gctgaggact atctatgcaa ccgatactcc 780
ctgtgtgctc cccgggactg cttaatgtga gcccttgtgg agcgattggc accaagaaag 840
caaggactaa gtcagaagtt caagtcccag ccttgccaca gcctcagggt gccctcgagc 900
acagcaagcc tcagttttcc catctgtaca atgagagagg tacacaaggt agactcgaag 960
gctctttgtt gccagggccc tgtgttcctt tgagtgtatg tgcttctcag gcccacagag 1020
gtcctttgtg tttcgtatgt gaactgctct ctaggaaacc catgtaactg tctgtgtcct 1080
ggggcacata catgaggact catgtgggcc gtattgtgtg tttgtgccgg ggggagggga 1140
gaccccagaa caatgtcccc caccccaccc ccctcctcaa taggcggaag ccactggctt 1200
cctccctttc ctgcctcctg cctcctttgt gccagcaaga ctgagtactg gagagagaca 1260
ggggatggga aaaatcagtc cagctgtccc caggtctgcc cttaccataa ccttcccccc 1320
acctcaagtg actcctccca ggccacaccc atccccagcc ttgtgggggc cagattgggg 1380
ggcctagagg ctcaaaggca gaatgagtcc tcccaccccc taccctgcca cccctcccac 1440
ccaagccacc tcatttcctc ttcctcccca gcaccgaccc acactgacca acacaggctg 1500
agcagtcagg cccacagcat ctgaccccag gcccagctcg tcctggctgg cctgggtcgg 1560
cctctggagt gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 1620
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 1680
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 1740
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 1800
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 1860
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 1920
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 1980
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 2040
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 2100
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 2160
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 2220
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 2280
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 2340
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 2400
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 2460
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 2520
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 2580
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 2640
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 2700
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 2760
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 2820
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 2880
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 2940
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 3000
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 3060
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 3120
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 3180
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 3240
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 3300
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 3360
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 3420
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 3480
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 3540
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 3600
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 3660
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 3720
