CN110506119A - Aav衣壳设计 - Google Patents
Aav衣壳设计 Download PDFInfo
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- CN110506119A CN110506119A CN201780076991.3A CN201780076991A CN110506119A CN 110506119 A CN110506119 A CN 110506119A CN 201780076991 A CN201780076991 A CN 201780076991A CN 110506119 A CN110506119 A CN 110506119A
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Abstract
在一些方面,本公开涉及具有不同组织靶向能力的重组腺相关病毒。在一些方面,本公开涉及使用重组腺相关病毒的基因转移方法。在一些方面,本公开涉及分离的AAV衣壳蛋白和编码其的分离的核酸。
Description
相关申请
本申请要求于2017年4月18日提交的题为“AAV CAPSID DESIGNS”的美国临时申请系列号USSN 62/486,642、于2016年11月4日提交,名称为“AAV CAPSID DESIGNS”的美国临时申请系列号62/417,756、于2016年10月13日提交的题为“AAV CAPSID DESIGNS”的美国临时申请系列号62/408,022的申请日的根据35U.S.C第119(e)段的权益,每篇申请的全部内容作为参考引入本文。
发明领域
在一些方面,本公开涉及用于鉴定细胞中腺相关病毒的分离的核酸、组合物和试剂盒。在一些方面,本公开提供了新AAV及其使用方法以及相关试剂盒。
发明背景
重组AAV腺相关病毒(rAAV)能够在靶组织中驱动稳定和持续的转基因表达,而没有显著的毒性和宿主免疫原性。因此,rAAV是用于长期治疗性基因表达的有希望的递送载体。然而,目前可用的rAAV载体的低转导效率和受限的组织嗜性能够限制它们作为可行和有效治疗的应用。另外,来自非人组织的主要治疗性AAV血清型的忠实临床翻译是一个问题。因此,仍然需要用于基因递送的新AAV载体。
发明概述
在一些方面,本公开涉及用于基因治疗应用的新AAV。在一些实施方案中,本文所述的AAV包含一种或多种衣壳蛋白的氨基酸变异,其赋予新的或增强的组织嗜性性质。根据一些实施方案,已经鉴定并且本文公开了AAV2、AAV2/3(例如,AAV2/3杂合体)和AAV8的变体,其具有有用的组织靶向性质。例如,提供了AAV8的变体,其可用于转导细胞,例如人肝细胞(例如,存在于肝组织中)、中枢神经系统细胞(CNS细胞)等。提供了AAV2、AAV2/3(例如,AAV2/3杂合体)和AAV8的变体,在一些实施方案中,其可用于靶向眼组织(例如,眼睛)、胃肠道、呼吸系统、乳房组织、胰腺组织、泌尿道组织、子宫组织、与某些癌症(例如,乳腺癌、前列腺癌等)相关的组织和其他组织的细胞。在一些实施方案中,本文所述的变体AAV靶向除了其相应的野生型AAV靶向的组织以外的组织。
本公开在一些方面提供了分离的核酸,其包含编码选自以下的多肽的序列:SEQID NO:1-409、435-868和1726-1988,其编码AAV衣壳蛋白。在一些实施方案中,提供了分离的核酸的片段。在某些实施方案中,分离的核酸的片段不编码与SEQ ID NO:869、870或871中任一个的序列相同的肽。
在一些方面,本公开提供核酸,其包含选自SEQ ID NO:410-434、876-1718和1989-2251的序列。在一些实施方案中,所述核酸编码表达AAV衣壳蛋白或其变体和/或AAV组装激活蛋白(AAP)或其变体。在一些实施方案中,所述AAP与所述AAV衣壳蛋白位于所述核酸的不同开放阅读框中。在一些实施方案中,所述AAP是AAV2AAP(AAP-2)或其变体。
在一些方面,本公开提供分离的AAV衣壳蛋白,其包含选自SEQ ID NO:1-409、435-868和1726-1988的氨基酸序列。在一些实施方案中,分离的AAV衣壳蛋白包含选自以下的氨基酸序列:SEQ ID NO:1-409、837-852或1726-1814,其中将所述序列中与SEQ ID NO:869所示序列的相应氨基酸不同的氨基酸替换为保守取代。
在一些方面,本公开提供AAV2/3杂合体衣壳蛋白。在一些实施方案中,分离的AAV衣壳蛋白包含选自以下的氨基酸序列:SEQ ID NO:435-628和1815-1988,其中将所述序列中与SEQ ID NO:869或870所示序列的相应氨基酸不同的氨基酸替换为保守取代。
在一些实施方案中,分离的AAV衣壳蛋白包含选自以下的序列:SEQ ID NO:629-836或853-868,其中将所述序列中与SEQ ID NO:871所示序列的相应氨基酸不同的氨基酸替换为保守取代。
在本公开的某些方面,提供了包含任何前述分离的AAV衣壳蛋白的组合物。在一些实施方案中,所述组合物还包含药学上可接受的载体。在一些实施方案中,提供了本公开的一种或多种分离的AAV衣壳蛋白和生理学上相容的载体的组合物。
在本公开的某些方面,提供了包含任何前述分离的AAV衣壳蛋白的重组AAV(rAAV)。在一些实施方案中,提供了包含rAAV的组合物。在某些实施方案中,包含所述人AAV的所述组合物还包含药学上可接受的载体。还提供了重组AAV,其中重组AAV包括一种或多种本公开的分离的AAV衣壳蛋白。
在本公开的一些方面,提供了宿主细胞,其含有包含选自以下的编码序列的核酸:SEQ ID NO:410-434、876-1718和1989-2251,其与启动子可操作地连接。在一些实施方案中,提供了包含宿主细胞和无菌细胞培养基的组合物。在一些实施方案中,提供了包含宿主细胞和冷冻保护剂的组合物。
根据本公开的一些方面,提供了用于将转基因递送至受试者的方法。在一些实施方案中,该方法包括向受试者施用前述任一种rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述受试者的靶组织的细胞。在一些实施方案中,受试者选自小鼠、大鼠、兔子、狗、猫、羊、猪和非人灵长类动物。在一个实施方案中,所述受试者是人。
在一些实施方案中,所述至少一种转基因是蛋白编码基因。在某些实施方案中,所述至少一种转基因编码小干扰核酸。在某些实施方案中,小干扰核酸是miRNA。在某些实施方案中,所述小干扰核酸是miRNA海绵或TuD RNA,其抑制所述受试者中至少一种miRNA的活性。在某些实施方案中,在所述靶组织的细胞中表达所述miRNA。在某些实施方案中,所述靶组织是肝脏、中枢神经系统(CNS)、眼、胃肠、呼吸、乳腺、胰腺、泌尿道或子宫组织。
在一些实施方案中,所述转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与所述结合位点杂交抑制所述转基因在靶组织以外的组织中的活性。
在某些实施方案中,rAAV通过静脉内、透皮、眼内、鞘内、脑内、口服、肌肉内、皮下、鼻内或通过吸入施用于受试者。
根据本公开的一些方面,提供了用于产生体细胞转基因动物模型的方法。在一些实施方案中,该方法包括向非人类动物施用前述任一种rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述非人类动物的靶组织的细胞。
在一些实施方案中,所述转基因是至少一种蛋白编码基因。在某些实施方案中,所述转基因编码至少一种小干扰核酸。在一些实施方案中,所述转基因编码至少一种报告分子。在某些实施方案中,小干扰核酸是miRNA。在某些实施方案中,所述小干扰核酸是miRNA海绵或TuD RNA,其抑制所述动物中至少一种miRNA的活性。在某些实施方案中,在所述靶组织的细胞中表达所述miRNA。在某些实施方案中,所述靶组织是肝脏、中枢神经系统(CNS)、眼、胃肠、呼吸、乳腺、胰腺、泌尿道或子宫组织。
在一些实施方案中,所述转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与所述结合位点杂交抑制所述转基因在靶组织以外的组织中的活性。
根据本公开的一些方面,提供用于产生体细胞动物模型的方法,其包括向非人动物施用前述任一种rAAV,其中所述rAAV包含至少一种转基因,其中所述转基因表达包含miRNA的至少一个结合位点的转录物,其中所述miRNA通过与所述转录物的结合位点杂交抑制所述转基因在靶组织以外的组织中的活性。
在一些实施方案中,所述转基因包含组织特异性启动子或诱导型启动子。在某些实施方案中,所述组织特异性启动子是肝脏特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、粘蛋白-2启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、视网膜劈裂素启动子、K12启动子、CC10启动子、表面活性蛋白C(SP-C)启动子、PRC1启动子、RRM2启动子、uroplakin 2(UPII)启动子或乳铁蛋白启动子。
在某些实施方案中,rAAV通过静脉内、透皮、眼内、鞘内、口服、肌肉内、皮下、鼻内或通过吸入施用于动物。根据本公开的一些方面,提供了通过任何前述方法产生的体细胞转基因动物模型。
在本公开的其他方面,提供了用于产生rAAV的试剂盒。在一些实施方案中,所述试剂盒包含容纳分离的核酸的容器,所述分离的核酸具有SEQ ID NO:410-434、876-1718和1989-2251中任一个的序列。在一些实施方案中,所述试剂盒包含容纳分离的核酸的容器,所述分离的核酸编码具有SEQ ID NO:1-409、435-868或1726-1988中任一个的序列的多肽。在一些实施方案中,所述试剂盒还包含用于生产所述rAAV的说明书。在一些实施方案中,所述试剂盒还包含至少一个容纳重组AAV载体的容器,其中所述重组AAV载体包含转基因。
在本公开的其他方面,提供了试剂盒,其包含容纳重组AAV的容器,所述重组AAV具有任何前述分离的AAV衣壳蛋白。在一些实施方案中,试剂盒的容器是注射器。
在其他方面,本公开涉及基于AAV的载体作为载体、基因递送、治疗、预防和研究目的以及体细胞转基因动物模型的开发的用途。
在一些方面,本公开涉及AAV血清型,其已经证明了不同的组织/细胞类型向性并且在没有载体相关毒理学的情况下能够在动物组织中以与腺病毒载体相似的水平实现稳定的体细胞基因转移(例如,高达100%的体内组织转导,取决于靶组织和载体剂量)。在其他方面,本公开涉及具有肝脏、中枢神经系统(CNS)、眼、胃肠、呼吸、乳腺、胰腺、泌尿道或子宫组织靶向能力的AAV血清型。这些组织与广泛的人类疾病相关,包括神经系统疾病、代谢疾病、糖尿病系统、眼部疾病、呼吸系统疾病、胃肠道疾病、泌尿道疾病和生殖疾病和某些癌症。
在一些实施方案中,所述rAAV包括至少一种转基因。转基因可以是引起病理状态的转基因。在一些实施方案中,转基因编码治疗病理状态的蛋白。
在另一个方面,本公开的新AAV可以用于将转基因递送至受试者的方法中。该方法通过向受试者施用本公开的rAAV来进行,其中rAAV包含至少一种转基因。在一些实施方案中,rAAV靶向受试者的预定组织。
在另一个方面,本公开的AAV可以用于产生体细胞转基因动物模型的方法中。该方法通过向动物施用本公开的rAAV来进行,其中rAAV包含至少一种转基因,其中转基因引起病理状态,并且其中rAAV靶向动物的预定组织。
转基因可以表达许多基因,包括癌症相关基因、促凋亡基因和凋亡相关基因。在一些实施方案中,转基因表达能够抑制癌症相关基因表达的小干扰核酸。在其他实施方案中,转基因表达能够抑制凋亡相关基因表达的小干扰核酸。其他实施方案中的小干扰核酸是miRNA或shRNA。根据其他实施方案,转基因表达毒素,任选其中毒素是DTA。在其他实施方案中,转基因表达报告基因,其任选地是报告酶,例如β-半乳糖苷酶或荧光蛋白,例如GFP或萤光素酶。
转基因可以表达miRNA。在其他实施方案中,转基因表达miRNA海绵,其中miRNA海绵抑制动物中一种或多种miRNA的活性。在一些实施方案中,miRNA可以是内源miRNA或其可以在肝、中枢神经系统(CNS)、眼、胃肠、呼吸、乳腺、胰腺、泌尿道或子宫组织的细胞中表达。
rAAV可以转导许多不同类型的组织,例如神经元、鳞状上皮细胞、肾近端或远端回旋的肾小管细胞、粘膜腺细胞、血管内皮细胞、子宫内膜细胞、视网膜细胞或某些癌细胞(例如,乳腺癌细胞、前列腺癌细胞等)。
在一些实施方案中,以1010、1011、1012、1013、1014或1015个基因组拷贝/受试者的剂量施用rAAV。在一些实施方案中,以1010、1011、1012、1013或1014个基因组拷贝/受试者的剂量施用rAAV。可以通过任何途径施用rAAV。例如,在一些实施方案中,它可以静脉内施用(例如,通过门静脉注射)。
在一些实施方案中,转基因包括组织特异性启动子,例如肝脏特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、粘蛋白-2启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、视网膜劈裂素启动子、K12启动子、CC10启动子、表面活性蛋白C(SP-C)启动子、PRC1启动子、RRM2启动子、uroplakin 2(UPII)启动子或乳铁蛋白启动子。
体细胞转基因动物模型可以是哺乳动物,例如小鼠、大鼠、兔子、狗、猫、羊、猪、非人灵长类动物。
在一些实施方案中,可以将推定的治疗剂施用于体细胞转基因动物模型,以确定推定的治疗剂对动物的病理状态的影响。
另一方面,本公开是通过本文所述方法产生的体细胞转基因动物。
根据本公开的另一方面,提供了用于产生rAAV的试剂盒,其产生在预定组织中具有病理状态的体细胞转基因动物。该试剂盒包括至少一个容纳重组AAV载体的容器,至少一个容纳rAAV包装组分的容器,以及构建和包装重组AAV的说明书。
rAAV包装组分可包括表达至少一个rep基因和/或至少一个cap基因的宿主细胞。在一些实施方案中,宿主细胞是293细胞。在其他实施方案中,宿主细胞表达至少一种辅助病毒基因产物,其影响含有重组AAV载体的rAAV的产生。所述至少一个cap基因可以编码来自靶向预定组织的AAV血清型的衣壳蛋白。
在其他实施方案中,rAAV包装组分包括辅助病毒,任选地其中辅助病毒是腺病毒或疱疹病毒。
rAAV载体和其中的组分可包括本文所述的任何元件。例如,在一些实施方案中,rAAV载体包含转基因,例如本文所述的任何转基因。在一些实施方案中,转基因表达miRNA抑制剂(例如,miRNA海绵或TuD RNA),其中miRNA抑制剂抑制体细胞转基因动物中一种或多种miRNA的活性。
本公开的每个限制均能够包含本公开的各种实施方案。因此,预期涉及任何一个元件或元件组合的本公开的每个限制均能够包括在本公开的每个方面中。本公开不限于其在以下说明书中阐述的或附图中示出的构造细节和部件布置的应用。本公开能够具有其他实施方案并且能够以各种方式实践或执行。
附图简要说明
图1A-1B显示了用于鉴定AAV变体的工作流程示意图。图1A描绘了在所选人组织中新AAV变体的高通量检测。使用高循环PCR扩增前病毒衣壳序列,然后进行低循环PCR以对扩增子文库进行条形码化以进行多重单分子实时(SMRT)测序。图1B显示了用于测序数据的生物信息学分析的管道(pipeline)的概述。
图2A-2D显示了与不同施用的所选AAV8变体体内检测FFLuc转基因活性有关的数据。图2A显示了在IV(静脉内)、IM(肌肉内)或IN(鼻内)注射后第6周评估不同AAV8变体的萤光素酶活性。图2B-2D的数据涉及每种变体B2(图2B)、B3(图2C)和B61(图2D)与AAV8相比的FFLuc活性的评估(平均值±SD,n=3,t检验)。
图3A-3B显示了与新生动物注射后第21天AAV8变体B61与AAV9相比递送的FFLuc转基因活性的评估相关的数据。检测了脑(图3A)和脊髓(图3B)的萤光素酶活性和基因组拷贝(平均值±SD,n=5,t检验)。
图4A-4B显示了AAV8变体B44与AAV8相比的右后肢肌内(IM)注射后体内检测FFLuc转基因活性的数据。图4A显示了在IM注射后第6周评估变体B44的整个动物萤光素酶表达。图4B显示了肌肉(RTA,右胫骨前肌;LTA,左胫骨前肌)、肝脏和心脏的评估。B44与AAV8相比的萤光素酶活性(左侧条形图)和相对比率(右侧条形图)(平均值±SD,n=3)。
图5显示了AAV8变体(B2、B3、B61)与其他AAV血清型的系统发生比较。
图6A显示了通过高通量向性筛选体内表征新AAV变体的工作流程的示意图。
图6B显示了通过高通量向性筛选NHP表征新AAV变体的工作流程的示意图。
图7显示了散点图,其显示具有一个或多个单氨基酸变体的不同AAV2衣壳变体(总共409个)和AAV2/3变体(总共194个)的分布。
图8显示了在发现的衣壳变体的多重筛选中使用的载体构建体的图。将独特的6-bp条形码克隆到转基因中并包装成候选衣壳变体。
图9显示了用于评估衣壳变体向性概况分析的索引转基因和高通量测序文库设计的示意图。能够使用侧翼BsrGI和SacI位点将含有6-bp条形码(第一条形码)和BstEII限制性位点的索引和衔接子盒克隆到载体构建体中。用BstEII酶切割来自含有宿主基因组和载体基因组的rAAV处理组织的全粗DNA。得到的5'-突出端用于特异性连接到含有第二条形码的衔接子,这允许进一步多重测序和流线型化(streamlining);和5'-生物素修饰,其可用于使用磁珠富集选择含有衔接子的片段。然后使用对衔接子和转基因序列特异的引物能够对富集的材料进行PCR扩增,以产生用于高通量测序的文库。从上到下显示SEQ ID NO:1719-1725。
详述
腺相关病毒(AAV)是一种小的(约26nm)复制缺陷型无包膜病毒,通常依赖于第二种病毒如腺病毒或疱疹病毒的存在,它才能在细胞中生长。不知晓AAV会引起疾病并诱导非常轻微的免疫反应。AAV能够感染分裂和非分裂细胞,并且可以将其基因组整合到宿主细胞的基因组中。这些特征使AAV成为创建基因治疗病毒载体的极具吸引力的候选者。基于血清型2的原型AAV载体为鼠和大型动物模型中的无毒和稳定的基因转移提供了概念验证,但在许多主要靶组织中表现出差的基因转移效率。在一些方面,本公开试图通过提供具有用于基因治疗和研究应用的不同组织靶向能力的新AAV来克服该缺点。
在本公开的一些方面,提供了具有不同组织靶向能力的新AAV衣壳蛋白。在一些实施方案中,从包含衣壳蛋白的AAV靶向的组织分离AAV衣壳蛋白。在一些方面,提供了用于将转基因递送至受试者中的靶组织的方法。转基因递送方法可用于基因治疗(例如,治疗疾病)或研究(例如,创建体细胞转基因动物模型)应用。
发现AAV的方法
AAV的大部分生物学都受其衣壳的影响。因此,发现新AAV的方法主要集中在分离AAV衣壳的DNA序列上。腺相关病毒(AAV)潜伏生命周期的中心特征是在宿主细胞中以整合和/或游离基因组的形式持续存在。用于分离新AAV的方法包括基于PCR的潜伏AAV DNA基因组的分子拯救,在腺病毒辅助功能存在下体外组织DNA的潜伏前病毒基因组的感染性病毒拯救,以及由等温噬菌体Phi-29聚合酶介导、通过滚环线性扩增从组织DNA中拯救环状原病毒基因组。所有这些分离方法都利用了AAV原病毒DNA基因组的潜伏期,并专注于拯救持久性病毒基因组DNA。
