靶向眼组织的病毒载体的制作方法

相关申请的交叉引用本申请要求2018年4月3日提交的美国临时申请序列号62/652,108的优先权，所述临时申请出于所有目的以引用方式整体并入本文。本公开涉及来自腺相关病毒(aav)和病毒衣壳的修饰的衣壳蛋白以及包含所述衣壳蛋白的病毒载体。特别地，本公开涉及修饰的aav衣壳蛋白和包含所述衣壳蛋白的衣壳，所述衣壳蛋白可以并入病毒载体中以关于目标靶组织(诸如眼组织)赋予希望的转导概况(profile)。序列表本申请含有已以ascii格式以电子版形式提交且在此以引用方式整体并入的序列表。所述ascii拷贝于2019年4月3日创建，名为strd-007_01wo_st25.txt且大小为652kb。
背景技术：
：从动物组织和腺病毒原种中分离出的新的腺相关病毒(aav)株扩大了可用于治疗性基因转移应用的aav载体的范围。目前正在进行对动物模型中这些aav分离株的组织嗜性作图的综合努力。将aav载体直接归巢到选择性器官的能力对于基因疗法和其他治疗应用是有用的。基因疗法显示出治疗眼科疾病的前景，并且已经证明aav能够转导眼中多种细胞类型和细胞层。本文提供的组合物和方法满足了本领域对具有期望的靶向特征，诸如靶向眼睛的特定区域(例如，视网膜色素上皮(rpe)或视网膜)的核酸递送载体的需求。技术实现要素：本文提供了特异性靶向并感染一种或多种目标组织诸如眼睛组织(例如，rpe或视网膜)的aav衣壳蛋白和aav病毒载体。在一些实施方案中，本公开提供了包含一个或多个氨基酸取代的重组腺相关病毒(aav)衣壳蛋白，其中一个或多个氨基酸取代修饰了aav衣壳蛋白上的一个或多个表面暴露环。在一些实施方案中，一个或多个表面暴露环的修饰导致关于靶组织的转导概况增强。在实施方案中，当将aav衣壳蛋白掺入aav载体中时，一个或多个表面暴露环的修饰导致向眼组织的转导增强。在一些实施方案中，当将aav衣壳蛋白掺入aav载体中时，与不包含修饰的亲本衣壳相比，一个或多个表面暴露环的修饰导致向视网膜色素上皮(rpe)和/或视网膜的转导增强。在一些实施方案中，本公开提供了一种重组aav衣壳蛋白，其中所述衣壳蛋白在所述aav衣壳蛋白的表面暴露环中包含取代，其中所述取代具有seqidno：14、15、16、17、18、19、20、21、22、187、188、189、190、191、192、193和194中任一者的序列。在一些实施方案中，重组aav衣壳包含与aav1、aav2、aav3、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12、aavrh8、aavrh10、aavrh32.33、aavrh74、牛aav和禽aav中任一者的衣壳蛋白具有至少80％序列同一性的氨基酸序列。在一些实施方案中，重组aav衣壳蛋白包含与seqidno：11-12、23-49或195-254中任一者具有至少90％序列同一性的氨基酸序列。在一些实施方案中，本公开提供了一种包含氨基酸取代的aav衣壳蛋白，其中所述氨基酸取代置换了对应于seqidno.11的氨基酸位置591-596或seqidno.12的氨基酸590-595的区域中的氨基酸。在一些实施方案中，本公开提供了一种重组aav衣壳蛋白，其中所述衣壳蛋白包含取代，所述取代包含在天然aav衣壳蛋白中不存在的六个氨基酸的序列(x1-x2-x3-x4-x5-x6)，其中x2是v且x5是l(seqidno：186)。在一些实施方案中，取代是在aav衣壳蛋白的表面暴露环中。在一些实施方案中，本公开提供了一种aav衣壳蛋白，其中所述衣壳蛋白包含seqidno：11-12、23-49或195-254中任一者的氨基酸序列。在一些实施方案中，本公开提供了一种包含aav衣壳蛋白的aav病毒载体，所述aav衣壳蛋白包含与seqidno：11-12、23-49或195-254中任一者的序列具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％同一性的氨基酸序列。在一些实施方案中，aav病毒载体特异性靶向并感染rpe和/或视网膜。在一些实施方案中，aav病毒载体与亲本或野生型aav病毒载体相比，表现出对rpe和/或视网膜的靶向和感染增加。本公开还提供了一种核苷酸序列或包含所述核苷酸序列的表达载体，所述核苷酸序列编码本公开的一种或多种重组aav衣壳蛋白。本公开还提供了一种细胞，其包含本公开的一种或多种核苷酸序列或表达载体。本公开还提供了一种aav衣壳，其包含本公开的重组aav衣壳蛋白。还提供了一种病毒载体以及一种组合物，所述病毒载体包含本公开的重组aav衣壳，所述组合物包含在药学上可接受的载体中的本公开的重组aav衣壳蛋白、aav衣壳和/或病毒载体。本公开另外提供了一种将核酸引入细胞中的方法，其包括使所述细胞与本公开的病毒载体接触。所述细胞可以是在受试者中，并且在一些实施方案中，所述受试者可以是人类受试者。在一些实施方案中，提供了一种治疗有需要的患者的方法，所述方法包括向所述患者施用治疗有效量的本公开的aav病毒载体。这些方面和其他方面在下文列出的具体实施方式中被更详细地解决。附图说明图1a和图1b。气泡图示出了对文库多样性、定向进化和新型抗原足迹的富集进行的分析。使用illuminamiseq平台对亲本(图1a)和进化(图1b)文库进行高通量测序。使用定制的perl脚本进行分析后，绘制了富集的氨基酸序列。每个气泡代表一个不同的衣壳氨基酸序列，其中气泡的半径与相应文库中该变体的读数的数量成比例。y轴代表转换成以2为底的对数的读数的绝对数量。数据沿x轴展开以便于可视化。独特克隆的减少百分比(70.3％)直接表明，在第一轮进化后去除了众多“不适合”的序列。图2a和图2b。示出用于第一轮进化的亲本(图2a)和进化(图2b)文库的气泡图。图2a和图2b示出了分别与图1a和图1b相同的数据，但所述数据已归一化为总读数百分比，从而允许在后续几轮进化中进行纵向比较。图3a和图3b。示出用于在视网膜中进行的第三轮进化的亲本(图3a)和进化(图3b)文库的气泡图，其数据已归一化为总读数百分比。图4a和图4b。示出用于在rpe中进行的第三轮进化的亲本(图3a)和进化(图3b)文库的气泡图，其数据已归一化为总读数百分比。图5。为示出包含突变衣壳蛋白(strd-1，seqidno：34；strd-2，seqidno：32；strd-3，seqidno：36；strd-4，seqidno：195；strd-5，seqidno：35；strd-6，seqidno：196；strd-7，seqidno：37；以及strd-8，seqidno：40)的各种aav-荧光素酶载体到培养物中的u87细胞中的转导的图。以10,000vg/细胞的感染复数(moi)来感染细胞。转导后48小时，测量相对光单位(rlu)。具体实施方式除非另外定义，否则本文中所用的所有技术和科学术语均具有与本公开所属领域的普通技术人员通常所理解的相同的含义。本文具体实施方式中所用的术语仅出于描述特定实施方案的目的并且不旨在是限制性的。本文提到的所有出版物、专利申请、专利、genbank或其他登录号以及其他参考文献均以引用方式整体并入本文。在本公开和所附权利要求书中，aav衣壳蛋白中所有氨基酸位置的指定是参考vp1衣壳亚基编号。本领域技术人员将理解的是，本文所述的修饰如果插入aavcap基因中，则可导致vp1、vp2和/或vp3衣壳亚基的修饰。可替代地，可独立地表达所述衣壳亚基以仅在衣壳亚基(vp1、vp2、vp3、vp1+vp2、vp1+vp3或vp2+vp3)的一个或两个中实现修饰。定义在本文的说明书和所附权利要求书中使用以下术语：除非上下文另外清楚地指出，否则单数形式“一个/种(a/an)”和“所述”旨在包括复数形式。此外，如本文所用的术语“约(about)”当涉及可测量值，诸如多核苷酸或多肽序列长度的量、剂量、时间、温度等时，意在涵盖指定量的±20％、±10％、±5％、±1％、±0.5％或者甚至±0.1％的变化。也如本文所用，“和/或”是指并且涵盖一个或多个相关所列项目的任何和所有可能的组合，以及当以替代选择(“或”)解释时的缺乏组合。除非上下文另外指出，否则特别预期本文所述的各种特征可以任何组合来使用。此外，本公开还预期在一些实施方案中，本文列出的任何特征或特征的组合可以被排除或省略。为了进一步说明，例如，如果说明书表明特定氨基酸可选自a、g、i、l和/或v，则此语言还表明所述氨基酸可选自这些氨基酸的任何子集，例如a、g、i或l；a、g、i或v；a或g；仅l；等等，就好像每个此类子组合都在本文明确地列出。此外，此类语言还表明可以不要求保护一种或多种指定的氨基酸。例如，在特定的实施方案中，所述氨基酸不是a、g或i；不是a；不是g或v；等等，就好像每个此类可能的免责声明都在本文明确地列出。如本文所用，术语“减少(reduce)”、“减少(reduces)”、“减少(reduction)”和类似术语意指降低至少约10％、约15％、约20％、约25％、约35％、约50％、约75％、约80％、约85％、约90％、约95％、约97％或更多。如本文所用，术语“增加(increase)”、“改善(improve)”、“增强(enhance)”、“增强(enhances)”、“增强(enhancement)”和类似术语表明增加至少约10％、约15％、约20％、约25％、约50％、约75％、约100％、约150％、约200％、约300％、约400％、约500％或更多。如本文所用，术语“细小病毒”涵盖细小病毒科，其包括自主复制的细小病毒和依赖病毒。自主细小病毒包括原细小病毒(protoparvovirus)属、红细小病毒属(erythroparvovirus)、博卡病毒属(bocaparvovirus)和浓核病毒(densovirus)亚科的成员。示例性自主细小病毒包括但不限于小鼠微小病毒、牛细小病毒、犬细小病毒、鸡细小病毒、猫泛白细胞减少症病毒、猫细小病毒、鹅细小病毒、h1细小病毒、番鸭细小病毒、b19病毒和现在已知或以后发现的任何其他自主细小病毒。其他自主细小病毒是本领域技术人员已知的。参见，例如，bernardn.fields等，virology，第2卷，第69章(第4版，lippincott-ravenpublishers；cotmore等，archivesofvirologydoi10.1007/s00705-013-1914-1)。如本文所用，术语“腺相关病毒”(aav)包括但不限于aav类型1、aav类型2、aav类型3(包括类型3a和类型3b)、aav类型4、aav类型5、aav类型6、aav类型7、aav类型8、aav类型9、aav类型10、aav类型11、aav类型12、aav类型13、aav类型rh32.33、aav型rh8、aav型rh10、aav型rh74、aav型hu.68、禽aav、牛aav、犬aav、马aav、绵羊aav、蛇aav、鬃狮蜥(beardeddragon)aav、aav2i8、aav2g9、aav-lk03、aav7m8、aavanc80、aavphp.b以及现在已知或以后发现的任何其他aav。参见，例如，bernardn.fields等，virology，第2卷，第69章(第4版，lippincott-ravenpublishers)。已鉴定出许多aav血清型和进化枝(参见，例如，gao等，(2004)j.virology78：6381-6388；moris等，(2004)virology33-：375-383；以及表2)。如本文所用，术语“嵌合aav”是指包含具有源自两种或更多种不同aav血清型的区域、结构域、个别氨基酸的衣壳蛋白的aav。在一些实施方案中，嵌合aav包含由源自第一aav血清型的第一区域和源自第二aav血清型的第二区域组成的衣壳蛋白。在一些实施方案中，嵌合aav包含由源自第一aav血清型的第一区域、源自第二aav血清型的第二区域和源自第三aav血清型的第三区域组成的衣壳蛋白。在一些实施方案中，所述嵌合aav可包含源自aav1、aav2、aav3、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11和/或aav12中两种或更多种的区域、结构域、个别氨基酸。例如，所述嵌合aav可包含来自如下文(表1)所示的第一aav血清型和第二aav血清型的区域、结构域和/或个别氨基酸，其中aavx+y表示嵌合aav，其包含源自aavx和aavy的序列：通过将来自多个aav血清型的个别氨基酸或区域包含在一个衣壳蛋白中，可获得具有多种所需特性的分别源自所述多个aav血清型的衣壳蛋白。aav和自主细小病毒的各种血清型的基因组序列以及天然末端重复(tr)序列、rep蛋白序列和衣壳亚基的序列是本领域已知的。此类序列可见于文献或公共数据库(诸如genbank)。参见，例如genbank登录号nc_002077、nc_001401、nc_001729、nc_001863、nc_001829、nc_001862、nc_000883、nc_001701、nc_001510、nc_006152、nc_006261、af063497、u89790、af043303、af028705、af028704、j02275、j01901、j02275、x01457、af288061、ah009962、ay028226、ay028223、nc_001358、nc_001540、af513851、af513852、ay530579；其公开内容以引用方式并入本文，用于教导细小病毒以及aav核酸和氨基酸序列。