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 3780
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 3840
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 3900
caacctcctc ctccctgggt tc 3922
<210> 98
<211> 3850
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 98
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataaa gcttccgacc gttagtcaga gaactgtaag tgctcagagc ctggctgaca 240
atgatctgga atgaaccaga taacaacata ataaaatctc agtaaaataa tttaacagtt 300
agcttggaag ctggtcagct ctggggaaat cagggtaaat tgtgctgtca tgaactgtcc 360
cacactgaca tcggccaaag tgaatatgaa ctttggtaga tccaatgcct gttctattta 420
tttttccagt gaaaagtatt ttgatagagc ttttcatttt gtaaatacac tgagttaacc 480
aaaatatcat ggatttccgt ttgttcttaa gacatgcaac tcgtctacgg ctataccact 540
ctgaacgcgc ccgatctcgg aagacatgca actcaaatgt aaatacagta gaatattact 600
taggtagaaa ctcctggtga ttttaaaaga ttggaaaaga atatgaggaa gagttgaata 660
atgcaaattc tagtgtgtgt gctaccgaag tgaacactta atgcacagtc tacagactag 720
gacattttat cgtgtgttgt aaaattgggt agaaacttgt gtttgtgaaa actgagcatt 780
aaaaccttac agagaccgtt tcttgtttac ttttgaaaaa aaaaagagtc acgtgagcct 840
cattttgtat ttgtgtgtgt gtgtgtgtgt gtgtctcccc tcctcccagc gtgtgtgtgc 900
tgggaggagg ggagacccca gaacaatgtc ctgcctccaa accttctcaa taggcggaag 960
ccactggctt cctccctttc ctgtctcccg tgctccagca atgcagatgg aagggaccga 1020
agggatggga gagagagccc aaccatcccc agatctgtcc ttgtcacaac ctgcctccca 1080
cctctaatgc ccccccttcc agagacttcc aggccacacc catcccgggc ttgtgggggc 1140
tggacacggg aggactacag gcgacaactc ttcccaccct ctctccctgc cacccctcct 1200
accctaacca tcatttcctc ttcctcccca gcaccgaggt gcactgagct ggacaggctg 1260
aacactcaga cccacagcaa ctgaccccgg gcccagctgg ccttggctgg cccagggcag 1320
cttccagagt gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 1380
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 1440
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 1500
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 1560
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 1620
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 1680
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 1740
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 1800
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 1860
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 1920
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 1980
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 2040
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 2100
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 2160
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 2220
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 2280
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 2340
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 2400
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 2460
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 2520
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 2580
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 2640
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 2700
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 2760