在一些方面,本公开涉及发现能够从受试者的体内组织鉴定具有期望组织嗜性的新AAV变体。不希望受任何特定理论的束缚,体内组织的使用利用了从受试者的正常组织和肿瘤组织分离的病毒基因组序列中观察到的基因组多样性的天然储库。因此,在一些实施方案中,体内组织通过选择性压力和/或免疫逃避充当病毒(例如,病毒衣壳蛋白)多样性的天然孵化器。
在一些方面,本公开涉及发现由AAV DNA的扩增产生的PCR产物(例如,从宿主细胞或受试者的体内组织中分离或提取的AAV DNA)能够经受高通量单分子、实时(SMRT)测序以鉴定新的衣壳蛋白变体。如本文所用,“单分子、实时(SMRT)测序”是指平行化的单分子测序方法,例如Roberts等人.(2013)Genome Biology 14:405,doi:10.1186/gb-2013-14-7-405所述。不希望受任何特定理论的束缚,SMRT测序的使用消除了对从其他常规高通量基因组测序方法获得的对齐的短读取片段进行病毒基因组重建和嵌合体预测的需要。
内源性潜伏AAV基因组在哺乳动物细胞(例如,非人灵长类动物组织例如肝脏、脾脏和淋巴结的细胞)中具有转录活性。不希望受理论束缚,假设为了维持AAV在宿主中的持久性,可能需要来自AAV基因的低水平转录,并且所得的cap RNA可以作为更合适和丰富的底物来检索用于载体开发的功能性cap序列。通过RNA检测方法(例如,RT-PCR)以可变丰度检测rep和cap基因转录物。cap基因转录物的存在和通过体外逆转录(RT)产生cap RNA的cDNA的能力显著增加了用于从组织中基于PCR的新cap序列的拯救模板的丰度,并增强了新AAV发现的灵敏度。
新cap序列也可以通过从具有极低丰度的原病毒AAV基因组的组织中分离的总细胞DNA转染细胞来鉴定。细胞可以进一步用提供辅助病毒功能(例如,腺病毒)的基因进行转染以在转染的细胞中触发和/或增强AAV基因转录。在一些实施方案中,可以通过从转染的细胞中分离cap mRNA、从mRNA产生cDNA(例如通过RT-PCR)并对cDNA测序来鉴定本公开的新cap序列。
分离的衣壳蛋白和编码其的核酸
从哺乳动物、特别是非人灵长类动物分离的AAV可用于产生用于临床开发和人类基因治疗应用的基因转移载体。在一些方面,本公开提供了使用本文公开的方法在各种体内组织(例如,肝脏、脑、胃、呼吸、乳腺、胰腺、直肠、前列腺、泌尿和宫颈组织)中发现的新AAV。在一些实施方案中,其中发现新AAV变体的组织是癌组织(例如,肿瘤或癌细胞)。在一些实施方案中,已经在从人组织分离的病毒基因组DNA中发现了编码这些新AAV的衣壳蛋白的核酸。表1中描述了已发现新AAV衣壳蛋白的组织的实例。关于AAV的核酸和蛋白序列以及其他信息列于表3-5和8以及序列表中。
编码AAV衣壳蛋白的本公开的分离的核酸包括具有SEQ ID NO:410-435、876-1718或1989-2251中任一个所示序列的任何核酸,以及具有与其基本同源的序列的任何核酸。在一些实施方案中,本公开的分离的核酸包括具有编码多肽的序列的任何核酸,所述多肽具有SEQ ID NO:1-409、435-868或1726-1988中任一个的序列。在一些实施方案中,本公开提供了分离的核酸,其与具有SEQ ID NO:410-435、876-1718和1989-2251中任一个所示序列的核酸具有基本同源性,但是不编码具有SEQ ID NO:869、870或871所示氨基酸序列的蛋白。
在一些实施方案中,本公开的分离的AAV衣壳蛋白包括具有SEQ ID NO:1-409、837-852或1726-1814中任一个所示的氨基酸序列的任何蛋白以及与其具有基本同源性的任何蛋白。在一些实施方案中,本公开提供了分离的衣壳蛋白,其与具有SEQ ID NO:1-409、837-852和1726-1814中任一个所示序列的蛋白具有基本同源性,但是不具有SEQ ID NO:869所示氨基酸序列。
在一些实施方案中,本公开的分离的AAV衣壳蛋白包括具有SEQ ID NO:435-628或1815-1988中任一个所示的氨基酸序列的任何蛋白以及与其具有基本同源性的任何蛋白。在一些实施方案中,本公开提供了分离的衣壳蛋白,其与具有SEQ ID NO:435-628和1815-1988中任一个所示序列的蛋白具有基本同源性,但是不具有SEQ ID NO:869或870所示氨基酸序列。
在一些实施方案中,本公开的分离的AAV衣壳蛋白包括具有SEQ ID NO:629-836或853-868中任一个所示的氨基酸序列的任何蛋白以及与其具有基本同源性的任何蛋白。在一些实施方案中,本公开提供了分离的衣壳蛋白,其与具有SEQ ID NO:629-836或853-868中任一个所示序列的蛋白具有基本同源性,但是不具有SEQ ID NO:871所示氨基酸序列。
“同源性”是指两个多核苷酸或两个多肽部分之间的同一性百分比。当提及核酸或其片段时,术语“基本同源性”表示,当用适当的核苷酸插入或缺失与另一核酸(或其互补链)最佳比对时,存在比对序列的约90至约100%的核苷酸序列同一性。当提及多肽或其片段时,术语“基本同源性”表示当用适当的缺口、插入或缺失与另一多肽最佳比对时,存在比对序列的约90至100%的核苷酸序列同一性。术语“高度保守”是指至少80%同一性,优选至少90%同一性,更优选超过97%同一性。在某些情况下,高度保守可能指的是100%的同一性。本领域技术人员通过例如使用本领域技术人员已知的算法和计算机程序容易地确定同一性。
如本文所述,核酸或多肽序列之间的比对使用多种公开或商业上可获得的多序列比对程序中的任何一种进行,例如“Clustal W”,可通过因特网上的Web服务器访问。或者,也可以使用Vector NTI实用程序。本领域已知的许多算法能够用于测量核苷酸序列同一性,包括上述程序中包含的那些。作为另一实例,使用BLASTN能够比较多核苷酸序列,BLASTN提供查询和搜索序列之间最佳重叠区域的比对和百分比序列同一性。类似的程序可用于比较氨基酸序列,例如“Clustal X”程序、BLASTP。通常,这些程序中的任何程序都在默认设置下使用,但是本领域技术人员可以根据需要改变这些设置。或者,本领域技术人员能够利用另一种算法或计算机程序,该算法或计算机程序至少提供由参考算法和程序提供的同一性或比对水平。比对可用于鉴定两种蛋白或肽之间的相应氨基酸。“相应的氨基酸”是蛋白或肽序列的氨基酸,其已经与另一种蛋白或肽序列的氨基酸比对。相应的氨基酸可以相同或不相同。作为不相同氨基酸的相应氨基酸可称为变体氨基酸。表6提供了变体氨基酸的实例。
或者对于核酸,通过在同源区域之间形成稳定双链体的条件下杂交多核苷酸,然后用单链特异性核酸酶消化,和消化片段的大小测定来确定同源性。基本上同源的DNA序列可以在Southern杂交实验中在例如严格条件下鉴定,如针对该特定系统所定义的。确定合适的杂交条件在本领域的技术范围内。
“核酸”序列是指DNA或RNA序列。在一些实施方案中,术语核酸捕获包括任何已知的DNA和RNA碱基类似物的序列,例如但不限于4-乙酰基胞嘧啶、8-羟基-N6-甲基腺苷、氮丙啶基胞嘧啶、假异胞嘧啶、5-(羧基羟基-甲基)尿嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、5-羧基甲基氨基甲基-2-硫尿嘧啶、5-羧甲基-氨基甲基尿嘧啶、二氢尿嘧啶、肌苷、N6-异戊烯腺嘌呤、1-甲基腺嘌呤、1-甲基假尿嘧啶、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N6-甲基腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基-氨基甲基-2-硫尿嘧啶、β-d-甘露糖辨苷、5'-甲氧基羰基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯腺嘌呤、尿嘧啶-5-氧乙酸甲基酯、尿嘧啶-5-氧乙酸、oxybutoxosine、假尿嘧啶、辨苷、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、-尿嘧啶-5-氧基乙酸甲酯、尿嘧啶-5-氧基乙酸、假尿嘧啶、辨苷、2-硫胞嘧啶和2,6-二氨基嘌呤。
在一些实施方案中,分离本公开的蛋白和核酸。如本文所用,术语“分离的”是指人工获得或产生的。如本文关于核酸所用,术语“分离的”一般意指:(i)通过例如聚合酶链反应(PCR)体外扩增;(ii)通过克隆重组产生;(iii)通过裂解和凝胶分离纯化;或(iv)通过例如化学合成合成。分离的核酸是易于通过本领域熟知的重组DNA技术操作的核酸。因此,已经公开了5'和3'限制性位点或已经公开了聚合酶链式反应(PCR)引物序列的载体中包含的核苷酸序列被认为是分离的,但是以其天然状态存在于其天然宿主中的核酸序列不被认为是分离的。分离的核酸可以是基本上纯化的,但不是必需的。例如,在克隆或表达载体中分离的核酸不是纯的,因为它可以仅包含其所在细胞中的微小百分比的物质。然而,这种核酸是分离的,因为该术语在本文中使用,因为它易于通过本领域普通技术人员已知的标准技术操作。如本文关于蛋白或肽所用,术语“分离的”一般是指人工获得或产生的蛋白或肽(例如,通过化学合成,通过重组DNA技术等)。
应该理解的是,可以进行保守氨基酸取代以提供衣壳蛋白的功能等同变体或同源物。在一些方面,本公开包括导致保守氨基酸取代的序列改变。如本文所用,保守氨基酸取代是指不改变其中进行氨基酸取代的蛋白的相对电荷或大小特征的氨基酸取代。变体可以根据改变本领域普通技术人员已知的多肽序列的方法制备,例如在编辑这些方法的参考文献中发现的,例如Molecular Cloning:A Laboratory Manual,J.Sambrook,等人编,第二版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,1989,或Current Protocols in Molecular Biology,F.M.Ausubel等人编,John Wiley&Sons,Inc.,New York。氨基酸的保守取代包括在以下组中的氨基酸之间进行的取代:(a)M、I、L、V;(b)F、Y、W;(c)K、R、H;(d)A、G;(e)S、T;(f)Q、N;和(g)E、D。因此,可以对本文公开的蛋白和多肽的氨基酸序列进行保守氨基酸取代。
编码包含AAV衣壳蛋白的多肽的分离的核酸的实例是具有选自以下的序列的核酸:SEQ ID NO:410-434、876-1718和1989-2251。编码AAV衣壳序列的分离的核酸片段可用于构建编码所需衣壳序列的核酸。片段可以具有任何合适的长度。在一些实施方案中,编码AAV衣壳序列的分离的核酸片段(部分)可用于构建编码所需衣壳序列的核酸。片段可以具有任何合适的长度(例如,长度为至少6、至少9、至少18、至少36、至少72、至少144、至少288、至少576、至少1152个或更多个核苷酸)。例如,编码第一AAV衣壳蛋白的多肽的核酸序列的片段可用于构建或可引入编码第二AAV衣壳序列的核酸序列内,以改变AAV衣壳的性质。在一些实施方案中,包含来自多种AAV血清型的衣壳序列片段的AAV衣壳蛋白被称为嵌合AAV衣壳。片段可以是不编码与SEQ ID NO:869、870或871中任一个的序列相同的肽的片段。例如,编码变体氨基酸(与已知的AAV血清型相比)的核酸序列的片段可用于构建或可引入编码AAV衣壳序列的核酸序列内,以改变AAV衣壳的性质。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型2、AAV2/3(例如,AAV2/3杂合体)或AAV8)相比,编码AAV变体的核酸序列可包含约1至约100个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型2、AAV2/3(例如,AAV2/3杂合体)或AAV8)相比,编码AAV变体的核酸序列可包含约5至约50个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型2、AAV2/3(例如,AAV2/3杂合体)或AAV8)相比,编码AAV变体的核酸序列可包含约10至约30个氨基酸变体。在一些实施方案中,与已知的AAV血清型(例如,AAV血清型2、AAV2/3(例如,AAV2/3杂合体)或AAV8)相比,编码AAV变体的核酸序列可包含1、或2、或3、或4、5、或6、或7、或8、或9、或10、或11、或12、或13、或14、或15、或16、或17、或18、或19、或20个氨基酸变体。例如,编码AAV变体的核酸序列(例如,SEQ ID NO:861)可以包含与已知的AAV血清型(例如,AAV8)相比的3个氨基酸变体。通过将包含编码变体氨基酸的区域的核酸序列的片段引入编码已知的AAV血清型的核酸序列中,可以构建具有3个氨基酸变体中的一个或多个的重组cap序列。片段可以通过任何合适的方法引入,包括使用定点诱变。因此,可以创建具有新属性的新AAV变体。
在一些方面,本公开提供了编码AAV组装激活蛋白(AAP)或其变体的分离的核酸。如本文所用,“组装激活蛋白”或“AAP”是蛋白伴侣,其功能是将新合成的衣壳蛋白(例如,VP蛋白,例如AAV VP1、VP2和VP3)靶向细胞的核仁,从而促进病毒基因组的包壳。通常,AAP编码在腺相关病毒的cap基因中。例如,AAP-2编码在AAV2的cap基因中。AAP的其他实例包括但不限于AAP-1、AAP-3、AAP-4、AAP-5、AAP-8、AAP-9、AAP-11和AAP-12,例如Sonntag等人,J.Virol.2011年12月.85(23):12686-12697所述。在一些实施方案中,从不是衣壳蛋白(例如,VP1、VP2、VP3)的cap基因的不同开放阅读框(ORF)翻译AAP。例如,在一些实施方案中,从cap基因的ORF1翻译衣壳蛋白(例如,AAV2VP1、VP2、VP3),并从cap基因的ORF2翻译AAP(例如,AAP-2)。在一些实施方案中,编码AAP的分离的核酸包含选自SEQ ID NO:410-434和876-1718的序列或由其组成。
重组AAV
在一些方面,本公开提供了分离的AAV。如本文关于AAV所用,术语“分离的”是指人工获得或产生的AAV。可以使用重组方法产生分离的AAV。此类AAV在本文中称为“重组AAV”。重组AAV(rAAV)优选具有组织特异性靶向能力,使得rAAV的转基因将特异性递送至一种或多种预定组织。AAV衣壳是确定这些组织特异性靶向能力的重要因素。因此,可以选择具有适合于被靶向组织的衣壳的rAAV。在一些实施方案中,rAAV包含具有SEQ ID NO:1-409、435-852、859-874或1726-1988中任一个所示的氨基酸序列的衣壳蛋白,或与其具有基本同源性的蛋白。
获得具有所需衣壳蛋白的重组AAV的方法是本领域熟知的。(参见,例如,US 2003/0138772),其内容通过引用整体并入本文)。通常,该方法包括培养宿主细胞,其含有编码AAV衣壳蛋白的核酸序列(例如,编码具有SEQ ID NO:1-409、435-868或1726-1988中任一所示序列的多肽的核酸)或其片段;功能性rep基因;由AAV反向末端重复序列(ITR)和转基因组成的重组AAV载体;和足够的辅助功能,以允许将重组AAV载体包装到AAV衣壳蛋白中。在一些实施方案中,衣壳蛋白是由AAV的cap基因编码的结构蛋白。在一些实施方案中,AAV包含三种衣壳蛋白,病毒体蛋白1至3(命名为VP1、VP2和VP3),所有这些都可从单个cap基因表达。因此,在一些实施方案中,VP1、VP2和VP3蛋白共享共同的核心序列。在一些实施方案中,VP1、VP2和VP3的分子量分别为约87kDa、约72kDa和约62kDa。在一些实施方案中,翻译后,衣壳蛋白在病毒基因组周围形成球形60聚体蛋白壳。在一些实施方案中,蛋白壳主要由VP3衣壳蛋白组成。在一些实施方案中,衣壳蛋白的功能是保护病毒基因组、递送基因组并与宿主相互作用。在一些方面,衣壳蛋白以组织特异性方式将病毒基因组递送至宿主。在一些实施方案中,VP1和/或VP2衣壳蛋白可以有助于包装的AAV的组织嗜性。在一些实施方案中,包装的AAV的组织嗜性由VP3衣壳蛋白决定。在一些实施方案中,通过衣壳蛋白中发生的突变增强或改变AAV的组织嗜性。
在一些方面,本公开描述了野生型AAV血清型的变体。在一些实施方案中,变体具有改变的组织嗜性。在一些实施方案中,本文所述的AAV变体包含cap基因内的氨基酸变异(例如,取代、缺失、插入)。如上所述,所有三种衣壳蛋白都是从单个cap基因转录而来。因此,在一些实施方案中,cap基因内的氨基酸变异存在于由所述cap基因编码的所有三种衣壳蛋白中。或者,在一些实施方案中,氨基酸变异可能不存在于所有三种衣壳蛋白中。在一些实施方案中,氨基酸变异仅发生在VP1衣壳蛋白中。在一些实施方案中,氨基酸变异仅发生在VP2衣壳蛋白中。在一些实施方案中,氨基酸变异仅发生在VP3衣壳蛋白内。在一些实施方案中,AAV变体包含cap基因中的一种以上变异。在一些实施方案中,一种以上的变异发生在相同的衣壳蛋白内(例如,在VP3内)。在一些实施方案中,一种以上的变异发生在不同衣壳蛋白内(例如,至少一种变异在VP2中和至少一种变异在VP3中)。
在一些实施方案中,本文描述的AAV变体是AAV2、AAV2/3(例如,AAV2/3杂合体)或AAV8的变体。已知AAV2有效地转导人中枢神经系统(CNS)组织、肾脏组织、眼组织(例如,感光细胞和视网膜色素上皮(RPE))和其他组织。因此,在一些实施方案中,本文所述的AAV3变体可用于将基因疗法递送至CNS组织、肾脏组织或眼组织。还已知AAV3有效地转导癌性人肝细胞。因此,在一些实施方案中,本文所述的AAV3变体可用于将基因疗法递送至癌性和正常人肝细胞。已知AAV8靶向肝脏组织、呼吸组织和眼的组织。因此,在一些实施方案中,本文所述的AAV8变体可用于将基因疗法递送至肝脏组织、呼吸组织和眼的组织。
应当理解的是,与相应的野生型AAV相比,本文所述的AAV2、AAV2/3(例如,AAV2/3杂合体)和AAV8变体可以包含cap基因内的一个或多个变异。因此,在一些实施方案中,本文所述的AAV2、AAV2/3(例如,AAV2/3杂合体)和AAV8变体可具有组织嗜性,其可用于将基因疗递送至野生型AAV2、AAV2/3(例如,AAV2/3杂种)或AAV8不靶向的其他组织类型。例如,在一些实施方案中,本文描述的AAV8变体(例如,B61;SEQ ID NO:865)可用于将基因疗递送至中枢神经系统(CNS)。在一些实施方案中,本文所述的AAV2、AAV2/3(例如,AAV2/3杂种)或AAV8变体可用于靶向肾细胞或肝细胞。在一些实施方案中,本文所述的AAV2、AAV2/3(例如,AAV2/3杂种)或AAV8变体可用于将基因疗递送至肝脏、脾脏、心脏或脑。