还参见，例如srivistava等，(1983)j.virology45：555；chiorini等，(1998)jvirology71：6823；chiorini等，(1999)j.virology73：1309；bantel-schaal等，(1999)jvirology73：939；xiao等，(1999)jvirology73：3994；muramatsu等，(1996)virology221：208；shade等，(1986)j.virol.58：921；gao等，(2002)proc.nat.acad.sci.usa99：11854；moris等，(2004)virology33：375-383；国际专利公布wo00/28061、wo99/61601、wo98/11244；以及美国专利号6,156,303；其公开内容以引用方式并入本文，用于教导细小病毒以及aav核酸和氨基酸序列。还参见表2。在bernardn.fields等，virology，第2卷，第69和70章(第4版，lippincott-ravenpublishers)中更详细地描述了自主细小病毒和aav的衣壳结构。还参见aav2(xie等，(2002)proc.nat.acad.sci.99：10405-10)、aav9(dimattia等，(2012)j.virol.86：6947-6958)、aav8(nam等，(2007)j.virol.81：12260-12271)、aav6(ng等，(2010)j.virol.84：12945-12957)、aav5(govindasamy等，(2013)j.virol.87，11187-11199)、aav4(govindasamy等，(2006)j.virol.80：11556-11570)、aav3b(lerch等，(2010)virology403：26-36)、bpv(kailasan等，(2015)j.virol.89：2603-2614)以及cpv(xie等，(1996)j.mol.biol.6：497-520以及tsao等，(1991)science251：1456-64)的晶体结构的描述。表2如本文所用，术语“嗜性”是指病毒优先进入某些细胞或组织，任选地随后表达(例如转录和任选地翻译)由细胞中的病毒基因组所携带的序列，例如对于重组病毒，表达目标异源核酸。本领域技术人员将理解的是，在缺乏反式作用因子，例如诱导型启动子或以其他方式调节的核酸序列的情况下，可能不会引发来自病毒基因组的异源核酸序列的转录。在raav基因组的情况下，来自病毒基因组的基因表达可来自稳定整合的原病毒、来自非整合的附加体以及病毒在细胞内可采取的任何其他形式。如本文所用，“全身嗜性”和“全身转导”(以及等效术语)表明本公开的病毒衣壳或病毒载体分别对整个身体的组织(例如，脑、肺、骨骼肌、心脏、肝脏、肾脏和/或胰腺)表现出嗜性或转导所述组织。在实施方案中，观察到肌肉组织(例如，骨骼肌、膈肌和心肌)的全身转导。在其他实施方案中，实现了骨骼肌组织的全身转导。例如，在特定实施方案中，转导整个身体的基本上所有的骨骼肌(虽然转导的效率可因肌肉类型而变化)。在特定实施方案中，实现了肢体肌肉、心肌和膈肌的全身转导。任选地，所述病毒衣壳或病毒载体通过全身途径(例如，全身途径，诸如静脉内、关节内或淋巴内)来施用。可替代地，在其他实施方案中，所述衣壳或病毒载体被局部递送(例如，至足趾、肌肉内、皮内、皮下、外部)。除非另外指出，否则“高效转导”或“高效嗜性”或类似术语可通过参考合适对照来确定(例如，分别为对照的转导或嗜性的至少约50％、约60％、约70％、约80％、约85％、约90％、约95％或更大)。在特定实施方案中，所述病毒载体高效地转导骨骼肌、心肌、膈肌、胰腺(包括p胰岛细胞)、脾脏、胃肠道(例如上皮和/或平滑肌)、中枢神经系统的细胞、眼睛、肺、关节细胞和/或肾脏或对其具有高效嗜性。合适对照将取决于各种因素，包括所需嗜性曲线。例如，aav8和aav9高效转导骨骼肌、心肌和膈肌，但是也具有高效转导肝脏的缺点。因此，可以鉴定出表明aav8或aav9的骨骼肌、心肌和/或膈肌的高效转导，但对肝脏的转导效率低得多的病毒载体。此外，因为目标嗜性曲线可反映出对于多个靶组织的嗜性，因此应当理解，合适的载体可代表一些权衡。为了说明，本公开的病毒载体在转导骨骼肌、心肌和/或膈肌中的效率可能低于aav8或aav9，但因为肝脏的转导水平低，尽管如此其可能还是非常理想的。类似地，可以通过参考合适对照来确定病毒对于靶组织是否“没有高效转导”或“不具有高效嗜性”或类似术语。在特定实施方案中，所述病毒载体对肝脏、肾脏、性腺和/或生殖细胞没有高效转导(即不具有高效嗜性)。在特定实施方案中，组织(例如，肝脏)的不合需要的转导是所需靶组织(例如，骨骼肌、膈肌、心肌和/或中枢神经系统的细胞)的转导水平的约20％或更少、约10％或更少、约5％或更少、约1％或更少、约0.1％或更少。除非另外指出，否则如本文所用，术语“多肽”涵盖肽和蛋白质两者。“多核苷酸”是核苷酸碱基的序列，并且可以是rna、dna或dna-rna杂合序列(包括天然存在的和非天然存在的核苷酸两者)，但是在代表性实施方案中，是单链或双链dna序列。如本文所用，“分离的”多核苷酸(例如，“分离的dna”或“分离的rna”)意指至少部分地与天然存在的生物体或病毒的至少一些其他组分分离的多核苷酸，例如通常发现与多核苷酸缔合的细胞或病毒结构组分或其他多肽或核酸。在代表性实施方案中，“分离的”核苷酸与起始材料相比至少富集约10倍、100倍、1000倍、10000倍或更多倍。同样地，“分离的”多肽意指至少部分地与天然存在的生物体或病毒的至少一些其他组分分离的多肽，例如通常发现与多肽缔合的细胞或病毒结构组分或其他多肽或核酸。在代表性实施方案中，“分离的”多肽与起始材料相比至少富集约10倍、约100倍、约1000倍、约10000倍或更多倍。如本文所用，“分离”或“纯化”(或语法等效物)病毒载体，意指将所述病毒载体至少部分地与起始材料中的至少一些其他组分分离。在代表性实施方案中，“分离的”或“纯化的”病毒载体与起始材料相比至少富集约10倍、约100倍、约1000倍、约10000倍或更多倍。“治疗性多肽”是可以缓解、减少、预防、延迟和/或稳定因细胞或受试者中蛋白质的缺乏或缺陷而引起的症状的多肽，和/或是以其他方式赋予受试者益处(例如，抗癌作用或移植存活率改善)的多肽。术语“治疗(treat)”、“治疗(treating)”或“治疗(treatmentof)”(及其语法变化)意指受试者病状的严重性降低、至少部分改善或稳定和/或实现至少一种临床症状的一些缓解、减轻、减少或稳定和/或存在疾病或病症进展的延迟。术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”(及其语法变化)是指预防和/或延迟受试者的疾病、病症和/或临床症状的发作，和/或疾病、病症和/或临床症状的发作相对于在缺乏本公开的方法的情况下会发生的发作的严重性降低。预防可以是完全预防，例如完全不存在疾病、病症和/或临床症状。预防也可以是部分预防，使得受试者中疾病、病症和/或临床症状的发生和/或发作的严重性低于在缺乏本公开的情况下发生的严重性。如本文所用，“治疗有效量”是指当向受试者施用以治疗疾病或疾病的至少一种临床症状时足以影响所述疾病或其症状的此类治疗的量。“治疗有效量”可根据例如疾病和/或疾病的症状、疾病的严重性和/或疾病或病症的症状、待治疗患者的年龄、体重和/或健康以及处方医师的判断而变化。在任何给定情况下的适当量可以由本领域技术人员确定或能够通过常规实验测定。如本文所用，术语“病毒载体”、“载体”或“基因递送载体”是指充当核酸递送媒介物并且包含包装在病毒粒子内的载体基因组(例如病毒dna[vdna])的病毒(例如aav)颗粒。可替代地，在一些情况下，术语“载体”可用于指单独的载体基因组/vdna。“raav载体基因组”或“raav基因组”是包含一种或多种异源核酸序列的aav基因组(即vdna)。raav载体通常仅需要顺式的末端重复(tr)来产生病毒。所有其他病毒序列都是非必要的，并且可以反式提供(muzyczka，(1992)curr.topicsmicrobiol.immunol.158：97)。通常，raav载体基因组将仅保留一个或多个tr序列，以便使可以被载体高效包装的转基因的大小最大化。结构和非结构蛋白编码序列可以反式提供(例如，从载体(诸如质粒)或通过将序列稳定整合到包装细胞中)。在实施方案中，raav载体基因组包含至少一个tr序列(例如，aavtr序列)，任选地两个tr(例如，两个aavtr)，其通常将是在载体基因组的5’末端和3’末端并侧接异源核酸，但不需要与之邻接。tr可以彼此相同或不同。术语“末端重复”或“tr”包括形成发夹结构并充当反向末端重复(即介导所需功能，诸如复制、病毒包装、整合和/或原病毒挽救等)的任何病毒末端重复或合成序列。tr可以是aavtr或非aavtr。例如，非aavtr序列，诸如其他细小病毒(例如犬细小病毒(cpv)、小鼠细小病毒(mvm)、人类细小病毒b-19)的序列或任何其他合适的病毒序列(例如，可用作sv40复制起点的sv40发夹)可用作tr，其可通过截短、取代、缺失、插入和/或添加来进一步修饰。此外，tr可以是部分或完全合成的，诸如samulski等的美国专利号5,478,745所述的“双d序列”。“aav末端重复”或“aavtr”可来自任何aav，包括但不限于血清型1、2、3、4、5、6、7、8、9、10、11、12、13或现在已知或以后发现的任何其他aav(参见例如表2)。aav末端重复不需要具有天然末端重复序列(例如，天然aavtr序列可通过插入、缺失、截短和/或错义突变来改变)，只要所述末端重复介导所需功能，例如复制、病毒包装、整合和/或原病毒挽救等。本公开的病毒载体可以进一步是如国际专利公布wo00/28004和chao等，(2000)moleculartherapy2：619所述的“靶向”病毒载体(例如，具有定向嗜性)和/或“杂合”细小病毒(即，其中病毒tr和病毒衣壳来自不同的细小病毒)。本公开的病毒载体可以进一步是如国际专利公布wo01/92551(其公开内容以引用方式整体并入本文)所述的双链细小病毒颗粒。因此，在一些实施方案中，可以将双链(双链体)基因组包装到本公开的病毒衣壳中。此外，病毒衣壳或基因组元件可包含其他修饰，包括插入、缺失和/或取代。如本文所用，术语“氨基酸”涵盖任何天然存在的氨基酸、其修饰形式和合成氨基酸。天然存在的左旋(l-)氨基酸示出在表3中。表3：氨基酸残基和缩写。可替代地，氨基酸可以是修饰的氨基酸残基(非限制性实例示出在表4中)和/或可以是通过翻译后修饰(例如，乙酰化、酰胺化、甲酰化、羟基化、甲基化、磷酸化或硫酸化)修饰的氨基酸。表4：修饰的氨基酸残基此外，非天然存在的氨基酸可以是“非天然”氨基酸(如wang等，annurevbiophysbiomolstruct.35：225-49(2006)所述)。这些非天然氨基酸可有利地用于将目标分子化学连接至aav衣壳蛋白。修饰的aav衣壳蛋白和包含所述修饰的aav衣壳蛋白的病毒衣壳和病毒载体。本公开提供了包含氨基酸序列中的修饰(例如，取代和/或缺失)的aav衣壳蛋白(vp1、vp2和/或vp3)以及包含所述修饰的aav衣壳蛋白的病毒衣壳和病毒载体。发明人已发现，本文所述的修饰可赋予包含所述修饰的aav衣壳蛋白的病毒载体一种或多种期望的特性，包括但不限于向目标靶组织的选择性转导。在一些实施方案中，目标靶组织可以是眼组织，诸如视网膜色素上皮(rpe)。因此，本公开解决了与常规aav载体相关联的一些限制。如本文所用，氨基酸序列中的“突变”或“修饰”可包括取代、插入和/或缺失，其中每一者可涉及一个、两个、三个、四个、五个、六个、七个、八个、九个、十个或更多个氨基酸。在特定的实施方案中，修饰是取代。本发明的修饰的病毒衣壳蛋白可以是但不限于aav衣壳蛋白，其中来自一种aav衣壳蛋白的氨基酸被取代成另一种aav衣壳蛋白，并且被取代和/或插入的氨基酸可以来自任何来源并且可以进一步是天然的或部分或完全合成的。在一些实施方案中，本公开提供了一种腺相关病毒(aav)衣壳蛋白，其包含一个或多个氨基酸取代，其中所述一个或多个取代修饰了aav衣壳蛋白上的一个或多个表面暴露环。所述一个或多个表面暴露环的修饰导致向靶组织的转导增强。所述靶组织可以是眼组织，诸如视网膜色素上皮(rpe)。所述一个或多个氨基酸取代可以是在通过肽表位作图和/或冷冻电子显微镜研究鉴定的一个或多个表面暴露环中。本公开的衣壳蛋白被修饰以产生存在于具有关于目标靶组织(例如眼组织，诸如视网膜色素上皮)的转导增强的表型的aav病毒颗粒或aav病毒载体中的aav衣壳。本公开的aav病毒颗粒或载体还可以具有逃避中和抗体的表型。