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 2820
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 2880
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 2940
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 3000
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 3060
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 3120
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 3180
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 3240
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 3300
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 3360
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 3420
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 3480
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 3540
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 3600
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 3660
caacctcctc ctccctgggt tctacgtaga taagtagcat ggcgggttaa tcattaacta 3720
caaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga 3780
ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct cagtgagcga 3840
gcgagcgcgc 3850
<210> 99
<211> 3514
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 99
ctctggagac gcgttacata aagcttccga ccgttagtca gagaactgta agtgctcaga 60
gcctggctga caatgatctg gaatgaacca gataacaaca taataaaatc tcagtaaaat 120
aatttaacag ttagcttgga agctggtcag ctctggggaa atcagggtaa attgtgctgt 180
catgaactgt cccacactga catcggccaa agtgaatatg aactttggta gatccaatgc 240
ctgttctatt tatttttcca gtgaaaagta ttttgataga gcttttcatt ttgtaaatac 300
actgagttaa ccaaaatatc atggatttcc gtttgttctt aagacatgca actcgtctac 360
ggctatacca ctctgaacgc gcccgatctc ggaagacatg caactcaaat gtaaatacag 420
tagaatatta cttaggtaga aactcctggt gattttaaaa gattggaaaa gaatatgagg 480
aagagttgaa taatgcaaat tctagtgtgt gtgctaccga agtgaacact taatgcacag 540
tctacagact aggacatttt atcgtgtgtt gtaaaattgg gtagaaactt gtgtttgtga 600
aaactgagca ttaaaacctt acagagaccg tttcttgttt acttttgaaa aaaaaaagag 660
tcacgtgagc ctcattttgt atttgtgtgt gtgtgtgtgt gtgtgtctcc cctcctccca 720
gcgtgtgtgt gctgggagga ggggagaccc cagaacaatg tcctgcctcc aaaccttctc 780
aataggcgga agccactggc ttcctccctt tcctgtctcc cgtgctccag caatgcagat 840
ggaagggacc gaagggatgg gagagagagc ccaaccatcc ccagatctgt ccttgtcaca 900
acctgcctcc cacctctaat gccccccctt ccagagactt ccaggccaca cccatcccgg 960
gcttgtgggg gctggacacg ggaggactac aggcgacaac tcttcccacc ctctctccct 1020
gccacccctc ctaccctaac catcatttcc tcttcctccc cagcaccgag gtgcactgag 1080
ctggacaggc tgaacactca gacccacagc aactgacccc gggcccagct ggccttggct 1140
ggcccagggc agcttccaga gtgccaccat ggagcccagc agcaagaagc tgacgggtcg 1200
cctcatgctg gccgtgggag gagcagtgct tggctccctg cagtttggct acaacactgg 1260
agtcatcaat gccccccaga aggtgatcga ggagttctac aaccagacat gggtccaccg 1320
ctatggggag agcatcctgc ccaccacgct caccacgctc tggtccctct cagtggccat 1380
cttttctgtt gggggcatga ttggctcctt ctctgtgggc cttttcgtta accgctttgg 1440
ccggcggaat tcaatgctga tgatgaacct gctggccttc gtgtccgccg tgctcatggg 1500
cttctcgaaa ctgggcaagt cctttgagat gctgatcctg ggccgcttca tcatcggtgt 1560
gtactgcggc ctgaccacag gcttcgtgcc catgtatgtg ggtgaagtgt cacccacagc 1620