在一些方面,本文描述的AAV变体可用于治疗CNS相关病症。如本文所用,“CNS相关病症”是中枢神经系统的疾病或病况。CNS相关病症可能影响脊髓(例如脊髓病)、脑(例如脑病)或脑和脊髓周围的组织。CNS相关病症可以是遗传起源的,通过体细胞突变遗传或获得。CNS相关病症可以是心理病况或病症,例如注意力缺陷多动障碍、自闭症谱系障碍、情绪障碍、精神分裂症、抑郁症、雷特综合征等。CNS相关病症可以是自身免疫病。CNS相关病症也可以是CNS的癌症,例如脑癌。作为癌症的CNS相关病症可以是CNS的原发性癌症,例如星形细胞瘤、成胶质细胞瘤等,或者可以是转移至CNS组织的癌症,例如已经转移至脑的肺癌。CNS相关病症的其他非限制性实例包括帕金森氏病、溶酶体贮积病、缺血、神经性疼痛、肌萎缩侧索硬化症(ALS)、多发性硬化症(MS)和Canavan病(CD)。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至心脏细胞(例如,心脏组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗心血管病症。如本文所用,“心血管病症”是心血管系统的疾病或病况。心血管疾病可能影响心脏、循环系统、动脉、静脉、血管和/或毛细血管。心血管病症可以是遗传起源的,通过体细胞突变遗传或获得。心血管疾病的非限制性实例包括风湿性心脏病、心脏瓣膜病、高血压性心脏病、动脉瘤、动脉粥样硬化、高血压(hypertension)(例如,高血压(high blood pressure))、外周动脉疾病(PAD)、缺血性心脏病、心绞痛、冠心病、冠状动脉疾病、心肌梗塞、脑血管疾病、短暂性脑缺血发作、炎性心脏病、心肌病、心包疾病、先天性心脏病、心力衰竭、中风和由于恰加斯病引起的心肌炎。
在一些实施方案中,本文描述的AAV变体可以靶向肺和/或肺系统的组织(例如,呼吸系统)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗肺病。如本文所用,“肺病”是肺系统的疾病或病况。肺病可能影响呼吸所涉及的肺或肌肉。肺病可以是遗传起源的,通过体细胞突变遗传或获得。肺病可以是肺癌,包括但不限于非小细胞肺癌、小细胞肺癌和肺类癌。肺病的进一步非限制性实例包括急性支气管炎、急性呼吸窘迫综合征(ARDS)、石棉沉着病、哮喘、支气管扩张、细支气管炎、闭塞性细支气管炎(BOOP)、支气管肺发育不良、棉尘肺、慢性支气管炎、球孢子菌病(球菌)、慢性阻塞性肺病(COPD)、隐源性组织性肺炎(COP)、囊性纤维化、肺气肿、汉坦病毒肺综合征、组织胞浆菌病、人类肺炎病毒、过敏性肺炎、流行性感冒、淋巴管瘤病、间皮瘤、中东呼吸综合征、非结核分枝杆菌、百日咳、尘肺病(黑肺病)、肺炎、原发性纤毛运动障碍、原发性肺动脉高压、肺动脉高压、肺纤维化、肺血管疾病、呼吸道合胞病毒(RSV)、结节病、严重急性呼吸系统综合症(SARS)、矽肺、睡眠呼吸暂停、突然婴儿死亡综合症(SIDS)和肺结核。
在一些实施方案中,本文描述的AAV变体可靶向肝组织。因此,在一些实施方案中,本文描述的AAV变体可用于治疗肝病。如本文所用,“肝病”是肝的疾病或病况。肝病可以是遗传起源的,通过体细胞突变遗传或获得。肝病可以是肝癌,包括但不限于肝细胞癌(HCC)、纤维板层癌、胆管癌、血管肉瘤和肝母细胞瘤。肺病的进一步非限制性实例包括Alagille综合征、Alpha 1抗胰蛋白酶缺乏症、自身免疫性肝炎、胆道闭锁、肝硬化、肝脏囊性疾病、脂肪肝病、半乳糖血症、胆结石、Gilbert综合征、血色素沉着症、妊娠肝病、新生儿肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、卟啉症、雷氏综合征、结节病、中毒性肝炎、1型糖原贮积病、酪氨酸血症、甲型-、乙型-、丙型-病毒性肝炎、威尔逊病和血吸虫病。
在一些实施方案中,本文描述的AAV变体可靶向肾脏组织。因此,在一些实施方案中,本文描述的AAV变体可用于治疗肾病。如本文所用,“肾病”是肝的疾病或病况。肾病可以是遗传起源的,通过体细胞突变遗传或获得。肾病可以是肾癌,包括但不限于肾细胞癌、透明细胞癌、1型乳头状癌、2型乳头状癌、嫌色细胞癌、嗜酸细胞癌、集合管癌、肾盂的移行细胞癌和威尔姆氏肿瘤。肾病的其他非限制性实例包括阿布德哈尔登-考夫曼-利尼亚克综合征(肾病性胱氨酸病)、急性肾衰竭/急性肾损伤、急性大叶性肾炎、急性磷酸盐肾病、急性肾小管坏死、腺嘌呤磷酸核糖基转移酶缺乏症、腺病毒肾炎、奥尔波特综合征、淀粉样变性、血管平滑肌脂肪瘤、镇痛肾病、血管紧张素抗体和局灶性节段性肾小球硬化、抗磷脂综合征、抗TNF-α治疗相关的肾小球肾炎、APOL1突变、表观的皮质激素过度综合征、马兜铃酸肾病、巴尔干地方性肾病、巴特综合征、甜菜尿症、β-地中海贫血肾病、胆汁性肾病、BK多瘤、C1q肾病、心肾综合征、CFHR5肾病、胆固醇栓塞、变应性肉芽肿性综合征、乳糜尿、塌陷性肾小球病、与CMV相关的崩解性肾小球病、先天性肾病综合征、Conorenal综合征(Mainzer-Saldino综合征或Saldino-Mainzer病)、对比剂肾病、硫酸铜中毒、皮质坏死、冷球蛋白血症、晶体诱导的急性肾损伤、获得性囊性肾病、胱氨酸尿症、致密性沉积病(MPGN2型)、登特病(X连锁隐性肾病)、透析不平衡综合征、糖尿病肾病、尿崩症、EAST综合征、异位输尿管、水肿、埃德海姆-切斯特病、法布里病、家族性低钙血症、范可尼综合征、弗雷泽综合征、纤连蛋白肾小球病、纤维性肾小球肾炎和免疫类型肾小球病、弗雷利综合征、局灶性节段性肾小球硬化症、局灶性硬化症、局灶性肾小球硬化症、Galloway Mowat综合征、吉特曼综合征、肾小球疾病、肾小球肾小管反流、糖尿、肺出血肾炎综合征、溶血性尿毒症综合征(HUS)、非典型溶血性尿毒症综合征(aHUS)、噬血细胞综合征、出血性膀胱炎、血瘀与阵发性夜间血红蛋白有关尿潴留和溶血性贫血、肝静脉闭塞性疾病、肝窦阻塞综合征、丙型肝炎相关肾病、肝肾综合征、HIV相关肾病(HIVAN)、马蹄肾(肾脏融合)、亨纳溃疡、醛固酮增多症、高钙血症、高钾血症、高镁血症、高钠血症、高尿酸血症、高磷血症、低钙血症、低钾血症、低钾血症引起的肾功能不全、低镁血症、低钠血症、低磷血症、IgA肾病、IgG4肾病、间质性膀胱炎、膀胱疼痛综合征、间质性肾炎、Ivemark综合征、肾结石(Kidney Stones)、肾结石(Nephrolithiasis)、钩端螺旋体病肾病、轻链沉积病、单克隆免疫球蛋白沉积病、利德尔综合征、莱特伍德-奥尔布赖特综合征、脂蛋白肾小球病、锂肾毒性、LMX1B突变导致遗传性FSGS、腰痛血尿、狼疮、系统性红斑狼疮、狼疮性肾病、狼疮性肾炎、莱姆病-相关的肾小球单发性肾炎、疟疾肾病、恶性高血压、软斑病、尿道口狭窄、肾髓质囊性病、髓质海绵肾、巨输尿管、三聚氰胺毒性和肾、膜增生性肾小球肾炎、膜性肾病、中美洲肾病、代谢性酸中毒、代谢性碱中毒、显微镜下多血管炎、乳汁碱性综合征、轻微病变、多囊性肾发育不良、多发性骨髓瘤、骨髓增生性肿瘤和肾小球病、指甲髌骨综合征、肾钙质沉着症、肾性系统性纤维化、肾病(游走肾,肾下垂)、肾病综合征、神经源性膀胱、结节性肾小球硬化、非淋球菌的、胡桃夹综合征、口面指综合征、直立性低血压、直立性蛋白尿、渗透性利尿、Page肾、乳头坏死、乳头肾综合征(肾脏-白内障综合征,孤立性肾发育不全)、腹膜-肾综合征、后尿道瓣膜、感染后肾小球肾炎、链球菌感染后肾小球肾炎、结节性多动脉炎、多囊肾病、后尿道瓣膜、先兆子痫、增生肾小球肾炎伴单克隆IgG沉积(Nasr病)、蛋白尿(尿液中的蛋白质)、假性醛固酮过多症、假性甲状旁腺功能减退症、肺肾综合征、肾盂肾炎(肾脏感染)、肾积脓、放射性肾病、再喂养综合征、反流性肾病、快速进展性肾小球肾炎、肾脓肿、肾周脓肿、肾发育不全、肾动脉瘤、肾动脉狭窄、肾细胞癌、肾囊肿、肾性低尿酸血症与运动诱导的急性肾功能衰竭、肾梗塞、肾性骨营养不良、肾小管性酸中毒、Reset Osmostat、下腔静脉后输尿管、腹膜后纤维化、横纹肌溶解症、与减肥手术有关的横纹肌溶解症、类风湿性关节炎相关肾脏病、结节病肾病、失盐、肾和脑、Schimke免疫骨发育不良、硬皮病肾危象、蛇纹石腓骨-多囊肾综合征,埃克斯纳综合征,镰状细胞性肾病、硅曝光和慢性肾脏病、造血细胞移植后肾病、与干细胞移植有关的肾病、薄基底膜病、良性家族性血尿、膀胱三角区炎、结节性硬化、肾小管发育不全、肿瘤溶解综合征、尿毒症、尿毒症视神经病变、输尿管口囊肿、尿道肉瘤、尿道狭窄、尿失禁、尿路感染、尿路梗阻、膀胱肠瘘、膀胱输尿管返流、希佩尔-林道综合征、华法林相关肾病、韦格纳肉芽肿病、韦格纳肉芽肿多血管炎和温德里希综合征。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至眼组织(例如,眼的组织或细胞)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗眼部病症。如本文所用,“眼部病症”是眼的疾病或病况。眼部疾病可能影响眼、巩膜、角膜、前房、后房、虹膜、瞳孔、晶状体、玻璃体液、视网膜或视神经。眼部病症可以是遗传起源的,通过体细胞突变遗传或获得。眼部疾病和病症的非限制性实例包括但不限于:年龄相关性黄斑变性、视网膜病、糖尿病性视网膜病、黄斑水肿、青光眼、色素性视网膜炎和眼癌。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至胃肠组织(例如胃肠道组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗胃肠道病症。如本文所用,“胃肠道病症”是胃肠道的疾病或病况。胃肠疾病可能影响粘膜(例如,上皮、固有层、粘膜肌层等)、粘膜下层(例如,粘膜下丛、肠神经丛等)、胃肠道的肌层、浆膜和/或外膜、口腔、食道、幽门、胃十二指肠、小肠、盲肠、阑尾、结肠、肛管或直肠。胃肠道病症可以是遗传起源的,通过体细胞突变遗传或获得。胃肠道疾病和病症的非限制性实例包括但不限于:炎性肠病(IBD)、克罗恩病、溃疡性结肠炎、肠易激综合征、腹腔疾病,胃食管反流病(GERD)、失弛缓症(achakasua)、憩室炎(diverticulitus)、腹泻和某些癌症(例如,肠癌、胃癌、结肠癌、直肠癌等)。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至乳腺组织(例如,乳房的组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗乳房病症。如本文所用,“乳房病症”是乳房的疾病或病况。乳房疾病可能影响乳房的纤维组织、脂肪组织、小叶或导管。乳房病症可以是遗传起源的,通过体细胞突变遗传或获得。乳房疾病和病症的非限制性实例包括但不限于:乳腺炎、乳腺钙化、脂肪坏死、纤维腺瘤、纤维化和单纯囊肿、溢乳、增生和乳腺癌。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至胰腺组织(例如,胰脏的组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗胰脏病症。如本文所用,“胰脏病症”是胰脏的疾病或病况。胰脏疾病可能影响胰脏头部、胰脏颈部、胰脏腺体、胰脏尾部、胰岛(例如朗格汉斯岛)、腺泡或柱状上皮。胰脏病症可以是遗传起源的,通过体细胞突变遗传或获得。胰脏疾病和病症的非限制性实例包括但不限于:糖尿病(例如,1型糖尿病和2型糖尿病)、胰腺炎(例如急性胰腺炎、慢性胰腺炎)和胰腺癌。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至泌尿道组织(例如泌尿道组织,如膀胱组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗泌尿道病症。如本文所用,“泌尿道病症”是泌尿道的疾病或病况。泌尿道疾病可能会影响膀胱、输尿管、尿道或前列腺。泌尿道病症可以是遗传起源的,通过体细胞突变遗传或获得。泌尿道疾病和病症的非限制性实例包括但不限于:尿路感染、肾结石、膀胱控制问题(例如,尿潴留、尿失禁等)、膀胱炎和膀胱癌。
在一些实施方案中,本文所述的AAV变体可用于将基因疗法递送至子宫组织(例如子宫的组织)。因此,在一些实施方案中,本文描述的AAV变体可用于治疗子宫病症。如本文所用,“子宫病症”是子宫的疾病或病况。子宫疾病可能影响子宫颈、子宫颈管、子宫体(子宫底)、子宫内膜、子宫肌层或子宫外膜。子宫病症可以是遗传起源的,通过体细胞突变遗传或获得。子宫疾病和病症的非限制性实例包括但不限于:子宫腺肌病、子宫内膜异位症、子宫内膜增生、子宫腔粘连综合征和子宫内膜癌。
在宿主细胞中培养以将rAAV载体包装在AAV衣壳中的组分可以反式提供给宿主细胞。或者,任何一种或多种所需组分(例如,重组AAV载体、rep序列、cap序列和/或辅助功能)可由稳定的宿主细胞提供,所述宿主细胞使用本领域技术人员已知的方法经工程改造以含有一种或多种所需组分。最合适的是,这种稳定的宿主细胞含有在诱导型启动子控制下的所需组分。但是,所需的组分可能处于组成型启动子的控制之下。在适合与转基因一起使用的调节元件的讨论中,本文提供了合适的诱导型和组成型启动子的实例。在另一个替代方案中,选定的稳定宿主细胞可以含有在组成型启动子控制下的选定组分和在一种或多种诱导型启动子控制下的其他选定组分。例如,可以产生稳定的宿主细胞,其衍生自293细胞(其在组成型启动子的控制下含有E1辅助功能),但其含有在诱导型启动子控制下的rep和/或cap蛋白。本领域技术人员可以产生其他稳定的宿主细胞。
可以使用任何合适的遗传元件(载体)将产生本公开的rAAV所需的重组AAV载体、rep序列、cap序列和辅助功能递送至包装宿主细胞。在一些实施方案中,编码所有三种衣壳蛋白(例如VP1、VP2和VP3)的单一核酸在单一载体中递送到包装宿主细胞中。在一些实施方案中,编码衣壳蛋白的核酸通过两种载体递送到包装宿主细胞中;包含编码两种衣壳蛋白(例如VP1和VP2)的第一核酸的第一载体和包含编码单一衣壳蛋白(例如VP3)的第二核酸的第二载体。在一些实施方案中,将三种载体(每种载体包含编码不同衣壳蛋白的核酸)递送至包装宿主细胞。所选择的遗传元件可以通过任何合适的方法包括本文所述的那些进行递送。用于构建本公开的任何实施方案的方法是核酸操作领域技术人员已知的,包括基因工程、重组工程和合成技术。参见,例如,Sambrook等人,Molecular Cloning:A LaboratoryManual,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.。类似地,产生rAAV病毒体的方法是众所周知的,并且合适方法的选择不是对本公开的限制。参见,例如,K.Fisher等人,J.Virol.,70:520-532(1993)和美国专利号5,478,745。
在一些实施方案中,可以使用三重转染方法产生重组AAV(在美国专利号6,001,650中详细描述)。通常,通过用待包装成AAV颗粒的重组AAV载体(包含转基因)转染宿主细胞、AAV辅助功能载体和辅助功能载体来产生重组AAV。AAV辅助功能载体编码“AAV辅助功能”序列(例如rep和cap),其反式起作用以进行有效的AAV复制和衣壳化。优选地,AAV辅助功能载体支持有效的AAV载体产生,而不产生任何可检测的野生型AAV病毒体(例如含有功能性rep和cap基因的AAV病毒体)。适用于本发明的载体的非限制性实例包括描述于美国专利号6,001,650中的pHLP19和描述于美国专利号6,156,303中的pRep6cap6载体,其全部内容通过引用并入本文。辅助功能载体编码非AAV衍生的病毒和/或AAV依赖于其复制的细胞功能(例如“辅助功能”)的核苷酸序列。辅助功能包括AAV复制所需的那些功能,包括但不限于参与AAV基因转录激活、阶段特异性AAV mRNA剪接、AAV DNA复制、cap表达产物的合成和AAV衣壳组装的那些部分。基于病毒的辅助功能可以衍生自任何已知的辅助病毒,例如腺病毒、疱疹病毒(除了单纯疱疹病毒1型)和痘苗病毒。
在一些方面,本公开提供了转染的宿主细胞。术语“转染”用于指细胞对外源DNA的摄取,当外源DNA被引入例如细胞内(跨细胞膜)时,细胞已被“转染”。许多转染技术通常是本领域已知的。参见,例如,Graham等人(1973)Virology,52:456;Sambrook等人(1989)Molecular Cloning,a laboratory manual,Cold Spring Harbor Laboratories,NewYork;Davis等人(1986)Basic Methods in Molecular Biology,Elsevier;和Chu等人(1981)Gene13:197。此类技术可用于将一种或多种外源核酸(例如核苷酸整合载体和其他核酸分子)引入合适的宿主细胞中。
“宿主细胞”是指任何含有或能够携带感兴趣物质的细胞。宿主细胞通常是哺乳动物细胞。宿主细胞可以用作AAV辅助构建体、AAV小基因质粒、辅助功能载体或与重组AAV的产生相关的其他转移DNA的接受者。该术语包括已经被转染的原始细胞的后代。因此,如本文所用的“宿主细胞”可以指已经用外源DNA序列转染的细胞。应当理解,由于天然的、偶然的或有意的突变,单个亲本细胞的后代在形态学上或在基因组或总DNA互补物(complement)中可能不一定与原始亲本完全相同。
如本文所用,术语“细胞系”是指能够在体外连续或延长生长和分裂的细胞群。通常,细胞系是源自单个祖细胞的克隆群体。本领域进一步已知,在这种克隆群体的储存或转移期间,核染色中可发生自发或诱导的变化。因此,来自所提及的细胞系的细胞可能与祖先细胞或培养物不完全相同,并且所指的细胞系包括这些变体。
如本文所用,术语“重组细胞”是指已经引入了外源DNA区段(例如导致生物活性多肽转录或产生生物活性核酸如RNA的DNA区段)的细胞。
也可以用向AAV提供辅助功能的载体(例如,辅助载体)转染细胞。提供辅助功能的载体可提供腺病毒功能,包括例如E1a、E1b、E2a和E4ORF6。提供这些功能的腺病毒基因的序列可以从任何已知的腺病毒血清型获得,例如血清型2、3、4、7、12和40,并且还包括本领域已知的任何目前鉴定的人类型。因此,在一些实施方案中,所述方法涉及用表达AAV复制、AAV基因转录和/或AAV包装所必需的一种或多种基因的载体转染细胞。
如本文所用,术语“载体”包括任何遗传元件,例如质粒、噬菌体、转座子、粘粒、染色体、人工染色体、病毒、病毒体等,当与适当的控制元件结合时能够复制并且它能够在细胞之间转移基因序列。因此,该术语包括克隆和表达载体,以及病毒载体。在一些实施方案中,预期有用载体是其中待转录的核酸区段(例如核酸序列)位于启动子的转录控制下的那些载体。“启动子”是指由启动基因特异性转录所需的细胞合成机制或引入的合成机制识别的DNA序列。短语“可操作地定位”、“在控制下”或“在转录控制下”意指启动子相对于核酸处于正确的位置和方向,以控制RNA聚合酶的起始和基因的表达。术语“表达载体或构建体”意指含有核酸的任何类型的遗传构建体,其中部分或全部核酸编码序列能够被转录。在一些实施方案中,表达包括核酸的转录,例如,以从转录的基因产生生物活性多肽产物或抑制性RNA(例如shRNA、miRNA、miRNA抑制剂)。
在一些情况下,使用本领域熟知的方法,分离的衣壳基因能够用于构建和包装重组AAV,以确定与该基因编码的衣壳蛋白相关的功能特征。例如,分离的衣壳基因能够用于构建和包装包含报告基因(例如,B-半乳糖苷酶、GFP、萤光素酶等)的重组AAV(rAAV)。然后能够将rAAV递送至动物(例如,小鼠),并且通过检查报告基因在各种动物组织(例如,心脏、肝脏、肾脏)中的表达能够确定新分离的衣壳基因的组织靶向性质。本文公开了表征新分离的衣壳基因的其他方法,还有其他方法是本领域熟知的。
用于将重组载体包装在所需AAV衣壳中以产生本公开的rAAV的前述方法不意味着限制,并且其他合适的方法对于技术人员是显而易见的。
重组AAV载体