在一些实施方案中，所述一个或多个表面暴露环的一个或多个取代可将来自第一aav血清型的衣壳蛋白的一个或多个表面暴露环引入与所述第一aav血清型不同的第二aav血清型的衣壳蛋白中。本公开的aav衣壳蛋白可以是选自以下的aav血清型的衣壳蛋白：aav1、aav2、aav3、aav3b、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12、aavrh.8、aavrh.10、aavrh.32.33、aavrh74、牛aav、禽aav或现在已知或以后鉴定的任何其他aav。在一些实施方案中，所述aav衣壳蛋白是嵌合的。在一些实施方案中，氨基酸取代置换来自上段所列的任何一种血清型的aav衣壳蛋白中的任何六个氨基酸。例如，氨基酸取代可以置换来自上段所列的任何一种血清型的aav衣壳蛋白中的以下氨基酸(vp1编号)：397-402、403-408、409-414、415-420、421-426、427-432、433-438、439-444、445-450、451-456、457-462、463-468、469-474、475-480、481-486、487-492、493-489、490-495、496-501、500-505、506-510、511-517、523-528、529-534、535-540、541-546、547-552、553-558、559-560、561-565、566-571、572-577、578-583、584-589、590-595、596-601、602-607、608-613、614-619、620-625、626-631、632-637、638-642、643-648、649-654、655-670、617-676、677-682、683-688、689-694、695-700、701-706。在一些实施方案中，aav衣壳蛋白包含在衣壳序列中不存在的一个或多个氨基酸取代，其中所述氨基酸取代选自表5中列出的序列。表5：氨基酸取代序列取代seqidno.kvrdlf14rvlalr15rvhalr16rvhslr17gvgvlp18fvnaln19ivrsln20hvlrln21rvlalq22rvrglr187kvrtlr188mvgnlv189rvlglr190kvaglc191ivrplv192kvrgla193rvrglg194在一些实施方案中，氨基酸取代置换对应于seqidno.11的氨基酸位置591-596或seqidno.12的氨基酸590-595的区域中的氨基酸。在一些实施方案中，aav衣壳包含seqidno：11-12、23-49或195-254中任一者的氨基酸序列。在一些实施方案中，衣壳包含与seqidno：11-12、23-49或195-254中任一者具有至少90％、至少95％、至少96％、至少97％、至少98％或至少99％序列同源性的氨基酸序列。在一些实施方案中，重组衣壳蛋白具有与seqidno：32、35、37或40中任一者至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％同一性的序列。在一些实施方案中、seqidno：4的aav衣壳蛋白包含以下氨基酸取代中的一个或多个：k492e、k503e、n585s、t590k、t590r、t590g、t590f、t590i、t590h、t590m、d592r、d592l、d592h、d592g、d592n、d592a、r593d、r593a、r593s、r593v、r593r、r593g、r593t、r593n、r593p、t595f、t595r、t595p、t595n、t595q、t595v、t595c、t595a、t595g。在一些实施方案中，seqidno：11的aav衣壳蛋白包含以下氨基酸取代中的一个或多个：t591k、t591r、t591g、t591f、t5911、t591h、t591m、d593r、d593l、d593h、d593g、d593n、d593a、r594d、r594a、r594s、r594v、r594r、r594g、r594t、r594n、r594p、t596f、t596r、t596p、t596n、t596q、t596v、t596c、t596a、t596g。在一些实施方案中、seqidno：12的aav衣壳蛋白包含以下氨基酸取代中的一个或多个：t590k、t590r、t590g、t590f、t590i、t590h、t590m、d592r、d592l、d592h、d592g、d592n、d592a、r593d、r593a、r593s、r593v、r593r、r593g、r593t、r593n、r593p、t595f、t595r、t595p、t595n、t595q、t595v、t595c、t595a、t595g。在一些实施方案中，所述aav衣壳蛋白包含取代，所述取代包含在天然aav衣壳蛋白中不存在的六个氨基酸的序列(x1-x2-x3-x4-x5-x6)，其中x2是v且x5是l(seqidno：186)。在一些实施方案中，x1不为t、x3不为d、x4不为r并且x6不为t(seqidno：255)。在一些实施方案中，x1为k、g、f、i、h或r(seqidno：256)。在一些实施方案中，x3为r、l、h、g或n(seqidno：257)。在一些实施方案中，x4为d、a、s、v或r(seqidno：258)。在一些实施方案中，x6为f、r、p、n或q(seqidno：259)。在一些实施方案中，x1为k、x3为r、x4为d并且x6为f(seqidno：14)。在一些实施方案中，x1为r、x3为l、x4为a并且x6为r(seqidno：15)。在一些实施方案中，x1为r、x3为h、x4为a并且x6为r(seqidno：16)。在一些实施方案中，x1为r、x3为h、x4为s并且x6为r(seqidno：17)。在一些实施方案中，x1为g、x3为g、x4为v并且x6为p(seqidno：18)。在一些实施方案中，x1为f、x3为n、x4为a并且x6为n(seqidno：19)。在一些实施方案中，x1为i、x3为r、x4为s并且x6为n(seqidno：20)。在一些实施方案中，x1为h、x3为l、x4为r并且x6为n(seqidno：21)。在一些实施方案中，x1为r、x3为l、x4为a并且x6为q(seqidno：22)。在一些实施方案中，x1为r、x3为l、x4为a并且x6为q(seqidno：187)。在一些实施方案中，x1为k、x3为r、x4为t并且x6为r(seqidno：188)。在一些实施方案中，x1为m、x3为g、x4为n并且x6为v(seqidno：189)。在一些实施方案中，x1为r、x3为l、x4为g并且x6为r(seqidno：190)。在一些实施方案中，x1为k、x3为a、x4为g并且x6为c(seqidno：191)。在一些实施方案中，x1为i、x3为v、x4为r并且x6为v(seqidno：192)。在一些实施方案中，x1为k、x3为r、x4为g并且x6为a(seqidno：193)。在一些实施方案中，x1为r、x3为r、x4为g并且x6为g(seqidno：194)。本公开还提供了一种核苷酸序列或包含所述核苷酸序列的表达载体，所述核苷酸序列编码本公开的一种或多种aav衣壳蛋白。所述核苷酸序列可以是dna序列或rna序列。本公开还提供了一种细胞，其包含本公开的一种或多种核苷酸序列或表达载体。还提供了一种aav衣壳，其包含本公开的aav衣壳蛋白。本文还提供了一种病毒载体以及一种组合物，所述病毒载体包含本公开的aav衣壳，所述组合物包含在药学上可接受的载体中的本公开的aav衣壳蛋白、aav衣壳和/或病毒载体。在一些实施方案中，一个或多个表面暴露环的修饰导致关于目标靶组织(例如眼组织，诸如视网膜色素上皮(rpe))的转导概况增强。在一些实施方案中，一个或多个表面暴露环的修饰导致抗体与aav衣壳蛋白上的一个或多个抗原位点的结合受到抑制。在一些实施方案中，一个或多个表面暴露环的修饰导致包含所述aav衣壳蛋白的病毒颗粒的感染性的中和受到抑制。如本文所述，来自许多aav的衣壳蛋白的核酸序列和氨基酸序列是本领域已知的。因此，对于任何其他aav，可以容易地确定“对应”于天然aav衣壳蛋白的氨基酸位置的氨基酸(例如，通过使用序列比对)。本公开预期所述修饰的衣壳蛋白可通过修饰现在已知或以后发现的任何aav的衣壳蛋白来产生。此外，待修饰的aav衣壳蛋白可以是天然存在的aav衣壳蛋白(例如，aav2、aav3a或aav3b、aav4、aav5、aav6、aav7、aav8、aav9、aav10或aav11衣壳蛋白或表2中显示的aav中的任一者)，但不限于此。本领域技术人员将理解，对aav衣壳蛋白的各种操作是本领域已知的，并且本公开不限于天然存在的aav衣壳蛋白的修饰。例如，待修饰的衣壳蛋白与天然存在的aav相比可能已经具有改变(例如，其源自天然存在的aav衣壳蛋白，例如aav2、aav3a、aav3b、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12或现在已知或以后发现的任何其他aav)。在一些实施方案中，待修饰的衣壳蛋白可以是嵌合衣壳蛋白。在一些实施方案中，待修饰的衣壳蛋白可以是工程化的aav，诸如aav2i8、aav2g9、aav-lk03、aav7m8、aavanc80、aavphp.b。在一些实施方案中，待修饰的衣壳蛋白可以具有seqidno：11或seqidno：12的序列。因此，在特定实施方案中，待修饰的aav衣壳蛋白可源自天然存在的aav，但还包含一个或多个外来序列(例如，其对于天然病毒而言是外源性的)，所述外来序列插入和/或取代到所述衣壳蛋白中和/或已通过一个或多个氨基酸的缺失来改变。因此，当本文提及特异性aav衣壳蛋白(例如，aav2、aav3、aav4、aav5、aav6、aav7、aav8、aav9、aav10或aav11衣壳蛋白或来自表2所示的任何aav的衣壳蛋白)时，预期涵盖天然衣壳蛋白以及具有除本公开的修饰以外的改变的衣壳蛋白。此类改变包括取代、插入和/或缺失。在特定实施方案中，与天然aav衣壳蛋白序列相比，所述衣壳蛋白包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个、少于20个、少于30个、少于40个、少于50个、少于60个或少于70个插入其中(除本公开的插入以外)的氨基酸。在实施方案中，与天然aav衣壳蛋白序列相比，所述衣壳蛋白包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个、少于20个、少于30个、少于40个、少于50个、少于60个或少于70个氨基酸取代(除根据本公开的氨基酸取代以外)，在本公开的实施方案中，与天然aav衣壳蛋白序列相比，所述衣壳蛋白包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个、少于20个、少于30个、少于40个、少于50个、少于60个或少于70个氨基酸的缺失(除本公开的氨基酸缺失以外)。在特定实施方案中，aav衣壳蛋白具有天然aav衣壳蛋白序列或具有与天然aav衣壳蛋白序列具有至少约90％、约95％、约97％、约98％或约99％相似性或同一性的氨基酸序列。例如，在特定实施方案中，“aav4”衣壳蛋白涵盖天然aav4衣壳蛋白序列以及与天然aav4衣壳蛋白序列具有至少约90％、约95％、约97％、约98％或约99％相似性或同一性的序列。确定两种或更多种氨基酸序列之间的序列相似性或同一性的方法是本领域已知的。序列相似性或同一性可以使用本领域已知的标准技术来确定，包括但不限于smith和waterman，adv.appl.math.2，482(1981)的局部序列同一性算法，通过needleman和wunsch，jmol.biol.48，443(1970)的序列同一性比对算法，通过pearson和lipman，proc.natl.acad.sci.usa85，2444(1988)的搜索相似性方法，通过这些算法(wisconsingeneticssoftwarepackage，geneticscomputergroup，575sciencedrive，madison，wl中的gap、bestfit、fasta和tfasta)的计算机化实施方式，通过devereux等，nucl.acidres.12，387-395(1984)所述的最佳拟合序列程序，或通过检查。另一种合适的算法是描述于altschul等，jmol.biol.215，403-410，(1990)和karlin等，proc.natl.acad.sci.usa90，5873-5787(1993)中的blast算法。特别有用的blast程序是wu-blast-2程序，其从altschul等，methodsinenzymology，266，460-480(1996)；http://blast.wustl/edu/blast/readme.html中获得。wu-blast-2使用若干个搜索参数，所述参数可任选地设置为默认值。