ccttcgtggg gccctgggca ccctgcacca gctgggcatc gtcgtcggca tcctcatcgc 1680
ccaggtgttc ggcctggact ccatcatggg caacaaggac ctgtggcccc tgctgctgag 1740
catcatcttc atcccggccc tgctgcagtg catcgtgctg cccttctgcc ccgagagtcc 1800
ccgcttcctg ctcatcaacc gcaacgagga gaaccgggcc aagagtgtgc taaagaagct 1860
gcgcgggaca gctgacgtga cccatgacct gcaggagatg aaggaagaga gtcggcagat 1920
gatgcgggag aagaaggtca ccatcctgga gctgttccgc tcccccgcct accgccagcc 1980
catcctcatc gctgtggtgc tgcagctgtc ccagcagctg tctggcatca acgctgtctt 2040
ctattactcc acgagcatct tcgagaaggc gggggtgcag cagcctgtgt atgccaccat 2100
tggctccggt atcgtcaaca cggccttcac tgtcgtgtcg ctgtttgtgg tggagcgagc 2160
aggccggcgg accctgcacc tcataggcct cgctggcatg gcgggttgtg ccatactcat 2220
gaccatcgcg ctagcactgc tggagcagct accctggatg tcctatctga gcatcgtggc 2280
catctttggc tttgtggcct tctttgaagt gggtcctggc cccatcccat ggttcatcgt 2340
ggctgaactc ttcagccagg gtccacgtcc agctgccatt gccgttgcag gcttctccaa 2400
ctggacctca aatttcattg tgggcatgtg cttccagtat gtggagcaac tgtgtggtcc 2460
ctacgtcttc atcatcttca ctgtgctcct ggttctgttc ttcatcttca cctacttcaa 2520
agttcctgag actaaaggcc ggaccttcga tgagatcgct tccggcttcc ggcagggggg 2580
agccagccaa agtgacaaga cacccgagga gctgttccat cccctggggg ctgattccca 2640
agtgtgataa tggatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 2700
aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 2760
attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 2820
tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 2880
gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 2940
ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 3000
ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 3060
ccttggctgc tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 3120
ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 3180
cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 3240
catcattgcc tgcccgggtg gcatccctgt gacccctccc cagtgcctct cctggccctg 3300
gaagttgcca ctccagtgcc caccagcctt gtcctaataa aattaagttg catcattttg 3360
tctgactagg tgtccttcta taatattatg gggtggaggg gggtggtatg gagcaagggg 3420
cccaagttgg gaagaaacct gtagggcctg cgttacccag gctggagtgc agtggcacat 3480
ttctgctcac tgcaacctcc tcctccctgg gttc 3514
<210> 100
<211> 3010
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 载体基因组的完整多核苷酸序列
<400> 100
gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg 60
tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaact ccatcactag 120
gggttccttg tagttaatga ttaacccgcc atgctactta tctacgtact ctggagacgc 180
gttacataac cattttgcta gagaaggccg cggaggctca gagaggtgcg cacacttgcc 240
ctgagtcaca cagcgaatgc cctccgcggt cccaacgcag agagaacgag ccgatcggca 300
gcctgagcga ggcagtggtt agggggggcc ccggccccgg ccactcccct caccccctcc 360
ccgcagagcg ccgcccagga caggctgggc cccaggcccc gccccgaggt cctgcccaca 420
cacccctgac acaccggcgt cgccagccaa tggccggggt cctataaacg ctacggtccg 480
cgcgctctct gccaccatgg agcccagcag caagaagctg acgggtcgcc tcatgctggc 540
cgtgggagga gcagtgcttg gctccctgca gtttggctac aacactggag tcatcaatgc 600
cccccagaag gtgatcgagg agttctacaa ccagacatgg gtccaccgct atggggagag 660
catcctgccc accacgctca ccacgctctg gtccctctca gtggccatct tttctgttgg 720