本公开的“重组AAV(rAAV)载体”通常至少由转基因及其调节序列和5'和3'AAV反向末端重复序列(ITR)组成。将这种重组AAV载体包装到衣壳蛋白中并递送至选定的靶细胞。在一些实施方案中,转基因是与载体序列异源的核酸序列,其编码目的多肽、蛋白、功能性RNA分子(例如,miRNA、miRNA抑制剂)或其他基因产物。核酸编码序列以允许转基因在靶组织的细胞中转录、翻译和/或表达的方式与调节组分可操作地连接。
载体的AAV序列通常包含顺式作用的5'和3'反向末端重复序列(参见,例如,例如B.J.Carter,in"Handbook of Parvoviruses",ed.,P.Tijsser,CRC Press,pp.155 168(1990))。ITR序列的长度约为145bp。优选地,基本上编码ITR的整个序列用于分子中,尽管这些序列的某种程度的微小修饰是允许的。修饰这些ITR序列的能力在本领域技术范围内。(参见例如"Molecular Cloning.A Laboratory Manual",第二版,Cold Spring HarborLaboratory,New York(1989);和K.Fisher等人,J Virol.,70:520 532(1996)的教科书)。用于本公开的这种分子的实例是含有转基因的“顺式作用”质粒,其中所选择的转基因序列和相关的调节元件侧接5'和3'AAV ITR序列。AAV ITR序列可以从任何已知的AAV获得,包括目前鉴定的哺乳动物AAV类型。
在一些实施方案中,本公开提供了自身互补的AAV载体。如本文所用,术语“自身互补的AAV载体”(scAAV)是指含有双链载体基因组的载体,所述载体是通过不存在来自AAV的一个ITR的末端拆分位点(resolutionn site,TR)而产生的。不存在TR阻止在不存在TR的载体末端开始复制。通常,scAAV载体产生单链反向重复基因组,其中每端具有野生型(wt)AAVTR而中间具有突变TR(mTR)。
在一些实施方案中,本公开的rAAV是假型分型的rAAV。假型分型是与外源病毒包膜蛋白组合产生病毒或病毒载体的过程。结果是假型分型的病毒颗粒。使用该方法,外源病毒包膜蛋白能够用于改变宿主向性或病毒颗粒的增加/降低的稳定性。在一些方面,假型分型的rAAV包含来自两种或更多种不同AAV的核酸,其中来自一种AAV的核酸编码衣壳蛋白,并且至少一种其他AAV的核酸编码其他病毒蛋白和/或病毒基因组。在一些实施方案中,假型分型的rAAV是指包含一种AAV血清型的反向末端重复序列(ITR)和不同AAV血清型的衣壳蛋白的AAV。例如,含有用Y蛋白包裹的血清型X的ITR的假型分型的AAV载体将命名为AAVX/Y(例如,AAV2/1具有AAV2的ITR和AAV1的衣壳)。在一些实施方案中,假型分型的rAAV可用于组合来自一种AAV血清型的衣壳蛋白的组织特异性靶向能力与来自另一种AAV血清型的病毒DNA,从而允许将转基因靶向递送至靶组织。
除了上文鉴定的重组AAV载体的主要元件外,载体还包括常规的必要控制元件,其以允许其在用质粒载体转染或感染本公开产生的病毒的细胞中的转录、翻译和/或表达的方式与转基因可操作地连接。如本文所用,“可操作地连接”的序列包括与目的基因邻接的表达控制序列和反式或远距离起作用以控制目的基因的表达控制序列。
表达控制序列包括合适的转录起始、终止、启动子和增强子序列;有效的RNA处理信号,如剪接和聚腺苷酸化(多聚A)信号;稳定细胞质mRNA的序列;提高翻译效率的序列(例如Kozak共有序列);增强蛋白稳定性的序列;并且当需要时,增强编码产物分泌的序列。大量表达控制序列,包括天然的、组成型的、可诱导的和/或组织特异性的启动子,是本领域已知的并且可以使用。
如本文所用,当核酸序列(例如,编码序列)和调节序列以使得核酸序列的表达或转录置于受调节序列的影响或控制下的方式共价连接时,称其可操作地连接。如果希望将核酸序列翻译成功能性蛋白,则如果5'调节序列中的启动子的诱导导致编码序列的转录以及如果两个DNA序列之间的连接性质不会(1)导致移码突变的引入,(2)干扰启动子区域指导编码序列转录的能力,或(3)干扰将相应的RNA转录物翻译成蛋白的能力,则认为两个DNA序列可操作地连接。因此,如果启动子区能够影响该DNA序列的转录,使得所得的转录物可以翻译成所需的蛋白或多肽,则启动子区域将与核酸序列可操作地连接。类似地,两个或更多个编码区在它们以这样的方式连接时可操作地连接,即它们从共同启动子的转录导致两个或更多个蛋白的表达已在框内翻译。在一些实施方案中,可操作地连接的编码序列产生融合蛋白。在一些实施方案中,可操作地连接的编码序列产生功能性RNA(例如,shRNA、miRNA、miRNA抑制剂)。
对于编码蛋白的核酸,通常在转基因序列之后和3'AAV ITR序列之前插入多腺苷酸化序列。可用于本发明的rAAV构建体还可含有内含子,理想地位于启动子/增强子序列和转基因之间。一种可能的内含子序列源自SV-40,并且被称为SV-40T内含子序列。可以使用的另一种载体元件是内部核糖体进入位点(IRES)。IRES序列用于从单个基因转录物产生一种以上的多肽。IRES序列将用于产生含有多于一条多肽链的蛋白。这些和其他常见载体元件的选择是常规的,并且许多这样的序列是可用的[参见例如Sambrook等,以及其中引用的参考文献,例如,第3.18 3.26和16.17 16.27页和Ausubel等人,Current Protocols inMolecular Biology,John Wiley&Sons,New York,1989]。在一些实施方案中,口蹄疫病毒2A序列包含在多蛋白中;这是一种小肽(长度约为18个氨基酸),已被证明可介导多蛋白的裂解(Ryan,M D等人,EMBO,1994;4:928-933;Mattion,N M等人,J Virology,November1996;p.8124-8127;Furler,S等人,Gene Therapy,2001;8:864-873;和Halpin,C等人,ThePlant Journal,1999;4:453-459)。先前已在包括质粒和基因治疗载体(AAV和逆转录病毒)的人工系统中证明了2A序列的切割活性(Ryan,M D等人,EMBO,1994;4:928-933;Mattion,NM等人,J Virology,November 1996;p.8124-8127;Furler,S等人,Gene Therapy,2001;8:864-873;和Halpin,C等人,The Plant Journal,1999;4:453-459;de Felipe,P等人,GeneTherapy,1999;6:198-208;de Felipe,P等人,Human Gene Therapy,2000;11:1921-1931.;和Klump,H等人,Gene Therapy,2001;8:811-817)。
宿主细胞中基因表达所需的调控序列的确切性质可能因物种、组织或细胞类型而异,但一般来说(如所需要的)应包括分别涉及转录和翻译的起始的5'非转录序列和5'非翻译序列,例如TATA框、加帽序列、CAAT序列、增强子元件等。特别地,这种5'非转录调节序列将包括启动子区,其包括用于可操作连接基因的转录控制的启动子序列。调控序列还可以根据需要包括增强子序列或上游激活子序列。本公开的载体可任选地包括5'前导序列或信号序列。适当载体的选择和设计在本领域普通技术人员的能力和自由裁量权范围内。
组成型启动子的实例包括但不限于逆转录病毒劳氏肉瘤病毒(RSV)LTR启动子(任选地具有RSV增强子)、巨细胞病毒(CMV)启动子(任选地具有CMV增强子)[参见,例如Boshart等人,Cell,41:521-530(1985)]、SV40启动子、二氢叶酸还原酶启动子、β-肌动蛋白启动子、磷酸甘油激酶(PGK)启动子和EF1α启动子[Invitrogen]。
诱导型启动子允许调节基因表达,并且可以通过外源提供的化合物、环境因素例如温度或特定生理状态的存在来调节,例如急性期、细胞的特定分化状态、或仅在复制细胞中。诱导型启动子和诱导型系统可从各种商业来源获得,包括但不限于Invitrogen、Clontech和Ariad。已经描述了许多其他系统,并且本领域技术人员可以容易地选择这些系统。由外源提供的启动子调节的诱导型启动子的实例包括锌诱导型绵羊金属硫蛋白(MT)启动子、地塞米松(Dex)诱导型小鼠乳腺肿瘤病毒(MMTV)启动子、T7聚合酶启动子系统(WO98/10088);蜕皮激素昆虫启动子(No等人,Proc.Natl.Acad.Sci.USA,93:3346-3351(1996))、四环素可抑制系统(Gossen等人,Proc.Natl.Acad.Sci.USA,89:5547-5551(1992))、四环素诱导系统(Gossen等人,Science,268:1766-1769(1995),还参见Harvey等人,Curr.Opin.Chem.Biol.,2:512-518(1998))、RU486诱导系统(Wang等人,Nat.Biotech.,15:239-243(1997)和Wang等人,Gene Ther.,4:432-441(1997))和雷帕霉素诱导系统(Magari等人,J.Clin.Invest.,100:2865-2872(1997))。在本文中可能有用的其他类型的诱导型启动子是那些受特定生理状态调节的启动子,例如温度、急性期、细胞的特定分化状态、或仅在复制细胞中。
在另一个实施方案中,将使用转基因的天然启动子。当希望转基因的表达应该模拟天然表达时,天然启动子可能是优选的。当转基因的表达必须在时间上或发育上,或以组织特异性方式,或响应特定转录刺激时,可以使用天然启动子。在另一个实施方案中,其他天然表达控制元件,例如增强子元件、多腺苷酸化位点或Kozak共有序列也可用于模拟天然表达。
在一些实施方案中,调节序列赋予组织特异性基因表达能力。在一些情况下,组织特异性调节序列结合组织特异性转录因子,其以组织特异性方式诱导转录。此类组织特异性调节序列(例如,启动子、增强子等)是本领域熟知的。示例性组织特异性调控序列包括但不限于以下组织特异性启动子:肝特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、肌酸激酶(MCK)启动子、哺乳动物结蛋白(DES)启动子、α-肌球蛋白重链(a-MHC)启动子、胃肠特异性粘蛋白-2启动子、眼特异性视网膜激素启动子、眼特异性K12启动子、呼吸组织特异性CC10启动子、呼吸组织特异性表面活性蛋白C(SP-C)启动子、乳腺组织特异性PRC1启动子、乳腺组织特异性RRM2启动子、泌尿道组织特异性uroplakin 2(UPII)启动子、子宫组织特异性乳铁蛋白启动子或心肌肌钙蛋白T(cTnT)启动子。其他示例性启动子包括β-肌动蛋白启动子、乙型肝炎病毒核心启动子,Sandig等人,Gene Ther.,3:1002-9(1996);甲胎蛋白(AFP)启动子,Arbuthnot等人,Hum.Gene Ther.,7:1503-14(1996)),骨骨钙素启动子(Stein等人,Mol.Biol.Rep.,24:185-96(1997));骨唾液蛋白启动子(Chen等人,J.BoneMiner.Res.,11:654-64(1996)),CD2启动子(Hansal等人,J.Immunol.,161:1063-8(1998);免疫球蛋白重链启动子;细胞受体α-链启动子,神经元如神经元特异性烯醇化酶(NSE)启动子(Andersen等人,Cell.Mol.Neurobiol.,13:503-15(1993)),神经细丝轻链基因启动子(Piccioli等人,Proc.Natl.Acad.Sci.USA,88:5611-5(1991))和神经元特异性vgf基因启动子(Piccioli等人,Neuron,15:373-84(1995)),等等,这些对于本领域技术人员来说是显而易见的。
在一些实施方案中,将一种或多种miRNA的一个或多个结合位点引入rAAV载体的转基因中,以抑制转基因在携带转基因的受试者的一个或多个组织中的表达。本领域技术人员将理解,可以选择结合位点以组织特异性方式控制转基因的表达。例如,可以将肝特异性miR-122的结合位点引入转基因中以抑制该转基因在肝脏中的表达。mRNA中的靶位点可以在5'UTR、3'UTR或编码区中。通常,靶位点位于mRNA的3'UTR中。此外,可设计转基因使得多个miRNA通过识别相同或多个位点来调节mRNA。多个miRNA结合位点的存在可导致多个RISC的协同作用并提供高效的表达抑制。靶位点序列可包含总共5-100、10-60个或更多个核苷酸。靶位点序列可包含靶基因结合位点序列的至少5个核苷酸。
重组AAV载体:转基因编码序列
rAAV载体的转基因序列的组成将取决于所得载体的用途。例如,一种类型的转基因序列包括报告序列,其在表达时产生可检测的信号。在另一个实例中,转基因编码治疗性蛋白或治疗性功能性RNA。在另一个实例中,转基因编码旨在用于研究目的的蛋白或功能性RNA,例如,以产生携带转基因的体细胞转基因动物模型,例如,以研究转基因产物的功能。在另一个实例中,转基因编码蛋白或功能性RNA,其旨在用于产生疾病的动物模型。适当的转基因编码序列对于本领域技术人员是显而易见的。
可以在转基因中提供的报告序列包括但不限于编码β-内酰胺酶、β-半乳糖苷酶(LacZ)、碱性磷酸酶、胸苷激酶、绿色荧光蛋白(GFP)、氯霉素乙酰转移酶(CAT)、萤光素酶和在本领域中众所周知的其他那些。当与驱动其表达的调控元件相关联时,报告序列提供可通过常规手段检测的信号,包括酶、射线照相、比色、荧光或其他光谱测定、荧光激活细胞分选测定和免疫测定,包括酶联免疫吸附测定(ELISA)、放射免疫分析(RIA)和免疫组化。例如,在标记序列是LacZ基因的情况下,通过β-半乳糖苷酶活性的测定来检测携带信号的载体的存在。在转基因是绿色荧光蛋白或萤光素酶的情况下,携带信号的载体可以通过发光计中的颜色或光产生来目测测量。例如,此类报告分子可用于验证rAAV的组织特异性靶向能力和组织特异性启动子调控活性。
在一些方面,本公开提供了rAAV载体,其用于预防或治疗哺乳动物的一种或多种遗传缺陷或功能障碍的方法,诸如例如哺乳动物中的多肽缺乏或多肽过量,特别是用于治疗或减少人体内缺乏症的严重程度或程度,其表现出与细胞和组织中此类多肽缺乏有关的一种或多种疾病。该方法包括以足以治疗患有这种病症的受试者中的疾病或病症的量和时间给受试者施用药学上可接受的载体中的一种或多种治疗性肽、多肽、siRNA、微小RNA、反义核苷酸等的rAAV载体。
因此,本公开包括编码一种或多种肽、多肽或蛋白的rAAV载体的递送,其可用于治疗或预防哺乳动物受试者的疾病状态。示例性治疗性蛋白包括一种或多种选自生长因子、白细胞介素、干扰素、抗凋亡因子、细胞因子、抗糖尿病因子、抗凋亡剂、凝血因子、抗肿瘤因子的多肽。治疗性蛋白的其他非限制性实例包括BDNF、CNTF、CSF、EGF、FGF、G-SCF、GM-CSF、促性腺激素、IFN、IFG-1、M-CSF、NGF、PDGF、PEDF、TGF、VEGF、TGF-B2、TNF、催乳素、促生长素、XIAP1、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-10(187A)、病毒IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17和IL-18。
rAAV载体可包含待转移至受试者的基因,以治疗与基因表达降低、表达缺失或功能障碍相关的疾病。示例性基因和相关疾病状态包括但不限于:葡萄糖-6-磷酸酶,与糖原贮积缺乏型1A相关;磷酸烯醇丙酮酸-羧激酶,与Pepck缺乏有关;半乳糖-1磷酸尿苷酰转移酶,与半乳糖血症有关;苯丙氨酸羟化酶,与苯丙酮尿症有关;支链α-酮酸脱氢酶,与枫糖尿病有关;富马酰乙酰乙酸水解酶,与1型酪氨酸血症有关;甲基丙二酰辅酶A变位酶,与甲基丙二酸血症有关;中链酰基辅酶A脱氢酶,与中链乙酰辅酶A缺乏有关;正鸟氨酸氨甲酰转移酶,与正鸟氨酸氨甲酰转移酶缺陷有关;精氨基琥珀酸合成酶,与瓜氨酸血症有关;低密度脂蛋白受体蛋白,与家族性高胆固醇血症有关;UDP-葡糖醛酸基转移酶(glucouronosyltransferase),与克里格勒–纳贾尔病有关;腺苷脱氨酶,与严重联合免疫缺陷病有关;次黄嘌呤鸟嘌呤磷酸核糖转移酶,与痛风和莱施–奈恩综合征有关;生物素酶,与生物素酶缺乏有关;β-葡萄糖脑苷脂酶,与戈谢病有关;β-葡萄糖醛酸酶,与Sly综合征有关;过氧化物酶体膜蛋白70kDa,与脑肝肾综合征有关;胆色素原脱氨酶,与急性间歇性卟啉症有关;α-1抗胰蛋白酶治疗α-1抗胰蛋白酶缺乏症(肺气肿);促红细胞生成素用于治疗地中海贫血或肾衰竭引起的贫血;治疗缺血性疾病的血管内皮生长因子、血管生成素-1和成纤维细胞生长因子;用于治疗闭塞血管例如动脉粥样硬化、血栓形成或栓塞的血栓调节蛋白和组织因子途径抑制剂;用于治疗帕金森病的芳香族氨基酸脱羧酶(AADC)和酪氨酸羟化酶(TH);用于治疗充血性心力衰竭的受磷蛋白、sarco(endo)血浆网腺苷三磷酸酶-2(SERCA2)的β肾上腺素能受体,反义或突变形式,以及心脏腺苷酸环化酶;用于治疗各种癌症的p53等肿瘤抑制子基因;细胞因子,例如用于治疗炎症和免疫紊乱和癌症的各种白细胞介素之一;用于治疗肌营养不良症的肌营养不良蛋白或肌营养不良蛋白和肌营养不良蛋白或微小营养素;和,用于治疗糖尿病的胰岛素。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与中枢神经系统(CNS)相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与CNS疾病相关的基因的非限制性列表:DRD2,GRIA1,GRIA2,GRIN1,SLC1A1,SYP,SYT1,CHRNA7,3Rtau/4rTUS,APP,BAX,BCL-2,GRIK1,GFAP,IL-1,AGER,与阿尔茨海默病有关;UCH-L1,SKP1,EGLN1,Nurr-1,BDNF,TrkB,gstm1,S106β,与帕金森病有关;IT15,PRNP,JPH3,TBP,ATXN1,ATXN2,ATXN3,Atrophin 1,FTL,TITF-1,与亨廷顿病相关;FXN,与弗里德赖希共济失调有关;ASPA,与Canavan病有关;DMD,与肌营养不良有关;和SMN1,UBE1,DYNC1H1,与脊髓性肌萎缩有关。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及编码可用于治疗与心血管系统相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与心血管疾病相关的基因的非限制性列表:VEGF、FGF、SDF-1、连接子蛋白40、连接子蛋白43、SCN4a、HIF1α、SERCa2a、ADCY1和ADCY6。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与肺系统相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与肺病相关的基因的非限制性列表:TNFα、TGFβ1、SFTPA1、SFTPA2、SFTPB、SFTPC、HPS1、HPS3、HPS4、ADTB3A、IL1A、IL1B、LTA、IL6、CXCR1和CXCR2。