所述参数是动态值，并且由程序本身根据特定序列的组成和正搜索目标序列所针对的特定数据库的组成来建立；然而，可以调整所述值以提高灵敏度。此外，额外的有用算法是如altschul等，(1997)nucleicacidsres.25，3389-3402所报道的空位blast。本公开还提供了一种病毒衣壳，其包含本公开的修饰的aav衣壳蛋白、基本上由其组成或由其组成。在特定实施方案中，所述病毒衣壳是细小病毒衣壳，其进一步可以是自主细小病毒衣壳或依赖病毒衣壳。任选地，所述病毒衣壳是aav衣壳。在特定实施方案中，aav衣壳是aav1、aav2、aav3a、aav3b、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12、aavrh8、aavrh10、aavrh32.33、牛aav衣壳、禽aav衣壳或现在已知或以后鉴定的任何其他aav。aav血清型的非限制性列表示出在表2中。本公开的aav衣壳可以是表2中列出的或通过任何一个或多个插入、取代和/或缺失而源自任何前述衣壳的任何aav血清型。所述修饰的病毒衣壳可用作“衣壳载体”，例如，如在美国专利号5,863,541中已描述的。可以被所述修饰的病毒衣壳包装并转移到细胞中的分子包括异源dna、rna、多肽、有机小分子、金属或它们的组合。异源分子被定义为不是天然发现于aav感染中的那些分子，例如，不是由野生型aav基因组编码的那些分子。此外，可将治疗上有用的分子与嵌合病毒衣壳的外部缔合，以用于将所述分子转移到宿主靶细胞中。此类缔合的分子可包括dna、rna、有机小分子、金属、糖类、脂类和/或多肽。在本公开的一个实施方案中，所述治疗上有用的分子与所述衣壳蛋白共价连接(即，缀合或化学偶联)。共价连接分子的方法是本领域技术人员已知的。本公开的修饰的病毒衣壳还可用于产生针对新型衣壳结构的抗体。作为另一替代方案，可将外源性氨基酸序列插入所述修饰的病毒衣壳中，以用于向细胞呈递抗原，例如用于向受试者施用以产生对所述外源性氨基酸序列的免疫反应。在其他实施方案中，可在施用病毒载体之前和/或同时(例如，彼此几分钟或几小时内)施用所述病毒衣壳以阻断某些细胞位点，所述病毒载体递送编码目标多肽或目标功能性rna的核酸。例如，可递送本公开的衣壳以阻断肝细胞上的细胞受体，并且可以随后或同时施用递送载体，这可以减少肝细胞的转导并增强其他靶(例如骨骼肌、心肌和/或膈肌)的转导。根据代表性实施方案，可在施用根据本公开的修饰的病毒载体之前和/或同时向受试者施用修饰的病毒衣壳。此外，本公开提供了包含修饰的病毒衣壳的组合物和药物制剂；任选地，所述组合物还包含本公开的修饰的病毒载体。本公开还提供了编码本公开的修饰的病毒衣壳和衣壳蛋白的核酸(任选地，分离的核酸)。还提供了包含所述核酸的载体，以及包含本公开的核酸和/或载体的细胞(体内或培养物中)。作为一个实例，本公开提供了一种病毒载体，其包含：(a)本公开的修饰的aav衣壳；以及(b)含有至少一个末端重复序列的核酸，其中所述核酸被所述aav衣壳衣壳化。其他合适的载体包括但不限于病毒载体(例如，腺病毒、aav、疱疹病毒、牛痘、痘病毒、杆状病毒等)、质粒，噬菌体、yac、bac等。此类核酸、载体和细胞可以用作例如试剂(例如，辅助包装构建体或包装细胞)，用于产生如本文所述的修饰的病毒衣壳或病毒载体。根据本公开的病毒衣壳可以使用本领域已知的任何方法来产生，例如通过杆状病毒的表达(brown等，(1994)virology198：477-488)来产生。根据本公开的对aav衣壳蛋白的修饰是“选择性”修饰。此方法与先前在aav血清型之间进行整个亚基或大结构域交换的工作相反(参见，例如国际专利公布wo00/28004以及hauck等，(2003)j.virology77：2768-2774)。在特定实施方案中，“选择性”修饰导致少于或等于约20、约18、约15、约12、约10、约9、约8、约7、约6、约5、约4或约3个连续氨基酸的插入和/或取代和/或缺失。本公开的修饰的衣壳蛋白和衣壳还可包含现在已知或以后鉴定的任何其他修饰。例如，本公开的aav衣壳蛋白和病毒衣壳可以是嵌合的，因为它们可包含来自另一种病毒(任选地另一种细小病毒或aav)的全部或部分衣壳亚基，例如，如国际专利公布wo00/28004所述。在本公开的一些实施方案中，所述病毒衣壳可以是靶向的病毒衣壳，其包含指导所述病毒衣壳与存在于所需靶组织上的细胞表面分子相互作用的靶向序列(例如，在病毒衣壳中被取代或插入)(参见，例如，国际专利公布wo00/28004以及hauck等，(2003)j.virology77：2768-2774)；shi等，humangenetherapy17：353-361(2006)[描述了整合素受体结合基序rgd在aav衣壳亚基的位置520和/或位置584处的插入]；以及美国专利号7,314,912[描述了含有rgd基序的pi肽在aav2衣壳亚基的氨基酸位置447、534、573和587之后的插入])。在aav衣壳亚基内容许插入的其他位置是本领域已知的(例如，如grifman等，moleculartherapy3：964-975(2001)所述的位置449和588)。例如，本公开的病毒衣壳可能对某些目标靶组织(例如，肝脏、骨骼肌、心脏、膈肌、肾脏、脑、胃、肠、皮肤、内皮细胞和/或肺)具有相对低效的嗜性。靶向序列可以有利地掺入这些低转导载体中，从而赋予所述病毒衣壳所需嗜性以及任选地对特定组织的选择性嗜性。包含靶向序列的aav衣壳蛋白、衣壳和载体描述于例如国际专利公布wo00/28004中。作为另一个实例，如wang等，annurevbiophysbiomolstruct.35：225-49(2006))所述的一种或多种非天然存在的氨基酸可以掺入到本公开的aav衣壳亚基的正交位点处，作为将低转导载体重定向至所需靶组织的手段。这些非天然氨基酸可有利地用于将目标分子化学连接至aav衣壳蛋白，包括但不限于：聚糖(甘露糖-树突状细胞靶向)；rgd、蛙皮素或神经肽，用于靶向递送至特定癌症细胞类型；选自噬菌体展示的rna适体或肽，其靶向特异性细胞表面受体，诸如生长因子受体、整合素等。化学修饰氨基酸的方法是本领域已知的(参见，例如gregt.hermanson，bioconjugatetechniques，第1版，academicpress，1996)。在一些实施方案中，所述靶向序列可以是指导对特定细胞类型的感染的病毒衣壳序列(例如，自主细小病毒衣壳序列、aav衣壳序列或任何其他病毒衣壳序列)。作为另一个非限制性实例，肝素或硫酸乙酰肝素结合结构域(例如，呼吸道合胞病毒肝素结合结构域)可插入或取代到通常不结合hs受体的衣壳亚基(例如，aav4、aav5)中，以使得肝素和/或硫酸乙酰肝素与所得突变体结合。b19使用鞘糖脂作为其受体来感染原发性红细胞祖细胞(brown等，(1993)science262：114)。b19的结构已确定至分辨率(agbandje-mckenna等，(1994)virology203：106)。已将结合至鞘糖脂的b19衣壳的区域定位在氨基酸399-氨基酸406之间(chapman等，(1993)virology194：419)，即β桶形结构e与f之间的环出区域(chipman等，(1996)proc.nat.acad.sci.usa93：7502)。因此，b19衣壳的鞘糖脂受体结合结构域可以被取代到本公开的aav衣壳蛋白中，以将病毒衣壳或包含所述病毒衣壳的病毒载体靶向红系细胞。在一些实施方案中，所述外源性靶向序列可以是编码改变包含修饰的aav衣壳蛋白的病毒衣壳或病毒载体的嗜性的肽的任何氨基酸序列。在特定实施方案中，靶向肽或蛋白质可以是天然存在的，或者可替代地是完全或部分合成的。示例性靶向序列包括与细胞表面受体和糖蛋白结合的配体和其他肽，诸如rod肽序列、缓激肽、激素、肽生长因子(例如表皮生长因子、神经生长因子、成纤维细胞生长因子、血小板源性生长因子、胰岛素样生长因子i和ii等)、细胞因子、黑色素细胞刺激素(如α、β或γ)、神经肽和内啡肽等，以及其保留将细胞靶向其同源受体的能力的片段。其他说明性肽和蛋白质包括p物质、角质形成细胞生长因子、神经肽y、胃泌素释放肽、白介素2、鸡蛋清溶菌酶、促红细胞生成素、促性腺激素、皮质抑素、β-内啡肽、亮氨酸脑啡肽、强啡肽b(rimorphin)、α-新脑啡肽、血管紧张素、pneumadin、血管活性肠肽、神经降压素、胃动素及其如上所述的片段。作为又一替代方案，来自毒素(例如破伤风毒素或蛇毒素，诸如α-银环蛇毒素等)的结合结构域可以被取代到作为靶向序列的所述衣壳蛋白中。在又一个代表性实施方案中，aav衣壳蛋白可通过将如cleves(currentbiology7：r318(1997))所述的“非经典”输入/输出信号肽(例如，成纤维细胞生长因子1和成纤维细胞生长因子2、白介素1、hiv-1tat蛋白、疱疹病毒vp22蛋白等)取代到aav衣壳蛋白中来进行修饰。还涵盖指导特异性细胞摄取的肽基序，例如fvflp(seqidno：22)肽基序触发肝细胞摄取。噬菌体展示技术以及本领域已知的其他技术可用于鉴定识别任何目标细胞类型的肽。所述靶向序列可以编码靶向细胞表面结合位点的任何肽，所述结合位点包括受体(例如蛋白质、糖类、糖蛋白或蛋白聚糖)。细胞表面结合位点的实例包括但不限于硫酸乙酰肝素、硫酸软骨素和其他糖胺聚糖、在粘蛋白、糖蛋白和神经节苷脂上发现的唾液酸部分、mhc1糖蛋白、在膜糖蛋白上发现的糖类组分(包括甘露糖、n-乙酰-半乳糖胺、n-乙酰-葡糖胺、岩藻糖、半乳糖等)。在特定实施方案中，硫酸乙酰肝素(hs)或肝素结合结构域被取代到所述病毒衣壳中(例如，在以其他方式不与hs或肝素结合的aav衣壳中)。本领域已知hs/肝素结合是由富含精氨酸和/或赖氨酸的“碱性片段”介导的。在示例性实施方案中，可以采用基序bxxb(seqidno：51)之后的序列，其中“b”为碱性残基，并且x为中性和/或疏水性。作为非限制性实例，bxxb可以是rgnr(seqidno：52)。作为另一个非限制性实例，bxxb取代天然aav2衣壳蛋白中的氨基酸位置262至265或另一种aav血清型的衣壳蛋白中的对应位置。表6示出了合适的靶向序列的其他非限制性实例。表6：aav靶向序列作为又一个实施方案，所述靶向序列可以是可用于化学偶联至另一种靶向进入细胞的分子的肽(例如，其可包含可通过其r基团进行化学偶联的精氨酸和/或赖氨酸残基)。作为另一个实施方案，本公开的aav衣壳蛋白或病毒衣壳可包含如wo2006/066066所述的突变。例如，所述衣壳蛋白可包含在天然aav2衣壳蛋白的氨基酸位置263、705、708和/或716处的选择性氨基酸取代，或来自另一种aav血清型的衣壳蛋白中的对应变化。另外地或可替代地，在代表性实施方案中，所述衣壳蛋白、病毒衣壳或载体包含恰好在aav2衣壳蛋白的氨基酸位置264之后的选择性氨基酸插入或来自其他aav的衣壳蛋白中的对应变化。“恰好在氨基酸位置x之后”预期是指插入紧随指示的氨基酸位置之后(例如，“在氨基酸位置264之后”表明在位置265处的点插入或例如从位置265至位置268等的较大插入)。此外，在代表性实施方案中，本公开的衣壳蛋白、病毒衣壳或载体可包含诸如pct公布号wo2010/093784(例如，2i8)和/或pct公布号wo2014/144229(例如，双聚糖)所述的氨基酸修饰。在本公开的一些实施方案中，相对于本公开的衣壳蛋白、病毒衣壳或载体所来源的aav血清型的转导效率，本公开的衣壳蛋白、病毒衣壳或载体可具有等效或增强的转导效率。在本公开的一些实施方案中，相对于本公开的衣壳蛋白、病毒衣壳或载体所来源的aav血清型的转导效率，本公开的衣壳蛋白、病毒衣壳或载体可具有降低的转导效率。在本公开的一些实施方案中，相对于本公开的衣壳蛋白、病毒衣壳或载体所来源的aav血清型的嗜性，本公开的衣壳蛋白、病毒衣壳或载体可具有等效或增强的嗜性。在本公开的一些实施方案中，相对于本公开的衣壳蛋白、病毒衣壳或载体所来源的aav血清型的嗜性，本公开的衣壳蛋白、病毒衣壳或载体可具有改变或不同的嗜性。在本公开的一些实施方案中，本公开的衣壳蛋白、病毒衣壳或载体可具有对脑组织的嗜性或被工程化以具有对脑组织的嗜性。在本公开的一些实施方案中，本公开的衣壳蛋白、病毒衣壳或载体可具有对肝组织的嗜性或被工程化以具有对肝组织的嗜性。前述实施方案可用于将异源核酸递送至如本文所述的细胞或受试者。例如，修饰的载体可以用于治疗如本文所述的溶酶体贮积症，诸如粘多糖贮积症(例如，sly综合征[β-葡萄糖醛酸酶]、胡尔勒综合征(hurlersyndrome)[α-l-艾杜糖醛酸酶]、舍氏综合征(scheiesyndrome)[α-l-艾杜糖醛酸酶]、胡尔勒-舍氏综合征[α-l-艾杜糖醛酸酶]、亨特氏综合征(hunter’ssyndrome)[艾杜糖醛酸硫酸酯酶]、沙费利波综合征(sanfilipposyndrome)a[乙酰肝素磺酰胺酶]、沙费利波综合征b[n-乙酰葡糖胺糖苷酶]、沙费利波综合征c[乙酰coa：α-氨基葡萄糖苷乙酰转移酶]、沙费利波综合征d[n-乙酰氨基葡萄糖6-硫酸酯酶]、莫奎欧氏综合征(morquiosyndrome)a[半乳糖-6-硫酸盐硫酸酯酶]、莫奎欧氏综合征b[β-半乳糖苷酶]、马洛托-拉米综合征(maroteaux-lamysyndrome)[n-乙酰半乳糖胺-4-硫酸酯酶]等)、法布里病(fabrydisease)(α-半乳糖苷酶)、高雪氏病(gaucher’sdisease)(葡萄糖脑苷脂酶)或糖原贮积症(例如庞贝病(pompedisease)；溶酶体酸α-葡萄糖苷酶)。