gggcatgatt ggctccttct ctgtgggcct tttcgttaac cgctttggcc ggcggaattc 780
aatgctgatg atgaacctgc tggccttcgt gtccgccgtg ctcatgggct tctcgaaact 840
gggcaagtcc tttgagatgc tgatcctggg ccgcttcatc atcggtgtgt actgcggcct 900
gaccacaggc ttcgtgccca tgtatgtggg tgaagtgtca cccacagccc ttcgtggggc 960
cctgggcacc ctgcaccagc tgggcatcgt cgtcggcatc ctcatcgccc aggtgttcgg 1020
cctggactcc atcatgggca acaaggacct gtggcccctg ctgctgagca tcatcttcat 1080
cccggccctg ctgcagtgca tcgtgctgcc cttctgcccc gagagtcccc gcttcctgct 1140
catcaaccgc aacgaggaga accgggccaa gagtgtgcta aagaagctgc gcgggacagc 1200
tgacgtgacc catgacctgc aggagatgaa ggaagagagt cggcagatga tgcgggagaa 1260
gaaggtcacc atcctggagc tgttccgctc ccccgcctac cgccagccca tcctcatcgc 1320
tgtggtgctg cagctgtccc agcagctgtc tggcatcaac gctgtcttct attactccac 1380
gagcatcttc gagaaggcgg gggtgcagca gcctgtgtat gccaccattg gctccggtat 1440
cgtcaacacg gccttcactg tcgtgtcgct gtttgtggtg gagcgagcag gccggcggac 1500
cctgcacctc ataggcctcg ctggcatggc gggttgtgcc atactcatga ccatcgcgct 1560
agcactgctg gagcagctac cctggatgtc ctatctgagc atcgtggcca tctttggctt 1620
tgtggccttc tttgaagtgg gtcctggccc catcccatgg ttcatcgtgg ctgaactctt 1680
cagccagggt ccacgtccag ctgccattgc cgttgcaggc ttctccaact ggacctcaaa 1740
tttcattgtg ggcatgtgct tccagtatgt ggagcaactg tgtggtccct acgtcttcat 1800
catcttcact gtgctcctgg ttctgttctt catcttcacc tacttcaaag ttcctgagac 1860
taaaggccgg accttcgatg agatcgcttc cggcttccgg caggggggag ccagccaaag 1920
tgacaagaca cccgaggagc tgttccatcc cctgggggct gattcccaag tgtgataatg 1980
gatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 2040
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 2100
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 2160
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 2220
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 2280
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 2340
ttgggcactg acaattccgt ggtgttgtcg gggaaatcat cgtcctttcc ttggctgctc 2400
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 2460
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 2520
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgca tcattgcctg 2580
cccgggtggc atccctgtga cccctcccca gtgcctctcc tggccctgga agttgccact 2640
ccagtgccca ccagccttgt cctaataaaa ttaagttgca tcattttgtc tgactaggtg 2700
tccttctata atattatggg gtggaggggg gtggtatgga gcaaggggcc caagttggga 2760
agaaacctgt agggcctgcg ttacccaggc tggagtgcag tggcacattt ctgctcactg 2820
caacctcctc ctccctgggt tctacgtaga taagtagcat ggcgggttaa tcattaacta 2880
caaggaaccc ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga 2940
ggccgggcga ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct cagtgagcga 3000
gcgagcgcgc 3010
<210> 101
<211> 2611
<212> DNA
<213> 人工序列
<220>
<223> 实验室制造 - 表达盒的部分
<400> 101
ctctggagac gcgttacata accattttgc tagagaaggc cgcggaggct cagagaggtg 60
cgcacacttg ccctgagtca cacagcgaat gccctccgcg gtcccaacgc agagagaacg 120
agccgatcgg cagcctgagc gaggcagtgg ttaggggggg ccccggcccc ggccactccc 180
ctcaccccct ccccgcagag cgccgcccag gacaggctgg gccccaggcc ccgccccgag 240
gtcctgccca cacacccctg acacaccggc gtcgccagcc aatggccggg gtcctataaa 300
cgctacggtc cgcgcgctct ctgccaccat ggagcccagc agcaagaagc tgacgggtcg 360