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与肝脏相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与肝病相关的基因的非限制性列表:α1-AT、HFE、ATP7B、富马酰乙酰乙酸水解酶(FAH)、葡萄糖-6-磷酸酶、NCAN、GCKR、LYPLAL1和PNPLA3。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与肾脏相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与肾病相关的基因的非限制性列表:PKD1、PKD2、PKHD1、NPHS1、NPHS2、PLCE1、CD2AP、LAMB2、TRPC6、WT1、LMX1B、SMARCAL1、COQ2、PDSS2、SCARB3、FN1、COL4A5、COL4A6、COL4A3、COL4A4、FOX1C、RET、UPK3A、BMP4、SIX2、CDC5L、USF2、ROBO2、SLIT2、EYA1、MYOG、SIX1、SIX5、FRAS1、FREM2、GATA3、KAL1、PAX2、TCF2和SALL1。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与眼相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与眼病相关的基因的非限制性列表:CFH、C3、MT-ND2、ARMS2、TIMP3、CAMK4、FMN1、RHO、USH2A、RPGR、RP2、TMCO、SIX1、SIX6、LRP12、ZFPM2、TBK1、GALC、肌纤蛋白、CYP1B1、CAV1、CAV2、视神经蛋白和CDKN2B。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与乳房相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与乳房疾病相关的基因的非限制性列表:BRCA1、BRCA2、Tp53、PTEN、HER2、BRAF和PARP1。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与胃肠道相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与胃肠疾病相关的基因的非限制性列表:CYP2C19、CCL26、APC、IL12、IL10和IL-18。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与胰脏相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与胰脏疾病相关的基因的非限制性列表:PRSS1、SPINK1、STK11、MLH1、KRAS2、p16、p53和BRAF。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与尿路相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与尿路疾病相关的基因的非限制性列表:HSPA1B、CXCR1&2、TLR2、TLR4、TGF-1、FGFR3、RB1、HRAS、TP53和TSC1。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
在一些实施方案中,本公开涉及AAV,其包含编码可用于治疗与子宫相关的病况、疾病或病症的蛋白或功能性RNA的核酸。以下是与眼病(ocular disease)相关的基因的非限制性列表:DN-ER、MLH1、MSH2、MSH6、PMS1和PMS2。在一些实施方案中,本公开涉及重组AAV,其包含表达一种或多种前述基因或其片段的核酸。在一些实施方案中,本公开涉及包含表达一种或多种抑制一种或多种前述基因表达的功能性RNA的核酸的重组AAV。
本公开的rAAV能够用于恢复受试者中表达降低、沉默或以其他方式功能失调的基因的表达(例如,已在患有癌症的受试者中沉默的肿瘤抑制因子)。本公开的rAAV还能够用于敲低在受试者中异常表达的基因的表达(例如,在患有癌症的受试者中表达的癌基因)。在一些实施方案中,可以通过向患有癌症的受试者施用携带rAAV载体的rAAV,使用包含编码与癌症相关的基因产物的核酸(例如,肿瘤抑制子)的rAAV载体来治疗癌症。在一些实施方案中,可通过将携带rAAV载体的rAAV施用到患有癌症的受试者,用包含编码小干扰核酸(例如,shRNA、miRNA)的核酸的rAAV载体(其可抑制与癌症相关的基因产物(例如癌基因)的表达)来治疗癌症。在一些实施方案中,包含编码与癌症相关的基因产物的核酸(或抑制与癌症相关的基因表达的功能性RNA)的rAAV载体可用于研究目的,例如,用于研究癌症或鉴定治疗癌症的疗法。以下是已知与癌症发展相关的示例性基因的非限制性列表(例如癌基因和肿瘤抑制子):AARS、ABCB1、ABCC4、ABI2、ABL1、ABL2、ACK1、ACP2、ACY1、ADSL、AK1、AKR1C2、AKT1、ALB、ANPEP、ANXA5、ANXA7、AP2M1、APC、ARHGAP5、ARHGEF5、ARID4A、ASNS、ATF4、ATM、ATP5B、ATP5O、AXL、BARD1、BAX、BCL2、BHLHB2、BLMH、BRAF、BRCA1、BRCA2、BTK、CANX、CAP1、CAPN1、CAPNS1、CAV1、CBFB、CBLB、CCL2、CCND1、CCND2、CCND3、CCNE1、CCT5、CCYR61、CD24、CD44、CD59、CDC20、CDC25、CDC25A、CDC25B、CDC2L5、CDK10、CDK4、CDK5、CDK9、CDKL1、CDKN1A、CDKN1B、CDKN1C、CDKN2A、CDKN2B、CDKN2D、CEBPG、CENPC1、CGRRF1、CHAF1A、CIB1、CKMT1、CLK1、CLK2、CLK3、CLNS1A、CLTC、COL1A1、COL6A3、COX6C、COX7A2、CRAT、CRHR1、CSF1R、CSK、CSNK1G2、CTNNA1、CTNNB1、CTPS、CTSC、CTSD、CUL1、CYR61、DCC、DCN、DDX10、DEK、DHCR7、DHRS2、DHX8、DLG3、DVL1、DVL3、E2F1、E2F3、E2F5、EGFR、EGR1、EIF5、EPHA2、ERBB2、ERBB3、ERBB4、ERCC3、ETV1、ETV3、ETV6、F2R、FASTK、FBN1、FBN2、FES、FGFR1、FGR、FKBP8、FN1、FOS、FOSL1、FOSL2、FOXG1A、FOXO1A、FRAP1、FRZB、FTL、FZD2、FZD5、FZD9、G22P1、GAS6、GCN5L2、GDF15、GNA13、GNAS、GNB2、GNB2L1、GPR39、GRB2、GSK3A、GSPT1、GTF2I、HDAC1、HDGF、HMMR、HPRT1、HRB、HSPA4、HSPA5、HSPA8、HSPB1、HSPH1、HYAL1、HYOU1、ICAM1、ID1、ID2、IDUA、IER3、IFITM1、IGF1R、IGF2R、IGFBP3、IGFBP4、IGFBP5、IL1B、ILK、ING1、IRF3、ITGA3、ITGA6、ITGB4、JAK1、JARID1A、JUN、JUNB、JUND、K-ALPHA-1、KIT、KITLG、KLK10、KPNA2、KRAS2、KRT18、KRT2A、KRT9、LAMB1、LAMP2、LCK、LCN2、LEP、LITAF、LRPAP1、LTF、LYN、LZTR1、MADH1、MAP2K2、MAP3K8、MAPK12、MAPK13、MAPKAPK3、MAPRE1、MARS、MAS1、MCC、MCM2、MCM4、MDM2、MDM4、MET、MGST1、MICB、MLLT3、MME、MMP1、MMP14、MMP17、MMP2、MNDA、MSH2、MSH6、MT3、MYB、MYBL1、MYBL2、MYC、MYCL1、MYCN、MYD88、MYL9、MYLK、NEO1、NF1、NF2、NFKB1、NFKB2、NFSF7、NID、NINJ1、NMBR、NME1、NME2、NME3、NOTCH1、NOTCH2、NOTCH4、NPM1、NQO1、NR1D1、NR2F1、NR2F6、NRAS、NRG1、NSEP1、OSM、PA2G4、PABPC1、PCNA、PCTK1、PCTK2、PCTK3、PDGFA、PDGFB、PDGFRA、PDPK1、PEA15、PFDN4、PFDN5、PGAM1、PHB、PIK3CA、PIK3CB、PIK3CG、PIM1、PKM2、PKMYT1、PLK2、PPARD、PPARG、PPIH、PPP1CA、PPP2R5A、PRDX2、PRDX4、PRKAR1A、PRKCBP1、PRNP、PRSS15、PSMA1、PTCH、PTEN、PTGS1、PTMA、PTN、PTPRN、RAB5A、RAC1、RAD50、RAF1、RALBP1、RAP1A、RARA、RARB、RASGRF1、RB1、RBBP4、RBL2、REA、REL、RELA、RELB、RET、RFC2、RGS19、RHOA、RHOB、RHOC、RHOD、RIPK1、RPN2、RPS6KB1、RRM1、SARS、SELENBP1、SEMA3C、SEMA4D、SEPP1、SERPINH1、SFN、SFPQ、SFRS7、SHB、SHH、SIAH2、SIVA、SIVA TP53、SKI、SKIL、SLC16A1、SLC1A4、SLC20A1、SMO、SMPD1、SNAI2、SND1、SNRPB2、SOCS1、SOCS3、SOD1、SORT1、SPINT2、SPRY2、SRC、SRPX、STAT1、STAT2、STAT3、STAT5B、STC1、TAF1、TBL3、TBRG4、TCF1、TCF7L2、TFAP2C、TFDP1、TFDP2、TGFA、TGFB1、TGFBI、TGFBR2、TGFBR3、THBS1、TIE、TIMP1、TIMP3、TJP1、TK1、TLE1、TNF、TNFRSF10A、TNFRSF10B、TNFRSF1A、TNFRSF1B、TNFRSF6、TNFSF7、TNK1、TOB1、TP53、TP53BP2、TP53I3、TP73、TPBG、TPT1、TRADD、TRAM1、TRRAP、TSG101、TUFM、TXNRD1、TYRO3、UBC、UBE2L6、UCHL1、USP7、VDAC1、VEGF、VHL、VIL2、WEE1、WNT1、WNT2、WNT2B、WNT3、WNT5A、WT1、XRCC1、YES1、YWHAB、YWHAZ、ZAP70和ZNF9。
rAAV载体可以包含作为转基因的编码调节细胞凋亡的蛋白或功能性RNA的核酸。以下是与细胞凋亡相关的基因和编码这些基因及其同源物的产物的核酸和编码抑制这些基因及其在本公开的某些实施方案中用作转基因的同源物的表达的小干扰核酸(例如,shRNA、miRNA)的核酸的非限制性列表:RPS27A、ABL1、AKT1、APAF1、BAD、BAG1、BAG3、BAG4、BAK1、BAX、BCL10、BCL2、BCL2A1、BCL2L1、BCL2L10、BCL2L11、BCL2L12、BCL2L13、BCL2L2、BCLAF1、BFAR、BID、BIK、NAIP、BIRC2、BIRC3、XIAP、BIRC5、BIRC6、BIRC7、BIRC8、BNIP1、BNIP2、BNIP3、BNIP3L、BOK、BRAF、CARD10、CARD11、NLRC4、CARD14、NOD2、NOD1、CARD6、CARD8、CARD9、CASP1、CASP10、CASP14、CASP2、CASP3、CASP4、CASP5、CASP6、CASP7、CASP8、CASP9、CFLAR、CIDEA、CIDEB、CRADD、DAPK1、DAPK2、DFFA、DFFB、FADD、GADD45A、GDNF、HRK、IGF1R、LTA、LTBR、MCL1、NOL3、PYCARD、RIPK1、RIPK2、TNF、TNFRSF10A、TNFRSF10B、TNFRSF10C、TNFRSF10D、TNFRSF11B、TNFRSF12A、TNFRSF14、TNFRSF19、TNFRSF1A、TNFRSF1B、TNFRSF21、TNFRSF25、CD40、FAS、TNFRSF6B、CD27、TNFRSF9、TNFSF10、TNFSF14、TNFSF18、CD40LG、FASLG、CD70、TNFSF8、TNFSF9、TP53、TP53BP2、TP73、TP63、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5DRD2、GRIA1、GRIA2,GRIN1、SLC1A1、SYP、SYT1、CHRNA7、3Rtau/4rTUS、APP、BAX、BCL-2、GRIK1、GFAP、IL-1、AGER、UCH-L1、SKP1、EGLN1、Nurr-1、BDNF、TrkB、gstm1、S106β、IT15、PRNP、JPH3、TBP、ATXN1、ATXN2、ATXN3、Atrophin 1、FTL、TITF-1、FXN、ASPA、DMD和SMN1、UBE1、DYNC1H1。
本领域技术人员还将认识到,在编码蛋白或多肽的转基因的情况下,可以在转基因中产生导致保守氨基酸取代的突变,以提供功能等同的变体或蛋白或多肽的同源物。在一些方面,本公开包括导致转基因的保守氨基酸取代的序列改变。在一些实施方案中,转基因包含具有显性失活突变的基因。例如,转基因可以表达与野生型蛋白相同元件相互作用的突变蛋白,从而阻断野生型蛋白功能的某些方面。
有用的转基因产物还包括miRNA。miRNA和其他小干扰核酸通过靶RNA转录物切割/降解或靶信使RNA(mRNA)的翻译抑制来调节基因表达。通常,miRNA天然表达为最终的19-25个非翻译RNA产物。miRNA通过与靶mRNA的3'非翻译区(UTR)的序列特异性相互作用显示其活性。这些内源表达的miRNA形成发夹前体,其随后加工成miRNA双链体,并进一步加工成“成熟的”单链miRNA分子。该成熟miRNA指导多蛋白复合物miRISC,其基于它们与成熟miRNA的互补性识别靶mRNA的靶位点,例如在3'UTR区中。
以下非限制性的miRNA基因列表及其同源物可用作在该方法的某些实施方案中的转基因或作为转基因编码的小干扰核酸的靶标(例如,miRNA海绵、反义寡核苷酸,TuDRNA):hsa-let-7a、hsa-let-7a*、hsa-let-7b、hsa-let-7b*、hsa-let-7c、hsa-let-7c*、hsa-let-7d、hsa-let-7d*、hsa-let-7e、hsa-let-7e*、hsa-let-7f、hsa-let-7f-1*、hsa-let-7f-2*、hsa-let-7g、hsa-let-7g*、hsa-let-7i、hsa-let-7i*、hsa-miR-1、hsa-miR-100、hsa-miR-100*、hsa-miR-101、hsa-miR-101*、hsa-miR-103、hsa-miR-105、hsa-miR-105*、hsa-miR-106a、hsa-miR-106a*、hsa-miR-106b、hsa-miR-106b*、hsa-miR-107、hsa-miR-10a、hsa-miR-10a*、hsa-miR-10b、hsa-miR-10b*、hsa-miR-1178、hsa-miR-1179、hsa-miR-1180、hsa-miR-1181、hsa-miR-1182、hsa-miR-1183、hsa-miR-1184、hsa-miR-1185、hsa-miR-1197、hsa-miR-1200、hsa-miR-1201、hsa-miR-1202、hsa-miR-1203、hsa-miR-1204、hsa-miR-1205、hsa-miR-1206、hsa-miR-1207-3p、hsa-miR-1207-5p、hsa-miR-1208、hsa-miR-122、hsa-miR-122*、hsa-miR-1224-3p、hsa-miR-1224-5p、hsa-miR-1225-3p、hsa-miR-1225-5p、hsa-miR-1226、hsa-miR-1226*、hsa-miR-1227、hsa-miR-1228、hsa-miR-1228*、hsa-miR-1229、hsa-miR-1231、hsa-miR-1233、hsa-miR-1234、hsa-miR-1236、hsa-miR-1237、hsa-miR-1238、hsa-miR-124、hsa-miR-124*、hsa-miR-1243、hsa-miR-1244、hsa-miR-1245、hsa-miR-1246、hsa-miR-1247、hsa-miR-1248、hsa-miR-1249、hsa-miR-1250、hsa-miR-1251、hsa-miR-1252、hsa-miR-1253、hsa-miR-1254、hsa-miR-1255a、hsa-miR-1255b、hsa-miR-1256、hsa-miR-1257、hsa-miR-1258、hsa-miR-1259、hsa-miR-125a-3p、hsa-miR-125a-5p、hsa-miR-125b、hsa-miR-125b-1*、hsa-miR-125b-2*、hsa-miR-126、hsa-miR-126*、hsa-miR-1260、hsa-miR-1261、hsa-miR-1262、hsa-miR-1263、hsa-miR-1264、hsa-miR-1265、hsa-miR-1266、hsa-miR-1267、hsa-miR-1268、hsa-miR-1269、hsa-miR-1270、hsa-miR-1271、hsa-miR-1272、hsa-miR-1273、hsa-miR-127-3p、hsa-miR-1274a、hsa-miR-1274b、hsa-miR-1275、hsa-miR-127-5p、hsa-miR-1276、hsa-miR-1277、hsa-miR-1278、hsa-miR-1279、hsa-miR-128、hsa-miR-1280、hsa-miR-1281、hsa-miR-1282、hsa-miR-1283、hsa-miR-1284、hsa-miR-1285、hsa-miR-1286、hsa-miR-1287、hsa-miR-1288、hsa-miR-1289、hsa-miR-129*、hsa-miR-1290、hsa-miR-1291、hsa-miR-1292、hsa-miR-1293、hsa-miR-129-3p、hsa-miR-1294、hsa-miR-1295、hsa-miR-129-5p、hsa-miR-1296、hsa-miR-1297、hsa-miR-1298、hsa-miR-1299、hsa-miR-1300、hsa-miR-1301、hsa-miR-1302、hsa-miR-1303、hsa-miR-1304、hsa-miR-1305、hsa-miR-1306、hsa-miR-1307、hsa-miR-1308、hsa-miR-130a、hsa-miR-130a*、hsa-miR-130b、hsa-miR-130b*、hsa-miR-