本领域技术人员将理解的是，对于一些aav衣壳蛋白而言，对应的修饰将是插入和/或取代，这取决于对应的氨基酸位置是部分还是完全存在于病毒中或者可替代地是完全不存在。本公开还涵盖包含本公开的修饰的衣壳蛋白和衣壳的病毒载体。在特定实施方案中，所述病毒载体是细小病毒载体(例如，其包含细小病毒衣壳和/或载体基因组)，例如aav载体(例如，其包含aav衣壳和/或载体基因组)。在代表性实施方案中，所述病毒载体包含修饰的aav衣壳和载体基因组，所述修饰的aav衣壳包含本公开的修饰的衣壳亚基。例如，在代表性实施方案中，所述病毒载体包含：(a)含有本公开的修饰的衣壳蛋白的修饰的病毒衣壳(例如，修饰的aav衣壳)；以及(b)含有末端重复序列(例如，aavtr)的核酸，其中所述含有末端重复序列的核酸被所述修饰的病毒衣壳衣壳化。所述核酸可以任选地包含两个末端重复(例如，两个aavtr)。在代表性实施方案中，所述病毒载体是含有编码目标多肽或目标功能性rna的异源核酸的重组病毒载体。以下更详细地描述了重组病毒载体。在特定实施方案中，本公开的病毒载体(i)与没有修饰的衣壳蛋白的病毒载体的转导水平相比，具有降低的肝转导；(ii)与没有修饰的衣壳蛋白的病毒载体观察到的水平相比，在动物受试者中表现出增强的病毒载体的全身转导；(iii)与没有修饰的衣壳蛋白的病毒载体的移动水平相比，显示出增强的跨内皮细胞的移动，和/或(iv)在眼组织(例如，视网膜色素上皮)的转导中表现出选择性增强，(v)在肝组织的转导中表现出选择性增强，和/或(vi)与没有修饰的衣壳蛋白的病毒载体的转导水平相比，脑组织(例如神经元)的转导水平降低。本领域技术人员将理解的是，本公开的修饰的衣壳蛋白、病毒衣壳和病毒载体不包括那些在其天然状态(即不是突变体)的指定位置处具有指示氨基酸的衣壳蛋白、衣壳和病毒载体。产生病毒载体的方法本公开进一步提供了产生本文所述的病毒载体的方法。因此，在一个实施方案中，本公开提供了一种产生对目标靶组织(例如眼组织)具有增强嗜性的aav载体的方法，其包括：a)鉴定在aav衣壳蛋白上形成三维表面暴露环的氨基酸残基；b)产生包含在(a)中鉴定的氨基酸残基的氨基酸取代的aav衣壳蛋白文库；c)产生包含来自(b)的aav衣壳蛋白文库的衣壳蛋白的aav颗粒；d)在可发生感染和复制的条件下使(c)的aav颗粒与细胞接触；e)选择可以完成至少一个感染周期并复制到与对照aav颗粒类似的滴度的aav颗粒：f)在可发生感染和复制的条件下，使(e)中选择的aav颗粒与目标靶组织的细胞接触；以及g)选择转导了目标靶组织的aav颗粒。鉴定表面暴露环氨基酸残基的方法的非限制性实例包括肽表位作图和/或冷冻电子显微镜。三维表面暴露环内的表面暴露环残基的分辨和鉴定允许它们通过随机、合理和/或简并诱变进行后续修饰，以产生可通过进一步选择和/或筛选来鉴定的具有期望的转导模式的aav衣壳。因此，在另一个实施方案中，本公开提供了一种产生关于目标靶组织具有增强的转导概况的aav载体的方法，其包括：a)鉴定在aav衣壳蛋白上形成三维表面暴露环的氨基酸残基；b)通过随机、合理和/或简并诱变，产生包含在(a)中鉴定的表面暴露环氨基酸残基的氨基酸取代的aav衣壳蛋白；c)产生包含来自(b)的aav衣壳蛋白的衣壳蛋白的aav颗粒；d)在可发生感染和复制的条件下使(c)的aav颗粒与细胞接触；e)选择可以完成至少一个感染周期并复制到与对照aav颗粒类似的滴度的aav颗粒；f)在可发生感染和复制的条件下使(e)中选择的aav颗粒与目标靶组织的细胞接触；以及g)选择转导了目标靶组织的aav颗粒。用于鉴定表面暴露环氨基酸残基的方法的非限制性实例包括肽表位作图和/或冷冻电子显微镜。通过随机、合理和/或简并诱变来产生包含表面环氨基酸残基的氨基酸取代的aav衣壳蛋白的方法是本领域已知的。这种综合方法提出了一种可用于修饰任何aav衣壳的平台技术。此平台技术的应用可得到源自原始aav衣壳模板的具有期望转导效率的aav变体。作为一项优势和益处，此技术的应用将扩大符合使用aav载体进行基因治疗的患者群组。在一个实施方案中，本公开提供了一种产生病毒载体的方法，所述方法包括向细胞提供：(a)包含至少一个tr序列(例如，aavtr序列)的核酸模板，以及(b)足以复制核酸模板并衣壳化成aav衣壳的aav序列(例如，编码本公开的aav衣壳的aavrep序列和aavcap序列)。任选地，所述核酸模板还包含至少一种异源核酸序列。在特定实施方案中，所述核酸模板包含两个aavitr序列，其位于异源核酸序列(如果存在的话)的5’和3’处，虽然它们不需要直接与之邻接。在此类条件下，提供了所述核酸模板以及aavrep序列和cap序列，所述条件使得在细胞中产生包含包装在aav衣壳内的核酸模板的病毒载体。所述方法还可包括从所述细胞收集所述病毒载体的步骤。可以从培养基和/或通过裂解所述细胞来收集所述病毒载体。所述细胞可以是允许aav病毒复制的细胞。可采用本领域已知的任何合适的细胞。在特定实施方案中，所述细胞是哺乳动物细胞。作为另一个选项，所述细胞可以是提供复制缺陷型辅助病毒中缺失的功能的反式互补包装细胞系，例如293细胞或其他反式互补细胞e1a。aav复制和衣壳序列可通过本领域已知的任何方法提供。当前方案通常表达在单个质粒上的aavrep/cap基因。虽然可以方便地提供aav复制和包装序列，但不需要一起提供。aavrep序列和/或cap序列可由任何病毒或非病毒载体提供。例如，rep/cap序列可由杂合腺病毒或疱疹病毒载体提供(例如，插入到缺失的腺病毒载体的e1a区域或e3区域中)。ebv载体也可用于表达aavcap基因和rep基因。此方法的一个优势是ebv载体是附加型的，但在整个连续细胞分裂中仍维持高拷贝数(即，作为染色体外元件稳定地整合到细胞中，命名为“基于ebv的核附加体”，参见margolski，(1992)curr.top.microbiol.immun.158：67)。作为另一种替代方案，rep/cap序列可以稳定地掺入细胞中。通常，aavrep/cap序列将不与tr侧接，以预防对这些序列进行挽救和/或包装。所述核酸模板可以使用本领域已知的任何方法提供给所述细胞。例如，所述模板可以由非病毒(例如质粒)或病毒载体供应。在特定实施方案中，所述核酸模板由疱疹病毒或腺病毒载体供应(例如，插入到缺失的腺病毒的e1a区域或e3区域中)。作为另一个说明，palombo等，(1998)j.virology72：5025描述了携带与aavtr侧接的报告基因的杆状病毒载体。如上文关于rep/cap基因所述，ebv载体也可用于递送所述模板。在另一个代表性实施方案中，所述核酸模板由复制的raav病毒提供。在其他实施方案中，包含所述核酸模板的aav原病毒稳定地整合到所述细胞的染色体中。为了增强病毒滴度，可以向所述细胞提供促进生产性aav感染的辅助病毒功能(例如，腺病毒或疱疹病毒)。aav复制所需的辅助病毒序列是本领域已知的。通常，这些序列将由辅助腺病毒或疱疹病毒载体提供。可替代地，腺病毒或疱疹病毒序列可以由另一种非病毒或病毒载体，例如，作为携带所有促进高效aav产生的辅助基因的非感染性腺病毒极微质粒来提供，如ferrari等，(1997)naturemed.3：1295，以及美国专利号6,040,183和6,093,570所述。此外，辅助病毒功能可由包装细胞提供，所述包装细胞具有嵌入在染色体中或维持为稳定染色体外元件的辅助序列。通常，辅助病毒序列不能被包装到aav病毒粒子中，例如不与tr侧接。本领域技术人员将理解的是，在单个辅助构建体上提供aav复制和衣壳序列以及辅助病毒序列(例如，腺病毒序列)可能是有利的。此辅助构建体可以是非病毒构建体或病毒构建体。作为一个非限制性说明，辅助构建体可以是包含aavrep/cap基因的杂合腺病毒或杂合疱疹病毒。在一个特定实施方案中，aavrep/cap序列和腺病毒辅助序列由单个腺病毒辅助载体供应。此载体进一步还可包含所述核酸模板。aavrep/cap序列和/或raav模板可以插入到腺病毒的缺失区域(例如，e1a区域或e3区域)中。在另一个实施方案中，aavrep/cap序列和腺病毒辅助序列由单个腺病毒辅助载体供应。根据此实施方案，raav模板可作为质粒模板来提供。在另一个说明性实施方案中，aavrep/cap序列和腺病毒辅助序列由单个腺病毒辅助载体提供，并且raav模板作为原病毒整合到细胞中。可替代地，raav模板由ebv载体提供，所述ebv载体作为染色体外元件(例如，作为基于ebv的核附加体)维持在细胞内。在另一个示例性实施方案中，aavrep/cap序列和腺病毒辅助序列由单个腺病毒辅助提供。raav模板可作为单独的复制病毒载体来提供。例如，raav模板可以由raav颗粒或第二重组腺病毒颗粒提供。根据前述方法，杂合腺病毒载体通常包含足以进行腺病毒复制和包装的腺病毒5’顺式序列和3’顺式序列(即，腺病毒末端重复和pac序列)。aavrep/cap序列以及raav模板(如果存在的话)嵌入在腺病毒主链中，并且与5’顺式序列和3’顺式序列侧接，使得这些序列可以包装到腺病毒衣壳中。如上文所述，腺病毒辅助序列和aavrep/cap序列通常不与tr侧接，使得这些序列不被包装到aav病毒粒子中。zhang等，((2001)genether.18：704-12)描述了同时包含腺病毒与aavrep基因和cap基因的嵌合辅助。疱疹病毒也可以用作aav包装方法中的辅助病毒。编码aavrep蛋白的杂合疱疹病毒可有利地促进可扩展的aav载体产生方案。已描述表达aav-2rep基因和cap基因的杂合单纯疱疹病毒i型(hsv-1)载体(conway等，(1999)genetherapy6：986和wo00/17377。作为另一种替代方案，本公开的病毒载体可以在昆虫细胞中使用杆状病毒载体产生，以递送rep/cap基因和raav模板，如例如urabe等，(2002)humangenetherapy13：1935-43所述。不含污染性辅助病毒的aav载体原种可以通过本领域已知的任何方法来获得。例如，aav和辅助病毒可以容易地基于大小进行区分。aav还可以基于对肝素底物的亲和力来与辅助病毒分离(zolotukhin等，(1999)genetherapy6：973)。可以使用缺失的复制缺陷型辅助病毒，以使得任何污染性辅助病毒都不具有复制能力。作为另一种替代方案，可以采用缺乏晚期基因表达的腺病毒辅助，因为仅需要腺病毒早期基因表达来介导aav病毒的包装。对晚期基因表达有缺陷的腺病毒突变体是本领域已知的(例如，ts100k和ts149腺病毒突变体)。重组病毒载体本公开的病毒载体可用于在体外、离体和体内将核酸递送至细胞。特别地，病毒载体可以有利地用于将核酸递送或转移至动物(包括哺乳动物)细胞。因此，在一些实施方案中，核酸(“货物核酸”)可以被本公开的衣壳蛋白衣壳化。在一些实施方案中，本公开提供了一种包含重组衣壳蛋白的aav载体，所述重组衣壳蛋白与seqidno：11-12、23-49或195-254中的任一者具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％序列同一性。在一些实施方案中，aav载体包含与seqidno：32、35、37或40中的任一者具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％序列同一性的重组衣壳蛋白。在一些实施方案中，aav病毒载体包含与11-12、23-49或195-254中的任一者具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％序列同一性的重组衣壳蛋白，并且还包含被衣壳蛋白衣壳化的货物核酸。在一些实施方案中，aav病毒载体包含与seqidno：32、35、37或40中的任一者具有至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或100％序列同一性的重组衣壳蛋白，并且还包含被衣壳蛋白衣壳化的货物核酸。在一些实施方案中，aav载体特异性靶向并感染眼睛的组织(诸如rpe或视网膜)。在一些实施方案中，与亲本aav衣壳相比，aav载体表现出对眼睛(例如，rpe或视网膜)的增强转导。在本公开的病毒载体中递送的货物核酸序列可以是任何目标异源核酸序列。目标核酸包括编码多肽的核酸，所述多肽包括治疗性(例如，用于医疗或兽医用途)或免疫原性(例如，用于疫苗)多肽或rna。