cctcatgctg gccgtgggag gagcagtgct tggctccctg cagtttggct acaacactgg 420
agtcatcaat gccccccaga aggtgatcga ggagttctac aaccagacat gggtccaccg 480
ctatggggag agcatcctgc ccaccacgct caccacgctc tggtccctct cagtggccat 540
cttttctgtt gggggcatga ttggctcctt ctctgtgggc cttttcgtta accgctttgg 600
ccggcggaat tcaatgctga tgatgaacct gctggccttc gtgtccgccg tgctcatggg 660
cttctcgaaa ctgggcaagt cctttgagat gctgatcctg ggccgcttca tcatcggtgt 720
gtactgcggc ctgaccacag gcttcgtgcc catgtatgtg ggtgaagtgt cacccacagc 780
ccttcgtggg gccctgggca ccctgcacca gctgggcatc gtcgtcggca tcctcatcgc 840
ccaggtgttc ggcctggact ccatcatggg caacaaggac ctgtggcccc tgctgctgag 900
catcatcttc atcccggccc tgctgcagtg catcgtgctg cccttctgcc ccgagagtcc 960
ccgcttcctg ctcatcaacc gcaacgagga gaaccgggcc aagagtgtgc taaagaagct 1020
gcgcgggaca gctgacgtga cccatgacct gcaggagatg aaggaagaga gtcggcagat 1080
gatgcgggag aagaaggtca ccatcctgga gctgttccgc tcccccgcct accgccagcc 1140
catcctcatc gctgtggtgc tgcagctgtc ccagcagctg tctggcatca acgctgtctt 1200
ctattactcc acgagcatct tcgagaaggc gggggtgcag cagcctgtgt atgccaccat 1260
tggctccggt atcgtcaaca cggccttcac tgtcgtgtcg ctgtttgtgg tggagcgagc 1320
aggccggcgg accctgcacc tcataggcct cgctggcatg gcgggttgtg ccatactcat 1380
gaccatcgcg ctagcactgc tggagcagct accctggatg tcctatctga gcatcgtggc 1440
catctttggc tttgtggcct tctttgaagt gggtcctggc cccatcccat ggttcatcgt 1500
ggctgaactc ttcagccagg gtccacgtcc agctgccatt gccgttgcag gcttctccaa 1560
ctggacctca aatttcattg tgggcatgtg cttccagtat gtggagcaac tgtgtggtcc 1620
ctacgtcttc atcatcttca ctgtgctcct ggttctgttc ttcatcttca cctacttcaa 1680
agttcctgag actaaaggcc ggaccttcga tgagatcgct tccggcttcc ggcagggggg 1740
agccagccaa agtgacaaga cacccgagga gctgttccat cccctggggg ctgattccca 1800
agtgtgataa tggatcaacc tctggattac aaaatttgtg aaagattgac tggtattctt 1860
aactatgttg ctccttttac gctatgtgga tacgctgctt taatgccttt gtatcatgct 1920
attgcttccc gtatggcttt cattttctcc tccttgtata aatcctggtt gctgtctctt 1980
tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg tgtgcactgt gtttgctgac 2040
gcaaccccca ctggttgggg cattgccacc acctgtcagc tcctttccgg gactttcgct 2100
ttccccctcc ctattgccac ggcggaactc atcgccgcct gccttgcccg ctgctggaca 2160
ggggctcggc tgttgggcac tgacaattcc gtggtgttgt cggggaaatc atcgtccttt 2220
ccttggctgc tcgcctgtgt tgccacctgg attctgcgcg ggacgtcctt ctgctacgtc 2280
ccttcggccc tcaatccagc ggaccttcct tcccgcggcc tgctgccggc tctgcggcct 2340
cttccgcgtc ttcgccttcg ccctcagacg agtcggatct ccctttgggc cgcctccccg 2400
catcattgcc tgcccgggtg gcatccctgt gacccctccc cagtgcctct cctggccctg 2460
gaagttgcca ctccagtgcc caccagcctt gtcctaataa aattaagttg catcattttg 2520
tctgactagg tgtccttcta taatattatg gggtggaggg gggtggtatg gagcaagggg 2580
cccaagttgg gaagaaacct gtagggcctg c 2611
<210> 102
<211> 302
<212> DNA
<213> 智人
<400> 102
accattttgc tagagaaggc cgcggaggct cagagaggtg cgcacacttg ccctgagtca 60
cacagcgaat gccctccgcg gtcccaacgc agagagaacg agccgatcgg cagcctgagc 120
gaggcagtgg ttaggggggg ccccggcccc ggccactccc ctcaccccct ccccgcagag 180
cgccgcccag gacaggctgg gccccaggcc ccgccccgag gtcctgccca cacacccctg 240
acacaccggc gtcgccagcc aatggccggg gtcctataaa cgctacggtc cgcgcgctct 300
ct 302
Claims (45)