132、hsa-miR-132*、hsa-miR-1321、hsa-miR-1322、hsa-miR-1323、hsa-miR-1324、hsa-miR-133a、hsa-miR-133b、hsa-miR-134、hsa-miR-135a、hsa-miR-135a*、hsa-miR-135b、hsa-miR-135b*、hsa-miR-136、hsa-miR-136*、hsa-miR-137、hsa-miR-138、hsa-miR-138-1*、hsa-miR-138-2*、hsa-miR-139-3p、hsa-miR-139-5p、hsa-miR-140-3p、hsa-miR-140-5p、hsa-miR-141、hsa-miR-141*、hsa-miR-142-3p、hsa-miR-142-5p、hsa-miR-143、hsa-miR-143*、hsa-miR-144、hsa-miR-144*、hsa-miR-145、hsa-miR-145*、hsa-miR-146a、hsa-miR-146a*、hsa-miR-146b-3p、hsa-miR-146b-5p、hsa-miR-147、hsa-miR-147b、hsa-miR-148a、hsa-miR-148a*、hsa-miR-148b、hsa-miR-148b*、hsa-miR-149、hsa-miR-149*、hsa-miR-150、hsa-miR-150*、hsa-miR-151-3p、hsa-miR-151-5p、hsa-miR-152、hsa-miR-153、hsa-miR-154、hsa-miR-154*、hsa-miR-155、hsa-miR-155*、hsa-miR-15a、hsa-miR-15a*、hsa-miR-15b、hsa-miR-15b*、hsa-miR-16、hsa-miR-16-1*、hsa-miR-16-2*、hsa-miR-17、hsa-miR-17*、hsa-miR-181a、hsa-miR-181a*、hsa-miR-181a-2*、hsa-miR-181b、hsa-miR-181c、hsa-miR-181c*、hsa-miR-181d、hsa-miR-182、hsa-miR-182*、hsa-miR-1825、hsa-miR-1826、hsa-miR-1827、hsa-miR-183、hsa-miR-183*、hsa-miR-184、hsa-miR-185、hsa-miR-185*、hsa-miR-186、hsa-miR-186*、hsa-miR-187、hsa-miR-187*、hsa-miR-188-3p、hsa-miR-188-5p、hsa-miR-18a、hsa-miR-18a*、hsa-miR-18b、hsa-miR-18b*、hsa-miR-190、hsa-miR-190b、hsa-miR-191、hsa-miR-191*、hsa-miR-192、hsa-miR-192*、hsa-miR-193a-3p、hsa-miR-193a-5p、hsa-miR-193b、hsa-miR-193b*、hsa-miR-194、hsa-miR-194*、hsa-miR-195、hsa-miR-195*、hsa-miR-196a、hsa-miR-196a*、hsa-miR-196b、hsa-miR-197、hsa-miR-198、hsa-miR-199a-3p、hsa-miR-199a-5p、hsa-miR-199b-5p、hsa-miR-19a、hsa-miR-19a*、hsa-miR-19b、hsa-miR-19b-1*、hsa-miR-19b-2*、hsa-miR-200a、hsa-miR-200a*、hsa-miR-200b、hsa-miR-200b*、hsa-miR-200c、hsa-miR-200c*、hsa-miR-202、hsa-miR-202*、hsa-miR-203、hsa-miR-204、hsa-miR-205、hsa-miR-206、hsa-miR-208a、hsa-miR-208b、hsa-miR-20a、hsa-miR-20a*、hsa-miR-20b、hsa-miR-20b*、hsa-miR-21、hsa-miR-21*、hsa-miR-210、hsa-miR-211、hsa-miR-212、hsa-miR-214、hsa-miR-214*、hsa-miR-215、hsa-miR-216a、hsa-miR-216b、hsa-miR-217、hsa-miR-218、hsa-miR-218-1*、hsa-miR-218-2*、hsa-miR-219-1-3p、hsa-miR-219-2-3p、hsa-miR-219-5p、hsa-miR-22、hsa-miR-22*、hsa-miR-220a、hsa-miR-220b、hsa-miR-220c、hsa-miR-221、hsa-miR-221*、hsa-miR-222、hsa-miR-222*、hsa-miR-223、hsa-miR-223*、hsa-miR-224、hsa-miR-23a、hsa-miR-23a*、hsa-miR-23b、hsa-miR-23b*、hsa-miR-24、hsa-miR-24-1*、hsa-miR-24-2*、hsa-miR-25、hsa-miR-25*、hsa-miR-26a、hsa-miR-26a-1*、hsa-miR-26a-2*、hsa-miR-26b、hsa-miR-26b*、hsa-miR-27a、hsa-miR-27a*、hsa-miR-27b、hsa-miR-27b*、hsa-miR-28-3p、hsa-miR-28-5p、hsa-miR-296-3p、hsa-miR-296-5p、hsa-miR-297、hsa-miR-298、hsa-miR-299-3p、hsa-miR-299-5p、hsa-miR-29a、hsa-miR-29a*、hsa-miR-29b、hsa-miR-29b-1*、hsa-miR-29b-2*、hsa-miR-29c、hsa-miR-29c*、hsa-miR-300、hsa-miR-301a、hsa-miR-301b、hsa-miR-302a、hsa-miR-302a*、hsa-miR-302b、hsa-miR-302b*、hsa-miR-302c、hsa-miR-302c*、hsa-miR-302d、hsa-miR-302d*、hsa-miR-302e、hsa-miR-302f、hsa-miR-30a、hsa-miR-30a*、hsa-miR-30b、hsa-miR-30b*、hsa-miR-30c、hsa-miR-30c-1*、hsa-miR-30c-2*、hsa-miR-30d、hsa-miR-30d*、hsa-miR-30e、hsa-miR-30e*、hsa-miR-31、hsa-miR-31*、hsa-miR-32、hsa-miR-32*、hsa-miR-320a、hsa-miR-320b、hsa-miR-320c、hsa-miR-320d、hsa-miR-323-3p、hsa-miR-323-5p、hsa-miR-324-3p、hsa-miR-324-5p、hsa-miR-325、hsa-miR-326、hsa-miR-328、hsa-miR-329、hsa-miR-330-3p、hsa-miR-330-5p、hsa-miR-331-3p、hsa-miR-331-5p、hsa-miR-335、hsa-miR-335*、hsa-miR-337-3p、hsa-miR-337-5p、hsa-miR-338-3p、hsa-miR-338-5p、hsa-miR-339-3p、hsa-miR-339-5p、hsa-miR-33a、hsa-miR-33a*、hsa-miR-33b、hsa-miR-33b*、hsa-miR-340、hsa-miR-340*、hsa-miR-342-3p、hsa-miR-342-5p、hsa-miR-345、hsa-miR-346、hsa-miR-34a、hsa-miR-34a*、hsa-miR-34b、hsa-miR-34b*、hsa-miR-34c-3p、hsa-miR-34c-5p、hsa-miR-361-3p、hsa-miR-361-5p、hsa-miR-362-3p、hsa-miR-362-5p、hsa-miR-363、hsa-miR-363*、hsa-miR-365、hsa-miR-367、hsa-miR-367*、hsa-miR-369-3p、hsa-miR-369-5p、hsa-miR-370、hsa-miR-371-3p、hsa-miR-371-5p、hsa-miR-372、hsa-miR-373、hsa-miR-373*、hsa-miR-374a、hsa-miR-374a*、hsa-miR-374b、hsa-miR-374b*、hsa-miR-375、hsa-miR-376a、hsa-miR-376a*、hsa-miR-376b、hsa-miR-376c、hsa-miR-377、hsa-miR-377*、hsa-miR-378、hsa-miR-378*、hsa-miR-379、hsa-miR-379*、hsa-miR-380、hsa-miR-380*、hsa-miR-381、hsa-miR-382、hsa-miR-383、hsa-miR-384、hsa-miR-409-3p、hsa-miR-409-5p、hsa-miR-410、hsa-miR-411、hsa-miR-411*、hsa-miR-412、hsa-miR-421、hsa-miR-422a、hsa-miR-423-3p、hsa-miR-423-5p、hsa-miR-424、hsa-miR-424*、hsa-miR-425、hsa-miR-425*、hsa-miR-429、hsa-miR-431、hsa-miR-431*、hsa-miR-432、hsa-miR-432*、hsa-miR-433、hsa-miR-448、hsa-miR-449a、hsa-miR-449b、hsa-miR-450a、hsa-miR-450b-3p、hsa-miR-450b-5p、hsa-miR-451、hsa-miR-452、hsa-miR-452*、hsa-miR-453、hsa-miR-454、hsa-miR-454*、hsa-miR-455-3p、hsa-miR-455-5p、hsa-miR-483-3p、hsa-miR-483-5p、hsa-miR-484、hsa-miR-485-3p、hsa-miR-485-5p、hsa-miR-486-3p、hsa-miR-486-5p、hsa-miR-487a、hsa-miR-487b、hsa-miR-488、hsa-miR-488*、hsa-miR-489、hsa-miR-490-3p、hsa-miR-490-5p、hsa-miR-491-3p、hsa-miR-491-5p、hsa-miR-492、hsa-miR-493、hsa-miR-493*、hsa-miR-494、hsa-miR-495、hsa-miR-496、hsa-miR-497、hsa-miR-497*、hsa-miR-498、hsa-miR-499-3p、hsa-miR-499-5p、hsa-miR-500、hsa-miR-500*、hsa-miR-501-3p、hsa-miR-501-5p、hsa-miR-502-3p、hsa-miR-502-5p、hsa-miR-503、hsa-miR-504、hsa-miR-505、hsa-miR-505*、hsa-miR-506、hsa-miR-507、hsa-miR-508-3p、hsa-miR-508-5p、hsa-miR-509-3-5p、hsa-miR-509-3p、hsa-miR-509-5p、hsa-miR-510、hsa-miR-511、hsa-miR-512-3p、hsa-miR-512-5p、hsa-miR-513a-3p、hsa-miR-513a-5p、hsa-miR-513b、hsa-miR-513c、hsa-miR-514、hsa-miR-515-3p、hsa-miR-515-5p、hsa-miR-516a-3p、hsa-miR-516a-5p、hsa-miR-516b、hsa-miR-517*、hsa-miR-517a、hsa-miR-517b、hsa-miR-517c、hsa-miR-518a-3p、hsa-miR-518a-5p、hsa-miR-518b、hsa-miR-518c、hsa-miR-518c*、hsa-miR-518d-3p、hsa-miR-518d-5p、hsa-miR-518e、hsa-miR-518e*、hsa-miR-518f、hsa-miR-518f*、hsa-miR-519a、hsa-miR-519b-3p、hsa-miR-519c-3p、hsa-miR-519d、hsa-miR-519e、hsa-miR-519e*、hsa-miR-520a-3p、hsa-miR-520a-5p、hsa-miR-520b、hsa-miR-520c-3p、hsa-miR-520d-3p、hsa-miR-520d-5p、hsa-miR-520e、hsa-miR-520f、hsa-miR-520g、hsa-miR-520h、hsa-miR-521、hsa-miR-522、hsa-miR-523、hsa-miR-524-3p、hsa-miR-524-5p、hsa-miR-525-3p、hsa-miR-525-5p、hsa-miR-526b、hsa-miR-526b*、hsa-miR-532-3p、hsa-miR-532-5p、hsa-miR-539、hsa-miR-541、hsa-miR-541*、hsa-miR-542-3p、hsa-miR-542-5p、hsa-miR-543、hsa-miR-544、hsa-miR-545、hsa-miR-545*、hsa-miR-548a-3p、hsa-miR-548a-5p、hsa-miR-548b-3p、hsa-miR-548b-5p、hsa-miR-548c-3p、hsa-miR-548c-5p、hsa-miR-548d-3p、hsa-miR-548d-5p、hsa-miR-548e、hsa-miR-548f、hsa-miR-548g、hsa-miR-548h、hsa-miR-548i、hsa-miR-548j、hsa-miR-548k、hsa-miR-548l、hsa-miR-548m、hsa-miR-548n、hsa-miR-548o、hsa-miR-548p、hsa-miR-549、hsa-miR-550、hsa-miR-550*、hsa-miR-551a、hsa-miR-551b、hsa-miR-551b*、hsa-miR-552、hsa-miR-553、hsa-miR-554、hsa-miR-555、hsa-miR-556-3p、hsa-miR-556-5p、hsa-miR-557、hsa-miR-558、hsa-miR-559、hsa-miR-561、hsa-miR-562、hsa-miR-563、hsa-miR-564、hsa-miR-566、hsa-miR-567、hsa-miR-568、hsa-miR-569、hsa-miR-570、hsa-miR-571、hsa-miR-572、hsa-miR-573、hsa-miR-574-3p、hsa-miR-574-5p、hsa-miR-575、hsa-miR-576-3p、hsa-miR-576-5p、hsa-miR-577、hsa-miR-578、hsa-miR-579、hsa-miR-580、hsa-miR-581、hsa-miR-582-3p、hsa-miR-582-5p、hsa-miR-583、hsa-miR-584、hsa-miR-585、hsa-miR-586、hsa-miR-587、hsa-miR-588、hsa-miR-589、hsa-miR-589*、hsa-miR-590-3p、hsa-miR-590-5p、hsa-miR-591、hsa-miR-592、hsa-miR-593、hsa-miR-593*、hsa-miR-595、hsa-miR-596、hsa-miR-597、hsa-miR-598、hsa-miR-599、hsa-miR-600、hsa-miR-601、hsa-miR-602、hsa-miR-603、hsa-miR-604、hsa-miR-605、hsa-miR-606、hsa-miR-607、hsa-miR-608、hsa-miR-609、hsa-miR-610、hsa-miR-611、hsa-miR-612、hsa-miR-613、hsa-miR-614、hsa-miR-615-3p、hsa-miR-615-5p、hsa-miR-616、hsa-miR-616*、hsa-miR-617、hsa-miR-618、hsa-miR-619、hsa-miR-620、hsa-miR-621、hsa-miR-622、hsa-miR-623、hsa-miR-624、hsa-miR-624*、hsa-miR-625、hsa-miR-625*、hsa-miR-626、hsa-miR-627、hsa-miR-628-3p、hsa-miR-628-5p、hsa-miR-629、hsa-miR-629*、hsa-miR-630、hsa-miR-631、hsa-miR-632、hsa-miR-633、hsa-miR-634、hsa-miR-635、hsa-miR-636、hsa-miR-637、hsa-miR-638、hsa-miR-639、hsa-miR-640、hsa-miR-641、hsa-miR-642、hsa-miR-643、hsa-miR-644、hsa-miR-645、hsa-miR-646、hsa-miR-647、hsa-miR-648、hsa-miR-649、hsa-miR-650、hsa-miR-651、hsa-miR-652、hsa-miR-653、hsa-miR-654-3p、hsa-miR-654-5p、hsa-miR-655、hsa-miR-656、hsa-miR-657、hsa-miR-658、hsa-miR-659、hsa-miR-660、hsa-miR-661、hsa-miR-662、hsa-miR-663、hsa-miR-663b、hsa-miR-664、hsa-miR-664*、hsa-miR-665、hsa-miR-668、hsa-miR-671-3p、hsa-miR-671-5p、hsa-miR-675、hsa-miR-7、hsa-miR-708、hsa-miR-708*、hsa-miR-7-1*、hsa-miR-7-2*、hsa-miR-720、hsa-miR-744、hsa-miR-744*、hsa-miR-758、hsa-miR-760、hsa-miR-765、hsa-miR-766、hsa-miR-767-3p、hsa-miR-767-5p、hsa-miR-768-3p、hsa-miR-768-5p、hsa-miR-769-3p、hsa-miR-769-5p、hsa-miR-770-5p、hsa-miR-802、hsa-miR-873、hsa-miR-874、hsa-miR-875-3p、hsa-miR-875-5p、hsa-miR-876-3p、hsa-miR-876-5p、hsa-miR-877、hsa-miR-877*、hsa-miR-885-3p、hsa-miR-885-5p、hsa-miR-886-3p、hsa-miR-886-5p、hsa-miR-887、hsa-miR-888、hsa-miR-888*、hsa-miR-889、hsa-miR-890、hsa-miR-891a、hsa-miR-891b、hsa-miR-892a、hsa-miR-892b、hsa-miR-9、hsa-miR-9*、hsa-miR-920、hsa-miR-921、hsa-miR-922、hsa-miR-923、hsa-miR-924、hsa-miR-92a、hsa-miR-92a-1*、hsa-miR-92a-2*、hsa-miR-92b、hsa-miR-92b*、hsa-miR-93、hsa-miR-93*、hsa-miR-933、hsa-miR-934、hsa-miR-935、hsa-miR-936、hsa-miR-937、hsa-miR-938、hsa-miR-939、hsa-miR-940、hsa-miR-941、hsa-miR-942、hsa-miR-943、hsa-miR-944、hsa-miR-95、hsa-miR-96、hsa-miR-96*、hsa-miR-98、hsa-miR-99a、hsa-miR-99a*、hsa-miR-99b和hsa-miR-99b*。