治疗性多肽包括但不限于囊性纤维化跨膜调节蛋白(cftr)、抗肌萎缩蛋白(dvstrophin)(包括小型抗肌萎缩蛋白和微型抗肌萎缩蛋白，参见例如vincent等，(1993)naturegenetics5：130；美国专利公布号2003/017131；国际公布号wo/2008/088895，wang等，proc.natl.acad.sci.usa97：13714-13719(2000)；以及gregorevic等，mol.ther.16：657-64(2008))、肌肉生长抑制素前肽、卵泡抑素、激活素11型可溶性受体、igf-1、载脂蛋白诸如apoa(apoa1、apoa2、apoa4、apoa-v)、apob(apob100、apob48)、apoc(apoci、apocii、apociii、apociv)、apod、apoe、apoh、apol、apo(a)、抗炎多肽诸如iκb显性突变体、淀粉样蛋白β、tau、肌长蛋白(sarcospan)、肌营养相关蛋白(utrophin)(tinsley等，(1996)nature384：349)、小型肌营养相关蛋白、凝血因子(例如凝血因子viii、凝血因子ix、凝血因子x等)、促红细胞生成素、血管抑素、内皮抑素、过氧化氢酶、酪氨酸羟化酶、超氧化物歧化酶、瘦素、ldl受体、脂蛋白脂肪酶、颗粒蛋白前体、鸟氨酸转氨甲酰酶、β-球蛋白、α-球蛋白、血影蛋白(spectrin)、α-1-抗胰蛋白酶、腺苷脱氨酶、次黄嘌呤鸟嘌呤磷酸核糖转移酶、β-葡萄糖脑苷脂酶、battenin、鞘磷脂酶、溶酶体己糖胺酶a、支链酮酸脱氢酶、共济蛋白(frataxin)、rp65蛋白、细胞因子(例如，α-干扰素、β-干扰素、γ-干扰素、白介素2、白介素4、α突触核蛋白、帕金蛋白(parkin)、粒细胞-巨噬细胞集落刺激因子、淋巴毒素等)、肽生长因子、神经营养因子和激素(例如生长激素(somatotropin)、胰岛素、胰岛素样生长因子1和胰岛素样生长因子2、血小板源性生长因子、表皮生长因子、成纤维细胞生长因子、神经生长因子、神经营养因子3和神经营养因子4、脑源性神经营养因子、骨形态发生蛋白[包括rankl和vegf]、胶质源性生长因子、转化生长因子α和转化生长因子β等)、亨廷顿蛋白(huntingin)、溶酶体酸α-葡萄糖苷酶、艾杜糖醛酸-2-硫酸酯酶、n-磺基葡萄糖胺磺基水解酶、α-半乳糖苷酶a、受体(例如肿瘤坏死生长因子可溶性受体)、s100a1、泛素蛋白连接酶e3、小白蛋白(parvalbumin)、腺苷酸环化酶6型、调节钙调控的分子(例如serca2a、pp1抑制剂1及其片段[例如，wo2006/029319和wo2007/100465])、实现g蛋白偶联受体激酶2型敲低的分子(例如截短的组成性活性barkct)、抗炎因子(诸如irap)、抗肌肉生长抑制素蛋白、天冬氨酸酰化酶、单克隆抗体(包括单链单克隆抗体；示例性的mab是mab)、神经肽及其片段(例如，甘丙肽、神经肽y(参见u.s.7,071,172))、血管生成抑制剂，诸如血管抑制蛋白(vasohibin)和其他vegf抑制剂(例如，血管抑制蛋白2[参见，wojp2006/073052])。其他说明性异源核酸序列编码自杀基因产物(例如，胸苷激酶、胞嘧啶脱氨酶、白喉毒素和肿瘤坏死因子)、增强或抑制宿主因子转录的蛋白(例如，与转录增强子或抑制剂元件连接的核酸酶死亡的cas9、与转录增强子或抑制剂元件连接的锌指蛋白、与转录增强子或抑制剂元件连接的转录激活因子样(tal)效应子)、赋予对用于癌症治疗的药物的抗性的蛋白质、肿瘤抑制基因产物(例如，p53、rb、wt-1)、trail、fas-配体、rs1、opsin、tkr-β、c3、cfh以及对有需要的受试者具有治疗效果的任何其他多肽。在一些实施方案中，aav载体可以用于递送补体蛋白，诸如c21a、c4b、c3a、c3b、c5a、c5b、c6、c7、c8或c9。aav载体还可用于递送单克隆抗体和抗体片段，例如针对肌肉生长抑制素的抗体或抗体片段(参见例如fang等，naturebiotechnology23：584-590(2005))。编码多肽的异源核酸序列包括编码报告多肽(例如，酶)的那些异源核酸序列。报告多肽是本领域已知的，包括但不限于绿色荧光蛋白、β-半乳糖苷酶、碱性磷酸酶、荧光素酶和氯霉素乙酰转移酶基因。任选地，异源核酸编码分泌的多肽(例如，在其天然状态下是分泌的多肽或已被工程化为例如通过与本领域已知的分泌信号序列可操作地缔合来分泌的多肽)。可替代地，在本公开的特定实施方案中，异源核酸可以编码反义核酸、核酶(例如，如美国专利号5,877,022所述)、实现剪接体介导的/ram剪接的rna(参见puttaraju等，(1999)naturebiotech.17：246；美国专利号6,013,487；美国专利号6,083,702)、包括介导基因沉默的sirna、shrna或mirna的干扰rna(rnai)(参见sharp等，(2000)science287：2431)以及其他非翻译rna，诸如“指导”rna(gorman等，(1998)proc.nat.acad.sci.usa95：4929；yuan等的美国专利号5,869,248)等。示例性非翻译rna包括针对多重耐药性(mdr)基因产物的rnai(例如，用于治疗和/或预防肿瘤和/或向心脏施用以预防化学疗法的损害)、针对肌肉生长抑制素的rnai(例如，用于杜氏肌营养不良症(duchennemusculardystrophy))、针对vegf的rnai(例如，用于治疗和/或预防肿瘤)、针对受磷蛋白的rnai(例如，用于治疗心血管疾病，参见例如andino等，j.genemed.10：132-142(2008)和li等，actapharmacolsin.26：51-55(2005))；受磷蛋白抑制性或显性负分子，诸如受磷蛋白s16e(例如，用于治疗心血管疾病，参见例如hoshijima等，nat.med.8：864-871(2002))、针对腺苷激酶的rnai(例如用于癫痫)以及针对病原生物和病毒的rnai(例如乙型肝炎和/或丙型肝炎病毒、人类免疫缺陷病毒、cmv、单纯疱疹病毒、人类乳头瘤病毒等)。此外，可以递送指导替代性剪接的核酸序列。为了说明，可以将与抗肌萎缩蛋白外显子51的5’剪接位点和/或3’剪接位点互补的反义序列(或其他抑制性序列)与u1或u7小核(sn)rna启动子一起递送以诱导此外显子的跳跃。例如，包含位于反义/抑制性序列的5’的u1或u7snrna启动子的dna序列可以被包装在本公开的修饰的衣壳中并递送。在一些实施方案中，可以递送指导基因编辑的核酸序列。例如，所述核酸可以编码指导rna。在一些实施方案中，指导rna是包含crrna序列和tracrrna序列的单指导rna(sgrna)。在一些实施方案中，所述核酸可以编码核酸酶。在一些实施方案中，所述核酸酶是锌指核酸酶、归巢核酸内切酶、talen(转录激活因子样效应核酸酶)、ngago(阿尔古蛋白(agronaute)核酸内切酶)、sgn(结构指导的核酸内切酶)、rgn(rna指导的核酸酶)或其修饰的或截短的变体。在一些实施方案中，rna指导的核酸酶是cas9核酸酶、cas12(a)核酸酶(cpf1)、cas12b核酸酶、cas12c核酸酶、trpb样核酸酶、cas13a核酸酶(c2c2)、cas13b核酸酶、cas14b核酸酶或其修饰的或截短的变体。在一些实施方案中，cas9核酸酶从化脓性链球菌(s.pyogenes)或金黄色葡萄球菌(s.aureus)中分离或源自化脓性链球菌或金黄色葡萄球菌。在一些实施方案中，可以递送指导基因敲低的核酸序列。例如，所述核酸序列可以编码sirna、shrna、microrna或反义核酸。所述病毒载体还可以包含与宿主染色体上的基因座具有同源性并与之重组的异源核酸。例如，可以利用此方法来纠正宿主细胞中的遗传缺陷。所述病毒载体还可以包含与宿主染色体上的基因座具有同源性并与之重组的异源核酸。例如，可以利用此方法来纠正宿主细胞中的遗传缺陷。本公开还提供了表达免疫原性多肽的病毒载体，例如用于疫苗接种。所述核酸可以编码本领域已知的任何目标免疫原，包括但不限于来自人类免疫缺陷病毒(hiv)、猴免疫缺陷病毒(siv)、流感病毒、hiv或sivgag蛋白、肿瘤抗原、癌症抗原、细菌抗原、病毒抗原等的免疫原。细小病毒作为疫苗载体的用途是本领域已知的(参见例如miyamura等，(1994)proc.nat.acad.sciusa91：8507；young等的美国专利号5,916,563、mazzara等的美国专利号5,905,040、samulski等的美国专利号5,882,652、美国专利号5,863,541)。所述抗原可以呈现于细小病毒衣壳中。可替代地，所述抗原可以从引入到重组载体基因组中的异源核酸表达。如本文所述和/或如本领域已知的任何目标免疫原可由本公开的病毒载体提供。免疫原性多肽可以是适用于引发免疫反应和/或保护受试者使其免于感染和/或疾病的任何多肽，所述感染和/或疾病包括但不限于微生物、细菌、原生动物、寄生虫、真菌和/或病毒感染和疾病。例如，免疫原性多肽可以是正粘病毒免疫原(例如，流感病毒免疫原，诸如流感病毒血凝素(ha)表面蛋白或流感病毒核蛋白，或马流感病毒免疫原)或慢病毒免疫原(例如，马感染性贫血病毒免疫原、猴免疫缺陷病毒(siv)免疫原或人类免疫缺陷病毒(hiv)免疫原，诸如hiv或siv包膜gp160蛋白、hiv或siv基质/衣壳蛋白以及hiv或sivgag、pol和env基因产物)。免疫原性多肽还可以是沙粒病毒免疫原(例如，拉沙热病毒免疫原，诸如拉沙热病毒核衣壳蛋白和拉沙热包膜糖蛋白)、痘病毒免疫原(例如牛痘病毒免疫原，诸如牛痘li或l8基因产物)、黄病毒免疫原(例如黄热病病毒免疫原或日本脑炎病毒免疫原)、丝状病毒免疫原(例如埃博拉病毒免疫原或马尔堡病毒免疫原，诸如np和gp基因产物)、布尼亚病毒免疫原(例如rvfv、cchf和/或sfs病毒免疫原)或冠状病毒免疫原(例如感染性人类冠状病毒免疫原，诸如人类冠状病毒包膜糖蛋白或猪传染性胃肠炎病毒免疫原或禽感染性支气管炎病毒免疫原)。免疫原性多肽进一步可以是脊髓灰质炎免疫原、疱疹免疫原(例如cmv、ebv、hsv免疫原)、腮腺炎免疫原、麻疹免疫原、风疹免疫原、白喉毒素或其他白喉免疫原、百日咳抗原、肝炎(例如，甲型肝炎、乙型肝炎、丙型肝炎等)免疫原和/或本
技术领域：
现在已知的或以后被鉴定为免疫原的任何其他疫苗免疫原。可替代地，免疫原性多肽可以是任何肿瘤或癌症细胞抗原。任选地，所述肿瘤或癌症抗原在所述癌症细胞表面上表达。示例性癌症和肿瘤细胞抗原描述于s.a.rosenberg(immunity10：281(1991))中。其他说明性癌症和肿瘤抗原包括但不限于：brca1基因产物、brca2基因产物、gp100、酪氨酸酶、gage-1/2、bage、rage、lage、ny-eso-1、cdk-4、β-连环蛋白、mum-1、半胱天冬酶-8、kiaa0205、hpve、sart-1、frame、p15、黑色素瘤肿瘤抗原(kawakami等，(1994)proc.natl.acad.sci.usa91：3515；kawakami等，(1994)j.exp.med.，180：347；kawakami等，(1994)cancerres.54：3124)、mart-1、gp100、mage-1、mage-2、mage-3、cea、trp-1、trp-2、p-15、酪氨酸酶(brichard等，(1993)jexp.med.178：489)；her-2/neu基因产物(美国专利号4.968.603)、ca125、lk26、fb5(内皮唾液酸蛋白)、tag72、afp、ca19-9、nse、du-pan-2、ca50、span-1、ca72-4、hcg、stn(唾液酸化tn抗原)、c-erbb-2蛋白、psa、l-canag、雌激素受体、乳脂球蛋白、p53肿瘤抑制蛋白(levine，(1993)ann.rev.biochem.62：623)；粘蛋白抗原(国际专利公布号wo90/05142)；端粒酶；核基质蛋白；前列腺酸性磷酸酶；乳头状瘤病毒抗原；和/或现在已知或以后发现与以下癌症相关联的抗原：黑色素瘤、腺癌、胸腺瘤、淋巴瘤(例如非霍奇金淋巴瘤(non-hodgkin’slymphoma)、霍奇金淋巴瘤(hodgkin’slymphoma))、肉瘤、肺癌、肝癌、结肠癌、白血病、子宫癌、乳腺癌、前列腺癌、卵巢癌、宫颈癌、膀胱癌、肾癌、胰腺癌、脑癌以及现在已知或以后发现的任何其他癌症或恶性病状或其转移(参见例如rosenberg，(1996)ann.rev.med.47：481-91)。作为另一种替代方案，所述异源核酸可以编码期望在体外、离体或体内的细胞中产生的任何多肽。例如，可以将病毒载体引入到培养的细胞中，并从中分离表达的基因产物。本领域技术人员将理解的是，目标异源核酸可与适当的控制序列可操作地缔合。例如，所述异源核酸可与表达控制元件，诸如转录/翻译控制信号、复制起点、聚腺苷酸化信号、内部核糖体进入位点(ires)、启动子和/或增强子等可操作地缔合。此外，可以在转录后水平上实现目标异源核酸的调节表达，例如通过存在或不存在选择性地阻断在特定位点处的剪接活性的寡核苷酸、小分子和/或其他化合物来调节不同内含子的选择性剪接(例如，如wo2006/119137所述)。本领域技术人员将理解的是，根据所需的水平和组织特异性表达，可以使用多种启动子/增强子元件。根据所需表达模式，启动子/增强子可以是组成型或诱导型的。启动子/增强子可以是天然的或外来的，并且可以是天然的或合成的序列。关于外来的，预期是指在引入转录起始区域的野生型宿主中未发现所述转录起始区域。