1.一种表达盒,其包含可操作地连接至启动子的编码GLUT1或其功能变体的多核苷酸序列。
2.根据权利要求1所述的表达盒,其中所述启动子是内皮启动子,任选地Tie-1启动子、Tie-2(TEK)启动子、FLT-1启动子、FLK-1(KDR)启动子、ICAM-2启动子、VE-钙粘蛋白(CDH5)启动子、VWF启动子、ENG启动子、PDGFB启动子、ESM1启动子、APLN启动子或封闭蛋白-5(Ple261)启动子,条件是内皮启动子不是Glut1启动子。
3.根据权利要求1或权利要求2所述的表达盒,其中所述启动子是FLT-1启动子。
4.根据权利要求3所述的表达盒,其中所述FLT-1启动子是人FLT-1(hFLT-1)启动子。
5.根据权利要求4所述的表达盒,其中所述hFLT-1启动子与SEQ IDNO:1具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
6.根据权利要求1或权利要求2所述的表达盒,其中所述启动子是Tie-1启动子。
7.根据权利要求6所述的表达盒,其中所述Tie-1启动子是人Tie-1(hTie-1)启动子。
8.根据权利要求7所述的表达盒,其中所述hTie-1启动子与SEQ ID NO:2具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
9.根据权利要求1或权利要求2所述的表达盒,其中所述启动子是血管内皮-钙粘蛋白(VE-钙粘蛋白)启动子。
10.根据权利要求9所述的表达盒,其中所述VE-钙粘蛋白启动子是人VE-钙粘蛋白(hVE-钙粘蛋白)启动子。
11.根据权利要求10所述的表达盒,其中所述hVE-钙粘蛋白启动子与SEQ ID NO:3具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
12.根据权利要求1所述的表达盒,其中所述启动子是泛在启动子。
13.根据权利要求1或权利要求12所述的表达盒,其中所述启动子是CMV启动子。
14.根据权利要求1或权利要求12所述的表达盒,其中所述启动子是CAG启动子。
15.根据权利要求1至14中任一项所述的表达盒,其中所述表达盒包含polyA信号,任选地人生长激素(hGH)polyA。
16.根据权利要求1至15中任一项所述的表达盒,其中所述表达盒包含土拨鼠肝炎病毒转录后调控元件(WPRE),任选地WPRE(x)。
17.根据权利要求1至16中任一项所述的表达盒,其中所述表达盒包含3'非翻译区(3’UTR),其包含与SEQ ID NO:4具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性的序列。
18.根据权利要求1至17中任一项所述的表达盒,其中编码GLUT1的所述多核苷酸序列是SLC2A1多核苷酸。
19.根据权利要求18所述的表达盒,其中所述SLC2A1多核苷酸是人SLC2A1多核苷酸。
20.根据权利要求17至19中任一项所述的表达盒,其中编码GLUT1的所述多核苷酸序列与SEQ ID NO:5具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
21.根据权利要求1至20中任一项所述的表达盒,其中所述表达盒侧接5'和3'反向末端重复序列(ITR),任选地AAV2 ITR,任选地与SEQ ID NO:6或SEQ ID NO:7具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性的ITR。
22.根据权利要求1至21中任一项所述的表达盒,其中所述表达盒与SEQ ID NO:8-16、SEQ ID NO:97、SEQ ID NO:99和SEQ ID NO:101中的任何一个具有至少75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
23.一种基因治疗载体,其包含根据权利要求1至21中任一项所述的表达盒。
24.根据权利要求23所述的载体,其中所述基因治疗载体是重组腺相关病毒(rAAV)载体。
25.根据权利要求24所述的载体,其中所述rAAV载体是AAV6、AAV8、AAV9、AAVrh.74或AAVrh.10载体或其功能变体。
26.根据权利要求24或权利要求25所述的载体,其中所述rAAV载体不是AAV2载体。
27.根据权利要求24至26中任一项所述的载体,其中所述rAAV载体包含衣壳蛋白,其与SEQ ID NO:15-17中的任何一个具有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的同一性。
28.一种治疗和/或预防有此需要的受试者中的疾病或病症的方法,其包括向所述受试者施用根据权利要求23至27中任一项所述的载体。
29.根据权利要求28所述的方法,其中所述疾病或病症是神经系统病症。
30.根据权利要求28或权利要求29所述的方法,其中所述疾病或病症是葡萄糖转运蛋白1缺乏综合征(GLUT1DS)或De Vivo病。
31.根据权利要求28至30中任一项所述的方法,其中所述载体通过脑室内(ICV)注射进行施用。
32.根据权利要求28至31中任一项所述的方法,其中所述施用导致脑中的编码GLUT1的多核苷酸序列表达,任选地处于与参考rAAV载体相比增加的水平。
33.根据权利要求28至32中任一项所述的方法,其中所述施用导致脑中的GLUT1蛋白的表达增加和/或CSF中的葡萄糖水平和/或乳酸盐水平增加,任选地处于与参考rAAV载体相比增加的水平,其中任选地所述增加是至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或更高的增加。
34.根据权利要求28至33中任一项所述的方法,其中所述载体以1E12个载体基因组(vg)、1E13 vg、1E14 vg或3E14 vg的剂量进行施用。
35.根据权利要求28至34中任一项所述的方法,其中与使用内源性Glut1启动子或泛在启动子执行的方法相比,所述方法引起通过脑微血管内皮细胞增加的葡萄糖摄取。
36.一种在细胞中表达GLUT1的方法,其包括使所述细胞与根据权利要求23至27中任一项所述的载体接触。
37.根据权利要求36所述的方法,其中所述细胞是内皮细胞。
38.根据权利要求37所述的方法,其中所述内皮细胞是脑微血管内皮细胞。
39.根据权利要求37或权利要求38所述的方法,其中所述内皮细胞是体内内皮细胞。
40.根据权利要求36所述的方法,其中所述细胞是神经元。
41.根据权利要求40所述的方法,其中所述神经元是体内神经元。
42.根据权利要求36至40中任一项所述的方法,其中所述方法包括将所述载体体内施用于受试者。
43.根据权利要求36至41中任一项所述的方法,其中与接触包含内源性Glut1启动子或泛在启动子的载体的细胞相比,所述载体引起通过细胞增加的葡萄糖摄取。
44.一种药物组合物,其包含根据权利要求23至27中任一项所述的载体。
45.一种试剂盒,其包含根据权利要求23至27中任一项所述的载体或根据权利要求43所述的药物组合物和任选地使用说明书。
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