miRNA抑制其靶向的mRNA的功能,并因此抑制由mRNA编码的多肽的表达。因此,阻断(部分或完全)miRNA的活性(例如,沉默miRNA)可以有效地诱导或恢复表达被抑制的多肽的表达(对多肽去阻遏)。在一个实施方案中,通过miRNA的mRNA靶标编码的多肽的去阻遏是通过多种方法中的任何一种抑制细胞中的miRNA活性来实现的。例如,阻断miRNA的活性可以通过与miRNA互补或基本上互补的小干扰核酸(例如,反义寡核苷酸、miRNA海绵、TuDRNA)杂交来实现,从而阻断miRNA与其靶mRNA的相互作用。如本文所用,与miRNA基本上互补的小干扰核酸是能够与miRNA杂交并阻断miRNA活性的核酸。在一些实施方案中,与miRNA基本上互补的小干扰核酸是除了1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碱基之外与miRNA完全互补的小干扰核酸。在一些实施方案中,小干扰核酸序列与miRNA基本上互补,或者是与具有至少一个碱基的miRNA互补的小干扰核酸序列。
“miRNA抑制剂”是阻断miRNA功能、表达和/或加工的药剂。例如,这些分子包括但不限于抑制miRNA与Drosha复合物相互作用的微小RNA特异性反义、微小RNA海绵、坚韧诱饵RNA(TuD RNA)和微小RNA寡核苷酸(双链、发夹、短寡核苷酸)。如上所述,微小RNA抑制剂能够在来自rAAV载体的转基因的细胞中表达。微小RNA海绵通过互补的七聚体种子序列特异性地抑制miRNA(Ebert,M.S.Nature Methods,Epub 8月,12,2007)。在一些实施方案中,可以使用单个海绵序列沉默整个miRNA家族。TuD RNA实现对哺乳动物细胞中特定miRNA的有效和长期抑制(参见,例如,Takeshi Haraguchi,等人,Nucleic Acids Research,2009,Vol.37,No.6e43,其涉及TuD RNA的内容通过引用并入本文)。用于沉默细胞中miRNA功能(miRNA靶标的去阻遏)的其他方法对于本领域普通技术人员而言是显而易见的。
在一些实施方案中,重组RNA载体的克隆能力(capacity)可能限制所需的编码序列,并且可能需要完全替换病毒的4.8千碱基基因组。因此,在某些情况下,大基因可能不适合用于标准重组AAV载体。本领域技术人员将理解,本领域中可获得用于克服有限编码能力的选项。例如,两个基因组的AAV ITR可以退火形成头对尾的连环体,几乎使载体的能力加倍。剪接位点的插入允许从转录物中去除ITR。克服有限克隆能力的其他选择对于技术人员来说是显而易见的。
使用基于rAAV的基因转移产生的体细胞转基因动物模型
本公开还涉及使用基于重组腺相关病毒(rAAV)的方法生产疾病的体细胞转基因动物模型。该方法至少部分基于AAV血清型及其变体在成年动物中以组织特异性方式介导有效和稳定的基因转移的观察结果。将rAAV元件(衣壳、启动子、转基因产物)组合以获得以时间和组织特异性方式表达稳定转基因的体细胞转基因动物模型。通过本公开的方法产生的体细胞转基因动物可以用作人类疾病、病理状态和/或表征基因的作用的有用模型,其功能(例如,组织特异性、疾病作用)未知或不完全了解。例如,动物(例如,小鼠)可以在不同发育阶段(例如,年龄)用rAAV感染,所述rAAV包含具有特定组织靶向能力(例如,肝脏、心脏、胰腺)的衣壳和具有组织特异性启动子驱动参与疾病的基因的表达的转基因。感染后,rAAV感染靶组织的不同细胞并产生转基因产物。
在一些实施方案中,修饰转基因的编码区的序列。修饰可以改变由转基因编码的产物的功能。然后通过使用本文公开的方法产生体细胞转基因动物模型能够在体内研究修饰的效果。在一些实施方案中,编码区序列的修饰是无义突变,其产生片段(例如,截短形式)。在其他情况下,修饰是错义突变,其导致氨基酸取代。其他修改是可能的并且对于本领域技术人员而言是显而易见的。
在一些实施方案中,转基因引起病理状态。导致病理状态的转基因是其产物在疾病或病症中起作用(例如,引起疾病或病症,使动物易患疾病或病症)和/或可诱导动物疾病或病症的基因。然后能够观察动物以评估疾病的任何数量的方面(例如,进展,对治疗的反应等)。这些实施例不意味着限制,其他方面和实例在本文中公开并在下面更详细地描述。
在一些方面,本公开提供了通过靶向破坏特定细胞类型来产生体细胞转基因动物模型的方法。例如,1型糖尿病的模型可以通过胰腺β胰岛的靶向破坏来产生。在其他实例中,特定细胞类型的靶向破坏可用于评估特定细胞类型对人类疾病的作用。在这方面,编码细胞毒素(例如,白喉毒素A(DTA))或促凋亡基因(NTR、Box等)的转基因能够用作特定细胞类型的功能性消融的转基因。其产物杀死细胞的其他示例性转基因包括在本文公开的方法中,并且对于本领域普通技术人员而言是显而易见的。
在一些方面,本公开提供了用于产生体细胞转基因动物模型以研究基因过表达或敲低的长期效应的方法。特定靶组织中基因的长期过表达或敲低(例如,通过shRNA、miRNA、miRNA抑制剂等)能够干扰正常的代谢平衡并建立病理状态,从而产生疾病例如癌症的动物模型。在一些方面,本公开提供了产生体细胞转基因动物模型的方法,所述方法用于研究潜在致癌基因和其他基因的过表达或敲低基因的长期作用,以及用于研究靶组织中的肿瘤发生和基因功能。有用的转基因产物包括已知与癌症相关的蛋白和抑制这些蛋白表达的小干扰核酸。
本领域技术人员可以容易地选择其他合适的转基因,条件是它们可用于产生组织特异性病理状态和/或疾病的动物模型。
重组AAV施用方法
可以根据本领域已知的任何适当方法以组合物形式将rAAV递送至受试者。优选悬浮在生理学上相容的载体中(例如在组合物中)的rAAV可以施用于受试者,例如宿主动物,例如人、小鼠、大鼠、猫、狗、绵羊、兔、马、牛、山羊、猪、豚鼠、仓鼠、鸡、火鸡或非人灵长类动物(如猕猴)。在一些实施方案中,宿主动物不包括人。
将rAAV递送至哺乳动物受试者可以通过例如肌内注射或通过施用于哺乳动物受试者的血流。可以通过注射到静脉、动脉或任何其他血管中来施用到血流中。在一些实施方案中,通过分离的肢体灌注将rAAV施用到血流中,所述分离的肢体灌注是外科领域中公知的技术,该方法基本上使技术人员能够在施用rAAV病毒体之前将肢体与体循环分离。本领域技术人员还可以使用描述于美国专利No.6,177,403中的分离的肢体灌注技术的变形将病毒体施用到分离的肢体的脉管系统中,以潜在地增强对肌肉细胞或组织的转导。此外,在某些情况下,可能需要将病毒体递送至受试者的CNS。“CNS”是指脊椎动物的脑和脊髓的所有细胞和组织。因此,该术语包括但不限于神经元细胞、神经胶质细胞、星形胶质细胞、脑脊髓液(CSF)、间质空间、骨、软骨等。重组AAV可以通过注射到例如心室区域以及纹状体(例如,纹状体的尾状核或壳核)、脊髓和神经肌肉接头或小脑小叶,直接递送至CNS或脑,所述注射使用针、导管或相关装置,使用本领域已知的神经外科技术,例如通过立体定向注射(参见,例如Stein等人,J Virol 73:3424-3429,1999;Davidson等人,PNAS 97:3428-3432,2000;Davidson等人,Nat.Genet.3:219-223,1993;和Alisky和Davidson,Hum.GeneTher.11:2315-2329,2000)。
本公开的组合物可以单独包含rAAV,或者与一种或多种其他病毒(例如,具有一种或多种不同转基因的第二种rAAV编码)组合。在一些实施方案中,组合物包含1、2、3、4、5、6、7、8、9、10或更多种不同的rAAV,每种rAAV具有一种或多种不同的转基因。
考虑到rAAV所针对的适应症,本领域技术人员可以容易地选择合适的载体。例如,一种合适的载体包括盐水,其可以用各种缓冲溶液(例如磷酸盐缓冲盐水)配制。其他示例性载体包括无菌盐水、乳糖、蔗糖、磷酸钙、明胶、葡聚糖、琼脂、果胶、花生油、芝麻油和水。载体的选择不是对本公开的限制。
任选地,除了rAAV和载体之外,本公开的组合物可以含有其他常规药物成分,例如防腐剂或化学稳定剂。合适的示例性防腐剂包括氯丁醇、山梨酸钾、山梨酸、二氧化硫、没食子酸丙酯、对羟基苯甲酸酯、乙基香草醛、甘油、苯酚和对氯苯酚。合适的化学稳定剂包括明胶和白蛋白。
以足够的量施用rAAV以转染所需组织的细胞,并提供足够水平的基因转移和表达,而没有过度的不利影响。常规和药学上可接受的施用途径包括但不限于直接递送至所选器官(例如,门静脉递送到肝脏)、口服、吸入(包括鼻内和气管内递送)、眼内、静脉内、肌肉内、皮下、皮内、瘤内和其他肠胃外的施用途径。如果需要,可以组合施用途径。
实现特定“治疗效果”所需的rAAV病毒体的剂量,例如基因组拷贝/每千克体重(GC/kg)中的剂量单位,将基于若干因素而变化,包括但不限于:rAAV病毒体施用途径,达到治疗效果所需的基因或RNA表达水平,所治疗的特定疾病或病症,以及基因或RNA产物的稳定性。基于上述因素以及本领域众所周知的其他因素,本领域技术人员可以容易地确定rAAV病毒体剂量范围以治疗患有特定疾病或病症的患者。
有效量的rAAV是足以靶向感染动物、靶向期望组织的量。在一些实施方案中,有效量的rAAV是足以产生稳定的体细胞转基因动物模型的量。有效量主要取决于诸如物种、年龄、体重、受试者健康和待靶向组织等因素,因此可在动物或组织之间变化。例如,有效量的rAAV通常在含有约109至1016个基因组拷贝的约1ml至约100ml的溶液的范围内。在一些实施方案中,以1010、1011、1012、1013、1014或1015个基因组拷贝/受试者的剂量施用rAAV。在一些实施方案中,以1010、1011、1012、1013或1014个基因组拷贝/受试者的剂量施用rAAV。在一些情况下,约1011至1012个rAAV基因组拷贝的剂量是合适的。在某些实施方案中,1012个rAAV基因组拷贝对靶向心脏、肝脏和胰腺组织是有效的。在一些情况中,通过多剂量的rAAV产生稳定的转基因动物。
在一些实施方案中,配制rAAV组合物以减少组合物中AAV颗粒的聚集,特别是在存在高rAAV浓度的情况下(例如,约1013GC/ml或更高)。用于减少rAAV聚集的方法是本领域众所周知的,包括例如添加表面活性剂、pH调节、盐浓度调节等。(参见,例如,Wright FR,等人,Molecular Therapy(2005)12,171–178,其内容通过引用并入本文。)
药学上可接受的赋形剂和载体溶液的配制对于本领域技术人员来说是公知的,因为开发合适的剂量和治疗方案以在各种治疗方案中使用本文所述的特定组合物。
通常,这些制剂可含有至少约0.1%或更多的活性化合物,尽管活性成分的百分比当然可以变化,并且可以方便地在总配方重量或体积的约1或2%至约70%或80%或更多之间变化。当然,可以制备每种治疗上有用的组合物中活性化合物的量,使得在任何给定单位剂量的化合物中获得合适的剂量。制备此类药物制剂的领域的技术人员将考虑诸如溶解度、生物利用度、生物半衰期、施用途径、产品保质期以及其他药理学考虑因素等因素,并且因此,各种剂量和治疗方案可能是可取的。
在某些情况下,希望通过皮下、胰腺内、鼻内、肠胃外、静脉内、肌肉内、鞘内或口服、腹膜内或通过吸入递送本文公开的适当配制的药物组合物中的基于rAAV的治疗构建体。在一些实施方案中,如美国专利号5,543,158;5,641,515和5,399,363(各自通过引用整体并入本文)中所述的施用模式可以用于递送rAAV。在一些实施方案中,优选的施用方式是通过门静脉注射。
适于注射使用的药物形式包括无菌水溶液或分散液和用于临时制备无菌可注射溶液或分散液的无菌粉末。分散体也可以在甘油、液体聚乙二醇及其混合物和油中制备。在通常的储存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。在许多情况下,该形式是无菌的并且流动到易于注射的程度。它必须在制造和储存条件下稳定,并且必须防止微生物如细菌和真菌的污染作用。载体能够是溶剂或分散介质,其含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等),其合适的混合物和/或植物油。例如,通过使用包衣如卵磷脂,在分散的情况下通过维持所需的粒度和通过使用表面活性剂,可以保持适当的流动性。可以通过各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等来防止微生物的作用。在许多情况下,优选包括等张剂,例如糖或氯化钠。通过在组合物中使用延迟吸收的试剂,例如单硬脂酸铝和明胶,能够实现可注射组合物的延长吸收。
对于可注射水溶液的给药,例如,如果需要,可以适当地缓冲溶液,并且首先用足够的盐水或葡萄糖使液体稀释剂等张。这些特定的水溶液特别适用于静脉内、肌肉内、皮下和腹膜内施用。就此而言,能够使用的无菌含水介质将是本领域技术人员已知的。例如,可以将一个剂量溶解在1ml等渗NaCl溶液中,并且将其添加到1000ml的皮下注射液中或者在建议的输注部位注射(参见例如,"Remington's Pharmaceutical Sciences"第15版,第1035-1038页和1570-1580)。取决于宿主的状况,必然发生剂量的一些变化。在任何情况下,负责施用的人员将确定个体宿主的适当剂量。
通过将所需量的活性rAAV掺入适当的溶剂中,根据需要与本文列举的各种其他成分一起制备无菌可注射溶液,然后过滤灭菌。通常,通过将各种灭菌的活性成分掺入无菌载体中来制备分散体,所述无菌载体含有基础分散介质和来自上面列举的那些的所需其他成分。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,其从先前无菌过滤的溶液中产生活性成分和任何其他所需成分的粉末。
本文公开的rAAV组合物还可以配制成中性或盐形式。药学上可接受的盐包括酸加成盐(与蛋白的游离氨基形成)并且与无机酸例如盐酸或磷酸,或有机酸如乙酸、草酸、酒石酸、杏仁酸等形成。用游离羧基形成的盐也可以衍生自无机碱,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,和有机碱,如异丙胺、三甲胺、组氨酸、普鲁卡因等。在配制时,溶液将以与剂量配方相容的方式并以治疗有效的量施用。制剂易于以多种剂型施用,例如可注射溶液、药物释放胶囊等。
如本文所用,“载体”包括任何和所有溶剂、分散介质、载体、包衣、稀释剂、抗细菌和抗真菌剂、等张和吸收延迟剂、缓冲剂、载体溶液、悬浮液、胶体等。这些介质和药剂用于药物活性物质的用途是本领域熟知的。补充的活性成分也能够掺入组合物中。短语“药学上可接受的”是指当给予宿主时不产生过敏或类似的不良反应的分子实体和组合物。
递送载体如脂质体、纳米胶囊、微粒、微球、脂质颗粒、囊泡等可用于将本公开的组合物引入合适的宿主细胞中。特别地,可以配制递送转基因的rAAV载体用于包封在脂质颗粒、脂质体、囊泡、纳米球或纳米颗粒等中的递送。
此类制剂可优选用于引入本文公开的核酸或rAAV构建体的药学上可接受的制剂。脂质体的形成和使用通常是本领域技术人员已知的。最近,开发了具有改善的血清稳定性和循环半衰期的脂质体(美国专利号5,741,516)。此外,已经描述了脂质体和脂质体样制剂作为潜在药物载体的各种方法(美国专利号5,567,434;5,552,157;5,565,213;5,738,868和5,795,587)。
脂质体已经成功地与许多细胞类型一起使用,这些细胞类型通常对其他程序的转染具有抗性。此外,脂质体没有DNA长度限制,这是典型的基于病毒的递送系统。脂质体已被有效地用于将基因、药物、放射治疗剂、病毒、转录因子和变构效应物引入多种培养的细胞系和动物中。此外,已经完成了几项成功的临床试验,这些试验检验了脂质体介导的药物递送的有效性。
脂质体由磷脂形成,磷脂分散在水性介质中并自发形成多层同心双层囊泡(也称为多层囊泡(MLV))。MLV通常具有25nm至4μm的直径。MLV的超声处理导致形成直径在200至500.ANG.的小单层囊泡(SUV),其在核中含有水溶液。
或者,可以使用rAAV的纳米胶囊制剂。纳米胶囊通常能够以稳定且可重复的方式捕获物质。为了避免由细胞内聚合物过载引起的副作用,应该使用能够在体内降解的聚合物设计这种超细颗粒(大小约0.1μm)。考虑使用满足这些要求的可生物降解的聚烷基-氰基丙烯酸酯纳米颗粒。
除了上述递送方法之外,还考虑以下技术作为将rAAV组合物递送至宿主的替代方法。已经在美国专利No.5,656,016中使用和描述了超声波导入(即,超声波),其作为提高药物渗透进入和通过循环系统的速率和功效的装置。考虑的其他药物递送替代物是骨内注射(美国专利No.5,779,708)、微芯片装置(美国专利No.5,797,898)、眼科制剂(Bourlais等人,1998)、透皮基质(美国专利号5,770,219和5,783,208)和反馈控制的递送(美国专利号5,697,899)。
试剂盒和相关组合物
在一些实施方案中,本文所述的药剂可以组装成药物或诊断或研究试剂盒,以促进它们在治疗、诊断或研究应用中的用途。试剂盒可包括容纳本公开的组分的一个或多个容器和使用说明。具体地,此类试剂盒可包括本文所述的一种或多种试剂,以及描述预期应用和这些试剂的正确使用的说明书。在某些实施方案中,试剂盒中的药剂可以是适合于特定应用和施用该药剂的方法的药物制剂和剂量。用于研究目的的试剂盒可包含用于进行各种实验的适当浓度或量的组分。
试剂盒可以设计成便于研究人员使用本文所述的方法,并且能够采用多种形式。在适用的情况下,试剂盒的每种组合物可以以液体形式(例如,在溶液中)或以固体形式(例如干粉)提供。在某些情况下,一些组合物可以是可构成的或可加工的(例如,以活性形式),例如,通过添加合适的溶剂或其他物质(例如,水或细胞培养基),其在试剂盒中可能提供或可能不提供。如本文所使用的,“说明书”能够定义说明和/或促销的组分,并且通常涉及与本公开的包装相关联或与之相关的书面说明书。说明书还可以包括以任何方式提供的任何口头或电子说明书,使得用户将清楚地认识到说明书与该试剂盒相关联,例如,视听(例如,录像带、DVD等)、因特网和/或基于网络的通讯等。书面说明书可以是由管理药品或生物制品的制造、使用或销售的政府机构规定的形式,该说明书也可以反映制造、使用或销售用于动物管理的机构的批准。