在特定实施方案中，启动子/增强子元件可以是靶细胞或待治疗的受试者原生的。在代表性实施方案中，启动子/增强子元件可以是异源核酸序列原生的。通常选择启动子/增强子元件，使得其在目标靶细胞中起作用。此外，在特定实施方案中，启动子/增强子元件是哺乳动物启动子/增强子元件。启动子/增强子元件可以是组成型或诱导型的。诱导型表达控制元件在希望提供对异源核酸序列表达的调节的那些应用中通常是有利的。用于基因递送的诱导型启动子/增强子元件可以是组织特异性或优选的启动子/增强子元件，并且包括肌肉特异性或优选的(包括心肌、骨骼肌和/或平滑肌特异性或优选的)、神经组织特异性或优选的(包括脑特异性或优选的)、眼特异性或优选的(包括视网膜特异性和角膜特异性)、肝脏特异性或优选的、骨髓特异性或优选的、胰腺特异性或优选的、脾脏特异性或优选的以及肺特异性或优选的启动子/增强子元件。其他诱导型启动子/增强子元件包括激素诱导型和金属诱导型元件。示例性诱导型启动子/增强子元件包括但不限于tet开/关元件、ru486诱导型启动子、蜕皮激素诱导型启动子、雷帕霉素诱导型启动子和金属硫蛋白启动子。在其中所述异源核酸序列被转录并且然后在靶细胞中翻译的实施方案中，通常包括用于高效翻译插入的蛋白质编码序列的特异性起始信号。可包含atg起始密码子和相邻序列的这些外源性翻译控制序列可具有多种来源，天然来源与合成来源均可。根据本公开的病毒载体提供了一种用于将异源核酸递送到广泛的细胞(包括分裂和非分裂细胞)中的手段。所述病毒载体可用于将目标核酸体外递送至细胞，例如以在体外产生多肽或用于离体基因治疗。所述病毒载体另外可用于将核酸递送至有需要的受试者的方法中，例如以表达免疫原性或治疗性多肽或功能性rna。以这种方式，可在受试者体内产生多肽或功能性rna。所述受试者可能需要所述多肽，因为所述受试者缺乏所述多肽。此外，可以实践所述方法，因为在受试者中多肽或功能性rna的产生可以赋予一些有益效果。所述病毒载体还可以用于在培养的细胞中或受试者中产生目标多肽或功能性rna(例如，使用受试者作为生物反应器以产生多肽或观察功能性rna对受试者的影响，例如与筛选方法有关)。通常，本公开的病毒载体可用于递送编码多肽或功能性rna的异源核酸，以治疗和/或预防递送治疗性多肽或功能性rna对其有益的任何疾病状态。示例性疾病状态包括但不限于：囊性纤维化(囊性纤维化跨膜调节蛋白)和其他肺部疾病、血友病a(因子viii)、血友病b(因子ix)、地中海贫血(β-球蛋白)、贫血(促红细胞生成素)以及其他血液病症。阿尔茨海默氏病(alzheimer’sdisease)(gdf；脑啡肽酶)、多发性硬化症(β-干扰素)、帕金森氏病(parkinson’sdisease)(胶质细胞系源性神经营养因子[gdnf])、亨廷顿氏病(huntington’sdisease)(去除重复的rnai)、卡纳万氏病(canavan’sdisease)、肌萎缩性脊髓侧索硬化症、癫痫(甘丙肽、神经营养因子)和其他神经系统病症、癌症(内皮抑素、血管抑素、trail、fas配体、细胞因子(包括干扰素)；rnai(包括针对vegf或多重耐药性基因产物的rnai)、mir-26a[例如用于肝细胞癌])、糖尿病(胰岛素)、肌营养不良症(包括杜氏肌营养不良症(duchenne))(抗肌萎缩蛋白、小型抗肌萎缩蛋白、胰岛素样生长因子i、肌聚糖[例如，α、β、γ]、针对肌生长抑制性肌肉生长抑制素前肽的rnai、卵泡抑素、激活素ii型可溶性受体、抗炎多肽(诸如iκb显性突变体)、肌长蛋白、肌营养相关蛋白、小型肌营养相关蛋白、针对抗肌萎缩蛋白基因中的剪接连接点的诱导外显子跳跃的反义或rnai[参见，例如wo/2003/095647]、针对u7snrna的诱导外显子跳跃的rnai[参见，例如wo/2006/021724])以及针对肌肉生长抑制素或肌肉生长抑制素前肽的抗体或抗体片段)以及贝克氏肌营养不良症、强直性肌营养不良1或2、面肩胛肱型肌营养不良症(fshd)、高雪氏病(gaucherdisease)(葡萄糖脑苷脂酶)、胡尔勒氏病(α-l-艾杜糖醛酸酶)、腺苷脱氨酶缺乏症(腺苷脱氨酶)、糖原贮积病(例如法布里病[α-半乳糖苷酶]和庞贝病[溶酶体酸α-葡萄糖苷酶])和其他代谢性病症、先天性肺气肿(α-1-抗胰蛋白酶)、莱施-尼汉综合征(lesch-nyhansyndrome)(次黄嘌呤鸟嘌呤磷酸核糖转移酶)、尼曼-皮克病(niemann-pickdisease)(鞘磷脂酶)、泰-萨克斯病(tay-sachsdisease)(溶酶体己糖胺酶a)、额颞痴呆、枫糖浆尿病(支链酮酸脱氢酶)、视网膜退行性疾病(以及其他眼部和视网膜疾病；例如，用于黄斑变性的pdgf和/或用于治疗/预防视网膜病症(例如i型糖尿病)的血管抑制蛋白或其他vegf抑制剂或其他血管生成抑制剂)、实体器官诸如脑(包括帕金森氏病[gdnf]、星形细胞瘤[内皮抑素、血管抑素和/或针对vegf的rnai]、胶质母细胞瘤[内皮抑素、血管抑素和/或针对vegf的rnai])、肝脏、肾脏、心脏的疾病(包括充血性心力衰竭或外周动脉疾病(pad))(例如，通过递送蛋白磷酸酶抑制剂i(i-1)及其片段(例如iic)、serca2a、调节受磷蛋白基因的锌指蛋白、barkct、[32-肾上腺素能受体、2-肾上腺素能受体激酶(bark)、磷酸肌醇3激酶(pi3激酶)、s100a1、小白蛋白、腺苷酸环化酶6型、实现g蛋白偶联受体激酶2型敲低的分子(诸如截短的组成性活性barkct)；辣椒素(calsarcin)、针对受磷蛋白的rnai；受磷蛋白抑制性或显性负分子诸如受磷蛋白s16e等)、关节炎(胰岛素样生长因子)、关节病症(胰岛素样生长因子1和/或胰岛素样生长因子2)、内膜增生(例如，通过递送enos、inos)、提高心脏移植的存活率(超氧化物歧化酶)、艾滋病(可溶性cd4)、肌肉消瘦(胰岛素样生长因子i)、肾虚(促红细胞生成素)、贫血(促红细胞生成素)、关节炎(抗炎因子，诸如irap和tnfa可溶性受体)、肝炎(α-干扰素)、ldl受体缺乏症(ldl受体)、高氨血症(鸟氨酸转氨甲酰酶)、克拉伯氏病(krabbe’sdisease)(半乳糖脑苷脂酶)、贝敦氏症(batten’sdisease)、脊髓性脑共济失调(包括sca1、sca2和sca3)、苯丙酮尿症(苯丙氨酸羟化酶)、自身免疫性疾病等。本公开可在器官移植后进一步使用，以增加移植的成功率和/或减少器官移植或辅助治疗的负面副作用(例如，通过施用免疫抑制剂或抑制性核酸来阻断细胞因子产生)。作为另一个实例，骨形态发生蛋白(包括bnp2、bnp7等，rankl和/或vegf)可以与同种异体骨例如在癌症患者的骨折或手术去除之后一起施用。在一些实施方案中，本公开的病毒载体可以用于递送编码多肽或功能性rna的异源核酸以治疗和/或预防肝脏疾病或病症。肝脏疾病或病症可以是例如原发性胆汁性肝硬化、非酒精性脂肪性肝病(nafld)、非酒精性脂肪性肝炎(nash)、自身免疫性肝炎、乙型肝炎、丙型肝炎、酒精性肝病、纤维化、黄疸、原发性硬化性胆管炎(psc)、布-加综合征(budd-chiarisyndrome)、血色素沉着症、威尔逊氏病(wilson’sdisease)、酒精性纤维化、非酒精性纤维化、肝脂肪变性、吉尔伯特综合征(gilbert’ssyndrome)、胆道闭锁、α-1-抗胰蛋白酶缺乏症、阿拉吉欧综合征(alagillesyndrome)、进行性家族性肝内胆汁淤积症、血友病b、遗传性血管性水肿(hae)、纯合子家族性高胆固醇血症(hofh)、杂合子家族性高胆固醇血症(hefh)、冯·吉尔克氏病(vongierke’sdisease)(gsdi)、血友病a、甲基丙二酸血症、丙酸血症、高胱氨酸尿症(homocystinuria)、苯丙酮酸尿症(pku)、酪氨酸血症1型、精氨酸酶1缺乏症、精氨琥珀酸裂解酶缺乏症、氨甲酰磷酸合成酶1缺乏症、瓜氨酸血症1型、柠檬素缺乏症、克里格勒-纳贾尔综合征(crigler-najjarsyndrome)1型、胱氨酸病、法布里病、糖原贮积病1b、lpl缺乏症、n-乙酰谷氨酸合成酶缺乏症、鸟氨酸转氨甲酰酶缺乏症、鸟氨酸移位酶缺乏症、原发性高草酸尿症1型或adascid。本公开还可以用于产生诱导多能干细胞(ips)。例如，本公开的病毒载体可用于将干细胞相关核酸递送到非多能细胞中，诸如成人成纤维细胞、皮肤细胞、肝细胞、肾细胞、脂肪细胞、心脏细胞、神经细胞、上皮细胞、内皮细胞等。编码与干细胞相关联的因子的核酸是本领域已知的。与干细胞和多能性相关联的此类因子的非限制性实例包括oct-3/4、sox家族(例如sox1、sox2、sox3和/或sox15)、klf家族(例如klfl、khzklf4和/或klf5)、myc家族(例如c-myc、l-myc和/或n-myc)、nanog和/或lin28。还可以实践本公开以治疗和/或预防代谢性病症，诸如糖尿病(例如胰岛素)、血友病(例如，因子ix或因子viii)、溶酶体贮积症(诸如粘多糖贮积症)(例如，sly综合征[β-葡萄糖醛酸酶]、胡尔勒综合征[α-l-艾杜糖醛酸酶]、舍氏综合征[α-l-艾杜糖醛酸酶]、胡尔勒-舍氏综合征[α-l-艾杜糖醛酸酶]、亨特氏综合征[艾杜糖醛酸硫酸酯酶]、沙费利波综合征a[乙酰肝素磺酰胺酶]、沙费利波综合征b[n-乙酰葡糖胺糖苷酶]、沙费利波综合征c[乙酰coa：α-氨基葡萄糖苷乙酰转移酶]、沙费利波综合征d[n-乙酰氨基葡萄糖6-硫酸酯酶]、莫奎欧氏综合征a[半乳糖-硫酸盐硫酸酯酶]、莫奎欧氏综合征b[β-半乳糖苷酶]、马洛托-拉米综合征[n-乙酰半乳糖胺-4-硫酸酯酶]等)、法布里病(α-半乳糖苷酶)、高雪氏病(葡萄糖脑苷脂酶)或糖原贮积症(例如庞贝病；溶酶体酸α-葡萄糖苷酶)。基因转移在了解疾病状态和提供疾病状态的治疗方面具有实质用途。存在许多缺陷基因已知并已被克隆的遗传疾病。通常，上述疾病状态分为两类：缺乏状态，经常为酶的缺乏状态，其通常以隐性方式遗传，以及不平衡状态，其可能涉及调节蛋白或结构蛋白，并且其通常以显性方式遗传。对于缺乏状态的疾病，基因转移可用于将正常基因带入受累组织中进行替代治疗，以及用于使用反义突变为所述疾病创建动物模型。对于不平衡的疾病状态，基因转移可用于在模型系统中创建疾病状态，然后可使用基因转移来尽力抵消所述疾病状态。因此，根据本公开的病毒载体允许治疗和/或预防遗传疾病。根据本公开的病毒载体也可用于在体外或体内向细胞提供功能性rna。功能性rna可以是例如非编码rna。在一些实施方案中，功能性rna在细胞中的表达可减少细胞对特定靶蛋白的表达。因此，可施用功能性rna以减少有需要的受试者中特定蛋白质的表达。在一些实施方案中，功能性rna在细胞中的表达可增加细胞对特定靶蛋白的表达。因此，可施用功能性rna以增加有需要的受试者中特定蛋白质的表达。在一些实施方案中，功能性rna的表达可调节细胞中特定靶rna的剪接。因此，可施用功能性rna以调节有需要的受试者中特定rna的剪接。在一些实施方案中，功能性rna在细胞中的表达可调节细胞对特定靶蛋白的功能。因此，可施用功能性rna以调节有需要的受试者中特定蛋白的功能。也可以在体外向细胞施用功能性rna，以调节基因表达和/或细胞生理，例如以优化细胞或组织培养系统或筛选方法。此外，根据本公开的病毒载体可用于诊断和筛选方法中，因此目标核酸在细胞培养系统或可替代地转基因动物模型中瞬时或稳定表达。如对本领域技术人员显而易见的，本公开的病毒载体还可用于各种非治疗目的，包括但不限于用于评定基因靶向、清除、转录、翻译等的方案中。病毒载体还可用于评估安全性(传播、毒性、免疫原性等)的目的。例如，在评估临床功效之前，美国食品和药物管理局认为此类数据是监管审批流程的一部分。另一方面，本公开的病毒载体可用于在受试者中产生免疫反应。根据此实施方案，可以向受试者施用含有编码免疫原性多肽的异源核酸序列的病毒载体，并且受试者针对所述免疫原性多肽产生主动免疫反应。免疫原性多肽为如上文所述。在一些实施方案中，引发了保护性免疫反应。可替代地，可以离体向细胞施用病毒载体，并且向受试者施用改变的细胞。将包含异源核酸的病毒载体引入到细胞中，并向受试者施用所述细胞，其中编码免疫原的异源核酸可被表达并在受试者中诱导针对免疫原的免疫反应。在特定实施方案中，所述细胞是抗原呈递细胞(例如树突状细胞)。“主动免疫反应”或“主动免疫”的特征在于在遇到免疫原后“宿主组织和细胞的参与”。其涉及淋巴网状组织中免疫活性细胞的分化和增殖，从而导致合成抗体或发展细胞介导的反应性，或两者兼而有之。”herbertb.herscowitz，immunophysiology：cellfunctionandcellularinteractionsinantibodyformation，inimmunology：basicprocesses117(josepha.bellanti编，1985)。可替代地说，在宿主暴露于通过感染或疫苗接种产生的免疫原后，会产生主动免疫反应。主动免疫可与被动免疫形成对比，被动免疫是通过将预先形成的物质(抗体、转移因子、胸腺移植物、白介素2)从主动免疫的宿主转移到非免疫宿主而获得的。如本文所用，“保护性”免疫反应或“保护性”免疫表示，免疫反应由于其预防或减少疾病的发生率而赋予受试者一些益处。