试剂盒可以在一个或多个容器中包含本文所述的任何一种或多种组分。作为实例,在一个实施方案中,试剂盒可包括用于混合试剂盒的一种或多种组分和/或分离和混合样品并施用于受试者的说明书。该试剂盒可包括容纳本文所述的药剂的容器。药剂可以是液体、凝胶或固体(粉末)的形式。药剂可以无菌制备、包装在注射器中并冷藏运输。或者,它可以容纳在小瓶或其他容器中用于储存。第二容器可以具有无菌制备的其他药剂。或者,试剂盒可包括预混合的活性剂,并在注射器、小瓶、管或其他容器中运输。试剂盒可具有将试剂施用于动物所需的一种或多种或所有组分,例如注射器、局部施用装置或静脉注射针管和袋,特别是在用于产生特定体细胞动物模型的试剂盒的情况下。
该试剂盒可具有多种形式,例如泡罩袋、收缩包装袋、真空密封袋、可密封的热成型托盘或类似的袋或托盘形式,其中附属品松散地包装在袋(pouch)、一个或多个管、容器、盒或袋(bag)内。在添加附属品后,可以对试剂盒进行灭菌,从而允许容器中的各个附属品以其他方式展开。能够使用任何适当的灭菌技术对试剂盒进行灭菌,例如辐射灭菌、加热灭菌或本领域已知的其他灭菌方法。取决于具体应用,该试剂盒还可以包括其他组分,例如,容器、细胞培养基、盐、缓冲液、试剂、注射器、针、用于施加或去除消毒剂的织物例如纱布、一次性手套、在施用之前对药剂的支持等。
试剂盒中包括的说明书可涉及检测细胞中潜伏AAV的方法。另外,本公开的试剂盒可包括说明书、阴性和/或阳性对照、容器、稀释剂和用于样品的缓冲液、样品制备管和用于序列比较的印刷或电子参考AAV序列的表。
实施例
实施例1:从人组织中分离具有所需组织嗜性和特性的转录活性新AAV衣壳序列。
该实施例描述了通过以下步骤分离的新AAV衣壳序列:1)存在于正常和患病人组织中的wtAAV基因组的PCR扩增;2)PCR扩增子文库的高通量单分子、实时(SMRT)测序;3)通过生物信息学分析进行变体鉴定/分析;和4)选择能够翻译成全长衣壳蛋白的高可信度ORF。在该实施例中使用的工作流程的示意图示于图1A-1B中。
该方法利用从正常组织和肿瘤组织分离的病毒基因组中观察到的天然基因组多样性库。因此,体内组织通过选择性压力和/或免疫逃避充当病毒基因组多样性的天然孵化器。因此,组织间和组织内变异性以及患者间多样性的发现受益于能够分析在人类组织和器官中发现的全部AAV变体谱的方法。
来自人组织的AAV基因组的PCR扩增
为了分离具有独特向性的新血清型的多种AAV变体,从中国成都四川大学华西医院收集了来自455名患者的844个人手术标本。这些组织包括广泛的组织/器官类型以及各种肿瘤类型(表1)。特别地,从9个正常肝组织、7个肝肿瘤、4个增大的前列腺组织、2个正常肺组织、1个胰腺肿瘤组织、1个乳腺癌组织、1个正常乳房组织、1个胃癌组织、1个正常胃组织、一个脑组织和一个胶质瘤样品中鉴定出AAV变体。
从人组织中提取总基因组DNA,并进行AAV衣壳序列的PCR扩增。表2中描述了该实施例中使用的PCR引物。简而言之,用于扩增4.1-kb AAV rep-cap序列的panAAV引物(例如,RepF318、AV2cas)或用于扩增2.3-kb AAV cap序列的panAAV引物(例如,CapF、CapR)用于PCR。
表1:用于wtAAV基因组扩增的临床标本
表2:PCR引物序列
引物 | 序列(5’-3’) | SEQ ID NO: |
RepF318 | GCCATGCCGGGGTTCTACGAGAT | 872 |
AV2cas | ACAGGAGACCAAAGTTCAACTGAAACGA | 873 |
CapF | GACTGCATCTTTGAACAATAAATGA | 874 |
CapR | GAAACGAATTAACCGGTTTATTGATTAA | 875 |
AAV PCR产物的高通量测序和生物信息学分析
对AAV PCR产物进行高通量单分子实时(SMRT)测序。该方法消除了对从其他常规高通量基因组测序方法获得的对齐的短读取片段进行病毒基因组重建和嵌合体预测的需要。
使用从开源生物信息学工具开发的变体分析管道,鉴定了超过600种先前未描述的、高可信度的AAV2、AAV2/3杂合体和AAV8衣壳序列变体。具体而言,鉴定了224个AAV8变体(含有1至10个单氨基酸变体);425个AAV2变体(含有1至20个单氨基酸变体);和194个AAV2/3杂合变体(含有10至50个单氨基酸变体)。表3、4和5总结了独特的衣壳蛋白变体。出于比较的目的,野生型AAV2、AAV3和AAV8衣壳氨基酸序列分别描述于SEQ ID NO:869、870和871。图7是散点图,其显示具有一个或多个单氨基酸变体的不同AAV2衣壳变体和AAV2/3变体的分布。
表3:通过SMRT测序和生物信息学分析鉴定的独特AAV2和AAV2/3杂合变体(氨基酸序列)。
提供4.1kb文库的DNA序列。
表4:通过SMRT测序和生物信息学分析鉴定的独特AAV8变体(氨基酸序列)。
表5:另外的AAV8变体衣壳蛋白
AAV8变体名称 | SEQ ID NO: |
B1 | 853 |
B2 | 854 |
B3 | 855 |
B4 | 856 |
B12 | 857 |
B18 | 858 |
B24 | 859 |
B41 | 860 |
B44 | 861 |
B45 | 862 |
B46 | 863 |
B60 | 864 |
B61 | 865 |
B62 | 866 |
B63 | 867 |
B64 | 868 |
实施例2:具有改善的体内向性的AAV8变体的鉴定。
通过标准分子克隆方法将候选AAV8变体的子集(例如,B2、B3、B44和B61)克隆到AAV包装载体中,并与由CB6启动子驱动的萤光素酶报告基因包装。将产生的载体注射到小鼠中,并通过动物全身成像和相对发光的定量分析体内萤光素酶转基因表达水平。观察到B2(SEQ ID NO:854)和B3(SEQ ID NO:855)变体在肌内注射后在肝脏中具有更高的表达(图2A-2D),而与AAV9相比,在新生小鼠IV注射后,B61(SEQ ID NO:865)变体在脑和脊髓中具有更高的转导效率(图3A-3B)。这是值得注意的,因为已经观察到野生型AAV8穿过血脑屏障的程度低于AAV9。与AAV8相比,一种AAV8变体B44(SEQ ID NO:861)在IM注射后具有更好的转导至肝脏的能力(图4A-4B)。
进行系统发生分析以比较AAV8衣壳变体B2、B3、B44和B61与其他AAV血清型。简言之,使用ClustalW将AAV8变体的氨基酸序列与其他公开的AAV序列比对,并使用MEGA6.06中的最小进化方法推断系统发育树。生物信息学分析的结果表明B2、B3、B44和B61序列与Clade E[AAV8]衣壳蛋白有关。图5。AAV8变体中的代表性氨基酸取代显示在表6中。
表6:相对于野生型AAV8,AAV8变体中的代表性氨基酸取代
AAV变体 | 代表性取代(相对于wt AAV8) |
B2 | E63G |
B3 | K259R |
B44 | L91Q,T234A,M374T |
B61 | M374T,M561V |
实施例3:体外评估rAAV基因组包装效率和候选衣壳变体的初始表征。
包含选定的AAV衣壳变体的包装质粒构建体的分子克隆
通过使用标准分子克隆策略(例如,亲本AAV2或AAV2/3衣壳表达质粒的定点诱变、基于PCR的克隆和Gibson Assembly或通过外包合成)替换常规病毒衣壳基因,将通过SMRT测序鉴定的AAV2和AAV2/3杂合衣壳变体克隆到包装质粒中。图8显示了待用于发现的衣壳变体的多重筛选的载体构建体。表7中显示了用于各种诊断策略的所提出的转基因盒的概述。
表7:用于各种诊断策略的转基因盒
通过高通量小规模载体生产和载体基因组滴定对包装效率进行多重评估
粗裂解物中rAAV的载体基因组的定量用于直接测试HEK 293包装细胞的三重转染后第一代(单链AAV)和第二代(自身互补AAV)载体的rAAV变体包装效率。这提供了有效率的替代方案,以执行小规模载体生产的完整工作流程,然后进行载体基因组的银染色和常规PCR滴定,以评估所有发现的变体的病毒质量。由于这种方法能够扩展到96孔形式的性能,因此它用来快速识别产生高滴度载体的变体。
新AAV变体的血清学评估
通过标准方法筛选具有高包装效率的候选变体的与当前AAV的抗体交叉反应性,例如衣壳免疫学测定以测试针对来自AAV免疫的兔的血清的新rAAV。此外,对每种候选变体进行合并的人IgG(IVIG)中和测定,以确定人群中预先存在的体液免疫的可能性。
实施例4:体内分析rAAV2和rAAV2/3变体以研究载体转导生物学、毒性的流行、组织/器官向性和生物分布谱。
小鼠研究
候选衣壳变体基于组织分布进行分组,并且由感兴趣的器官区分优先次序。对候选变体组进行聚类索引(图6A),由此将表达候选衣壳变体的多个包装质粒混合并表达以通过三重转染包装独特的DNA条形码转基因(例如,F9凝血因子IX(F.IX),评估肝脏靶向和分泌因子的表达效力;EGFP,通过器官/组织切片和比较免疫荧光显微术评估生物分布和组织特异性转导的程度;或萤光素酶(Luc),以通过活体动物成像评估CNS和肝脏转导的质量。
对于测量rAAV变体对肝靶向转基因表达和分泌的能力的研究,设计了包含甲状腺素结合球蛋白(TGB)(肝特异性启动子)的rAAV构建体。对于描述全动物载体转导的研究,设计了包含CMV增强子、鸡β-肌动蛋白启动子(CB6)调控盒的构建体。
通过不同的施用途径将包裹索引的转基因的载体注射到成年和新生小鼠中,并在1个月的纵向研究中筛选分泌的F.IX表达、EGFP表达或Luc表达以分析AAV变体介导的转基因表达。CNS/脑的施用途径包括外周血管内(IV,测试跨血脑屏障的转导)、脑室内(ICV)、实质内和鞘内。通过视网膜下注射进行视网膜施用。在一些实施方案中,IV注射也靶向肝脏。
将与对照动物(例如,由AAV2、AAV2/3或AAV8递送的转基因)相比表现出独特转基因表达的动物处死并收获器官。通过常规PCR扩增含有转基因信息的大量DNA提取物或cDNA文库,然后进行Illumina测序以追踪富集在每种组织中的条形码转基因,测定各个器官的条形码转基因的存在和丰度。图9概述了转基因索引的一般设计策略。可检测条形码转基因的丰度和组织/器官分布反映了每组的候选rAAV变体向性和转导效力。选择具有所需载体特性的高效候选组。来自所选组的各个候选变体用于包装条形码转基因用于第二轮筛选,以鉴定个体的、高度有效的变体。在多轮分层选择中迭代地执行聚类索引能够减少工作量。
非人灵长类动物(NHP)研究
通过类似于针对小鼠研究概述的聚类索引方法的模态筛选候选rAAV变体在非人灵长类动物中的生物分布(图6B)。在NHP中重新评估通过不同施用途径对靶器官的转导效率,以验证在前述小鼠研究中观察到的rAAV变体谱。
免疫原性、人群中中和抗体的流行、遗传毒性的能力和致病性的一般方面与初步评估一起进行测量,例如多组织和器官的组织病理学以检查T细胞或中性粒细胞浸润、通过ALT/AST活性监测肝毒性,并通过检查组织切片分析炎症,以确定非人灵长类动物(NHP)动物的转导谱。
实施例5:新AAV衣壳序列的分离。
分离另外的AAV衣壳序列。使用从生物信息学工具开发的变体分析管道,鉴定了另外263种先前未描述的、高可信度的AAV2和AAV2/3杂合体衣壳序列变体。出于比较的目的,野生型AAV2和AAV3衣壳氨基酸序列分别描述于SEQ ID NO:869和870。
表8:通过SMRT测序和生物信息学分析鉴定的另外的独特AAV2和AAV2/3杂合变体(氨基酸序列)。
为所有文库提供相应的DNA序列。AAV2衣壳变体的核酸序列对应于SEQ ID NO:1989-2077。AAV2/3衣壳变体的核酸序列对应于SEQ ID NO:2078-2251。
本公开不限于其在本说明书中阐述的或附图中示出的构造细节和部件布置的应用。本公开能够具有其他实施方案并且能够以各种方式实践或执行。此外,这里使用的措辞和术语是出于描述的目的,而不应被视为限制。本文中“包括”、“包含”或“具有”、“含有”、“涉及”及其变化形式的使用旨在涵盖其后列出的项目及其等同物以及附加项目。
已经如此描述了本公开的至少一个实施方案的若干方面,应当理解,本领域技术人员将容易想到各种改变、修改和改进。这些改变、修改和改进旨在成为本公开的一部分,并且旨在落入本公开的精神和范围内。因此,前面的描述和附图仅是示例性的。
Claims (50)
1.一种重组表达载体,其包含编码多肽的核酸,所述多肽具有选自以下的序列:SEQ IDNO:1至409、435-868或1726-1988或其片段,其不编码与SEQ ID NO:869、870或871中任一个的序列相同的肽。
2.一种分离的AAV衣壳蛋白,其包含选自以下的氨基酸序列:SEQ ID NO:1至409、435-868和1726-1988或其片段。
3.一种分离的AAV衣壳蛋白,其包含选自以下的氨基酸序列:SEQ ID NO:1-409、837-852或1726-1814,其中将所述序列中与SEQ ID NO:869所示序列的相应氨基酸不同的氨基酸替换为保守取代。
4.一种分离的AAV衣壳蛋白,其包含选自以下的氨基酸序列:SEQ ID NO:435-628或1815-1988,其中将所述序列中与SEQ ID NO:869或870所示序列的相应氨基酸不同的氨基酸替换为保守取代。
5.一种分离的AAV衣壳蛋白,其包含选自以下的氨基酸序列:SEQ ID NO:629-836或853-868,其中将所述序列中与SEQ ID NO:871所示序列的相应氨基酸不同的氨基酸替换为保守取代。
6.根据权利要求2至5中任一项所述的分离的AAV衣壳蛋白的肽片段,其与SEQ ID NO:869、870或871中任一个的序列不同。
7.一种分离的AAV衣壳蛋白,其包含权利要求6所述的肽片段。
8.一种重组表达载体,其包含编码权利要求2至5中任一项所述的分离的AAV衣壳蛋白的核酸序列。
9.一种组合物,其包含权利要求2至5中任一项所述的分离的AAV衣壳蛋白。
10.一种组合物,其包含权利要求2至5中任一项所述的分离的AAV衣壳蛋白和药学上可接受的载体。
11.一种重组AAV(rAAV),其包含权利要求2至5中任一项所述的分离的AAV衣壳蛋白。
12.一种组合物,其包含权利要求11所述的重组rAAV。
13.根据权利要求12所述的组合物,其还包含药学上可接受的载体。
14.一种宿主细胞,其含有包含选自以下的多肽的编码序列的核酸:SEQ ID NO:1-409、435-868和1726-1988,其与启动子可操作地连接。
15.一种组合物,其包含权利要求14所述的宿主细胞和无菌细胞培养基。
16.一种组合物,其包含权利要求15所述的宿主细胞和冷冻保护剂。
17.一种用于将转基因递送给受试者的方法,其包括:
向受试者施用权利要求11所述的rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述受试者的靶组织的细胞。
18.一种产生体细胞转基因动物模型的方法,其包括向非人动物施用权利要求11所述的重组rAAV,其中所述rAAV包含至少一种转基因,并且其中所述rAAV感染所述非人动物的靶组织的细胞。
19.根据权利要求17所述的方法,其中所述至少一种转基因是蛋白编码基因。
20.根据权利要求17所述的方法,其中所述至少一种转基因编码小干扰核酸。
21.根据权利要求20所述的方法,其中所述小干扰核酸是miRNA。
22.根据权利要求20所述的方法,其中所述小干扰核酸是miRNA海绵或TuD RNA,其抑制所述受试者或动物中至少一种miRNA的活性。
23.根据权利要求22所述的方法,其中在所述靶组织的细胞中表达所述miRNA。
24.根据权利要求17所述的方法,其中所述靶组织是肝脏、中枢神经系统(CNS)、眼、胃肠、呼吸、乳房、胰脏、泌尿道或子宫组织。
25.根据权利要求18所述的方法,其中所述转基因表达包含至少一个miRNA结合位点的转录物,其中所述miRNA通过与所述结合位点杂交抑制所述转基因在靶组织以外的组织中的活性。
26.一种产生体细胞转基因动物模型的方法,其包括向非人动物施用权利要求23所述的rAAV,其中所述rAAV包含至少一种转基因,其中所述转基因表达包含miRNA的至少一个结合位点的转录物,其中所述miRNA通过与所述转录物的结合位点杂交抑制所述转基因在靶组织以外的组织中的活性。
27.根据权利要求26所述的方法,其中所述转基因包含组织特异性启动子或诱导型启动子。
28.根据权利要求27所述的方法,其中所述组织特异性启动子是肝脏特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、粘蛋白-2启动子、胰多肽(PPY)启动子、突触蛋白-1(Syn)启动子、视网膜劈裂素启动子、K12启动子、CC10启动子、表面活性蛋白C(SP-C)启动子、PRC1启动子、RRM2启动子、uroplakin2(UPII)启动子或乳铁蛋白启动子。
29.根据权利要求17所述的方法,其中所述rAAV通过静脉内、透皮、眼内、鞘内、口服、肌肉内、皮下、鼻内或通过吸入施用。
30.根据权利要求17所述的方法,其中所述受试者选自小鼠、大鼠、兔子、狗、猫、羊、猪和非人灵长类动物。
31.根据权利要求17所述的方法,其中所述受试者是人。
32.一种通过权利要求18所述的方法产生的体细胞转基因动物模型。
33.一种生产rAAV的试剂盒,所述试剂盒包含:
容纳分离的核酸的容器,所述分离的核酸编码具有SEQ ID NO:1至409、435-868或1726-1988中任一个的序列的多肽。
34.根据权利要求33所述的试剂盒,其还包含用于生产所述rAAV的说明书。
35.根据权利要求34所述的试剂盒,其还包含至少一个容纳重组AAV载体的容器,其中所述重组AAV载体包含转基因。
36.一种试剂盒,其包含:
容器,其容纳具有权利要求2至5中任一项所述的分离的AAV衣壳蛋白的重组AAV。
37.根据权利要求36所述的试剂盒,其中所述容器是注射器。
38.根据权利要求2-5中任一项所述的分离的AAV衣壳蛋白,其中所述衣壳蛋白是VP1衣壳蛋白。
39.根据权利要求2-5中任一项所述的分离的AAV衣壳蛋白,其中所述衣壳蛋白是VP2衣壳蛋白。
40.根据权利要求2-5中任一项所述的分离的衣壳蛋白,其中所述衣壳蛋白是VP3衣壳蛋白。
41.一种假型AAV,其包含权利要求2至5或7中任一项所述的衣壳蛋白。
42.根据权利要求1所述的重组表达载体,其中所述核酸编码V1衣壳蛋白。
43.根据权利要求1所述的重组表达载体,其中所述核酸编码V2衣壳蛋白。
44.根据权利要求1所述的重组表达载体,其中所述核酸编码V3衣壳蛋白。
45.一种核酸,其包含选自SEQ ID NO:410-434、876-1718和1989-2251的序列。
46.根据权利要求45所述的核酸,其中将所述核酸工程化以表达AAV衣壳蛋白或其变体和/或AAV组装激活蛋白(AAP)或其变体。
47.根据权利要求45所述的核酸,其中所述AAP位于与所述AAV衣壳蛋白不同的核酸开放阅读框中。
48.根据权利要求46所述的核酸,其中所述AAP是AAV2 AAP(AAP-2)或其变体。
49.一种分离的蛋白,其由权利要求45所述的核酸编码。
50.一种重组AAV,其包含权利要求49所述的分离的蛋白。
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