可替代地，保护性免疫反应或保护性免疫可用于治疗和/或预防疾病，特别是癌症或肿瘤(例如，通过预防癌症或肿瘤形成、通过引起癌症或肿瘤消退和/或通过预防转移和/或通过预防转移性结节的生长)。保护性作用可以是完全的或部分的，只要治疗的益处大于其任何缺点。在特定实施方案中，包含异源核酸的病毒载体或细胞可以免疫原性有效量施用，如下文所述。本公开的病毒载体还可以通过施用表达产生针对癌细胞的免疫反应的一种或多种癌症细胞抗原(或免疫学上类似的分子)或任何其他免疫原的病毒载体来施用以用于癌症免疫治疗。为了说明，通过施用包含编码癌症细胞抗原的异源核酸的病毒载体，可在受试者中产生针对癌症细胞抗原的免疫反应，例如以治疗患有癌症的患者和/或预防受试者发展癌症。如本文所述，可以在体内或通过使用离体方法向受试者施用病毒载体。可替代地，癌症抗原可以作为病毒衣壳的一部分来表达或以其他方式与病毒衣壳缔合(例如，如上文所述)。作为另一种替代方案，可施用本领域已知的任何其他治疗性核酸(例如rnai)或多肽(例如细胞因子)以治疗和/或预防癌症。如本文所用，术语“癌症”涵盖形成肿瘤的癌症。同样地，术语“癌组织”涵盖肿瘤。“癌症细胞抗原”涵盖肿瘤抗原。术语“癌症”在本领域中具有其理解的含义，例如，有可能扩散到身体远处部位(即，转移)的组织不受控制生长。示例性癌症包括但不限于黑色素瘤、腺癌、胸腺瘤、淋巴瘤(例如，非霍奇金淋巴瘤、霍奇金淋巴瘤)、肉瘤、肺癌、肝癌、结肠癌、白血病、子宫癌、乳腺癌、前列腺癌、卵巢癌、宫颈癌、膀胱癌、肾癌、胰腺癌、脑癌以及现在已知或以后鉴定的任何其他癌症或恶性病状。在代表性实施方案中，本公开提供了一种治疗和/或预防形成肿瘤的癌症的方法。术语“肿瘤”在本领域中还被理解为例如多细胞生物体内未分化细胞的异常团块。肿瘤可以是恶性的或良性的。在代表性实施方案中，本文公开的方法用于预防并治疗恶性肿瘤。术语“治疗癌症”、“癌症的治疗”以及等效术语预期是指降低或至少部分消除癌症的严重性和/或减缓和/或控制疾病的进展和/或者稳定疾病。在特定实施方案中，这些术语表示预防或减少或至少部分消除癌症的转移，和/或预防或减少或至少部分消除转移性结节的生长。术语“癌症的预防”或“预防癌症”以及等效术语预期是指所述方法至少部分消除或减少和/或延迟癌症发作的发生率和/或严重性。可替代地说，受试者的癌症发作的可能性或概率可降低和/或癌症发作延迟。在特定实施方案中，可将细胞从患有癌症的受试者中去除并使其与根据本公开的表达癌症细胞抗原的病毒载体接触。然后向受试者施用修饰的细胞，从而引发针对癌症细胞抗原的免疫反应。此方法可有利地用于不能在体内产生足够免疫反应(即，不能产生足够数量的增强抗体)的免疫功能低下的受试者。本领域已知，免疫反应可通过免疫调节细胞因子(例如，α-干扰素、β-干扰素、γ-干扰素、ω-干扰素、τ-干扰素、白介素-1-α、白介素-1β、白介素2、白介素3、白介素4、白介素5、白介素6、白介素7、白介素8、白介素9、白介素10、白介素11、白介素12、白介素13、白介素14、白介素18、b细胞生长因子、cd40配体、肿瘤坏死因子-α、肿瘤坏死因子-β、单核细胞趋化蛋白1、粒细胞-巨噬细胞集落刺激因子和淋巴毒素)来增强。因此，可将免疫调节细胞因子(优选地，ctl诱导性细胞因子)与病毒载体一起施用于受试者。细胞因子可通过本领域中已知的任何方法来施用。可以向受试者施用外源性细胞因子，或者可替代地，可以使用合适的载体将编码细胞因子的核酸递送至受试者并且在体内产生细胞因子。受试者、药物制剂和施用模式根据本公开的病毒载体和衣壳可用于兽医施用和医疗施用两者中。合适的受试者包括禽类和哺乳动物两者。如本文所用，术语“禽类”包括但不限于鸡、鸭、鹅、鹌鹑、火鸡、野鸡、鹦鹉、长尾小鹦鹉等。如本文所用，术语“哺乳动物”包括但不限于人类、非人灵长类动物、牛、绵羊、山羊、马、猫、犬、兔形动物等。人类受试者包括新生儿、婴儿、少年、成人和老年受试者。在一些实施方案中，人类受试者可以小于6个月大、小于2岁、小于5岁、小于10岁、10-18岁、19-29岁、30-35岁、36-40岁或大于40岁。在代表性实施方案中，受试者“需要”本文所述的方法。在特定实施方案中，提供了一种药物组合物，其包含药学上可接受的载体中的本公开的病毒载体和/或衣壳和/或衣壳蛋白和/或病毒颗粒，以及任选地其他药用剂、药物试剂、稳定剂、缓冲剂、载体、佐剂、稀释剂等。对于注射，所述载体通常是液体。对于其他施用方法，所述载体可以是固体或液体。对于吸入施用，所述载体是可吸入的，并且任选地可以是呈固体或液体微粒形式。“药学上可接受的”意指无毒或在其他方面不合需要的材料，即可向受试者施用所述材料而不会引起任何不合需要的生物效应。本公开的一个方面是一种在体外将核酸转移至细胞的方法。根据适用于特定靶细胞的标准转导方法，可以适当的感染复数将病毒载体引入到细胞中。待施用的病毒载体的滴度可以根据靶细胞的类型和数量以及特定的病毒载体而变化，并且可以由本领域技术人员确定而无需过度的实验。在代表性实施方案中，将至少约103个感染性单位，任选地至少约105个感染性单位引入到细胞中。病毒载体引入到其中的细胞可以是任何类型的细胞，包括但不限于神经细胞(包括外周神经系统和中枢神经系统的细胞，特别是脑细胞，诸如神经元和少突胶质细胞)、肺细胞、眼部细胞(包括视网膜细胞、视网膜色素上皮和角膜细胞)、上皮细胞(例如肠道和呼吸道上皮细胞)、肌肉细胞(例如骨骼肌细胞、心肌细胞、平滑肌细胞和/或膈肌细胞)、树突状细胞、胰腺细胞(包括胰岛细胞)、肝细胞、心肌细胞、骨细胞(例如骨髓干细胞)、造血干细胞、脾细胞、角质形成细胞、成纤维细胞、内皮细胞、前列腺细胞、生殖细胞等。在代表性实施方案中，所述细胞可以是任何祖细胞。作为另一种可能性，所述细胞可以是干细胞(例如神经干细胞、肝干细胞)。作为又一种替代方案，所述细胞可以是癌细胞或肿瘤细胞。此外，如上文指出，所述细胞可以是来自任何来源的物种。为了向受试者施用修饰的细胞的目的，可以在体外将病毒载体引入到细胞中。在特定实施方案中，细胞已从受试者中移出，将病毒载体引入到其中，并且然后将所述细胞施用回受试者中。从受试者移出细胞用于离体操作、然后再将其引入到受试者中的方法是本领域已知的(参见，例如美国专利号5，399，346)。可替代地，可以将重组病毒载体引入到来自供体受试者的细胞、培养的细胞或来自任何其他合适来源的细胞中，并向有需要的受试者(即“受体”受试者)施用所述细胞。用于离体核酸递送的合适的细胞是如上文所述。向受试者施用的细胞剂量将根据受试者的年龄、病状和物种、细胞类型、由细胞表达的核酸、施用模式等而变化。通常，在药学上可接受的载体中每个剂量将施用至少约102至约108个细胞或至少约103至约106个细胞。在特定实施方案中，将用病毒载体转导的细胞以治疗有效量与药物载体组合施用于受试者。在一些实施方案中，将病毒载体引入到细胞中，并且可以向受试者施用所述细胞以引发针对所递送的多肽的免疫原性反应(例如，作为转基因表达或在衣壳中表达)。通常，施用大量表达免疫原性有效量的多肽的细胞与药学上可接受的载体的组合。“免疫原性有效量”是表达的多肽足以在施用药物制剂的受试者中引起针对所述多肽的主动免疫反应的量。在特定实施方案中，所述剂量足以产生保护性免疫反应(如上文所定义)。所赋予的保护程度不需要是完全的或永久的，只要施用免疫原性多肽的益处大于其任何缺点。因此，本公开提供了一种向细胞施用核酸的方法，所述方法包括使所述细胞与本公开的病毒载体、病毒颗粒和/或组合物接触。本公开的另一方面是一种向受试者施用本公开的病毒载体、病毒颗粒和/或病毒衣壳的方法。因此，本公开还提供了一种将核酸递送至受试者的方法，其包括向所述受试者施用本公开的病毒颗粒、病毒载体和/或组合物。根据本公开的病毒载体、病毒颗粒和/或衣壳向有需要的人类受试者或动物的施用可以通过本领域已知的任何手段来进行。任选地，在药学上可接受的载体中以治疗有效剂量递送病毒载体、病毒颗粒和/或衣壳。在优选实施方案中，递送治疗有效量的病毒载体、病毒颗粒和/或衣壳。可以进一步施用本公开的病毒载体和/或衣壳以引发免疫原性反应(例如，作为疫苗)。通常，本公开的免疫原性组合物包含免疫原性有效量的病毒载体和/或衣壳与药学上可接受的载体的组合。任选地，所述剂量足以产生保护性免疫反应(如上文所定义)。所赋予的保护程度不需要是完全的或永久的，只要施用免疫原性多肽的益处大于其任何缺点。受试者和免疫原是如上文所述。待向受试者施用的病毒载体和/或衣壳的剂量取决于施用模式、待治疗和/或预防的疾病或病状、个体受试者的病状、特定的病毒载体或衣壳以及待递送的核酸等，并且可以常规方式来确定。用于实现治疗效果的示例性剂量是至少约105、约106、约107、约108、约109、约1010、约1011、约1012、约1013、约1014、约1015个转导单位，任选地约108-1013个转导单位的滴度。在特定实施方案中，不止一次施用(例如两次、三次、四次或更多次施用)可用于在各种时间间隔(例如每天、每周、每月、每年等)的时间段内实现所需的基因表达水平。示例性施用模式包括口服、直肠、经粘膜、鼻内、吸入(例如通过气雾剂)、经颊(例如舌下)、阴道、鞘内、眼内、经皮肤、子宫内(或卵内)、肠胃外(例如静脉内、皮下、皮内、肌肉内[包括向骨骼肌、膈肌和/或心肌的施用]、皮内、胸膜内、脑内和关节内)、局部(例如，向皮肤和粘膜表面(包括气道表面)施用以及经皮肤施用)、淋巴内等，以及直接组织或器官注射(例如，向肝脏、骨骼肌、心肌、膈肌或脑注射)。也可以向肿瘤施用(例如，在肿瘤或淋巴结中或附近)。在一些实施方案中，例如通过玻璃体内、视网膜下、结膜下、球后、前房内和/或脉络膜上途径将病毒载体或组合物施用于受试者的眼睛。在任何给定的情况下，最合适的途径取决于所治疗和/或预防的病状的性质和严重性，并且取决于所使用的特定载体的性质。根据本公开的向骨骼肌的施用包括但不限于向四肢(例如上臂、下臂、大腿和/或小腿)、背部、颈部、头部(例如舌头)、胸部、腹部、骨盆/会阴和/或手指中的骨骼肌的施用。合适的骨骼肌包括但不限于小指展肌(在手中)、小趾展肌(在脚中)、拇展肌、小跖骨展肌(abductorossismetatarsiquinti)、拇短展肌、拇长展肌、短收肌、拇收肌(adductorhallucis)、长收肌、大收肌、拇收肌(adductorpollicis)、肘肌、前斜角肌、膝关节肌、肱二头肌、股二头肌、肱肌、肱桡肌、颊肌、喙肱肌、皱眉肌、三角肌、降口角肌、降下唇肌、二腹肌、背侧骨间肌(在手中)、背侧骨间肌(在脚中)、桡侧伸腕短肌、桡侧伸腕长肌、尺侧腕伸肌、小指伸肌、指伸肌、趾短伸肌、趾长伸肌、拇短伸肌(extensorhallucisbrevis)、拇长伸肌(extensorhallucislongus)、示指伸肌、拇短伸肌(extensorpollicisbrevis)、拇长伸肌(extensorpollicislongus)、桡侧腕屈肌、尺侧腕屈肌、屈小指短肌(在手中)、屈小趾短肌(在脚中)、屈趾短肌、屈趾长肌、指深屈肌、指浅屈肌、屈姆短肌(flexorhallucisbrevis)、屈姆长肌(flexorhallucislongus)、屈姆短肌(flexorpollicisbrevis)、屈姆长肌(flexorpollicislongus)、额肌、腓肠肌、颏舌骨肌、臀大肌、臀中肌、臀小肌、股薄肌、颈髂肋肌、腰髂肋肌、胸髂肋肌、髂肌、下孖肌、下斜肌、下直肌、冈下肌、棘间肌、间向肌、翼外肌、外直肌、背阔肌、提口角肌、提上唇肌、提上唇鼻翼肌、提上睑肌、肩胛提肌、长回旋肌、头最长肌、颈最长肌、胸最长肌、头长肌、颈长肌、蚓状肌(在手中)、蚓状肌(在脚中)、咬肌、翼内肌、内直肌、中斜角肌、多裂肌、下颔舌骨肌、头下斜肌、头上斜肌、闭孔外肌、闭孔内肌、枕肌、肩胛舌骨肌、小指对掌肌(opponensdigitiminimi)、拇对掌肌、眼轮匝肌、口轮匝肌、掌侧骨间肌、掌短肌、掌长肌、耻骨肌、胸大肌、胸小肌、腓骨短肌、腓骨长肌、第三腓骨肌、梨状肌、骨间足底肌、跖肌、颈阔肌、腘肌、后斜角肌、旋前方肌、旋前圆肌、腰大肌、股方肌、跖方肌、头前直肌、头外侧直肌、头后大直肌、头后小直肌、股直肌、大菱形肌、小菱形肌、笑肌、缝匠肌、小斜角肌、半膜肌、头半棘肌、颈半棘肌、胸半棘肌、半腱肌、前锯肌、短回旋肌、比目鱼肌、头棘肌、颈棘肌、胸棘肌、头夹肌、颈夹肌、胸锁乳突肌、胸骨舌骨肌、胸骨甲状肌、茎突舌骨肌、锁骨下肌、肩胛下肌、上孖肌、上斜肌、上直肌、旋后肌、冈上肌、颞肌、阔筋膜张肌、大圆肌、小圆肌、胸肌、甲状舌骨肌、胫骨前肌、胫骨后肌、斜方肌、肱三头肌、股中间肌、股外侧肌、股内侧肌、颧大肌和颧小肌以及如本领域中已知的任何其他合适的骨骼肌。可以通过静脉内施用、动脉内施用、腹膜内施用、肢体灌注(任选地，隔离的腿和/或手臂的肢体灌注；参见例如arruda等，(2005)blood105：3458-3464)和/或直接肌肉内注射来向骨骼肌递送病毒载体和/或衣壳。在特定实施方案中，通过肢体灌注，任选地隔离的肢体灌注(例如通过静脉内或关节内施用)来向受试者(例如，患有肌营养不良症诸如dmd的受试者)的肢体(手臂和/或腿)施用病毒载体和/或衣壳。在本公开的实施方案中，可以有利地施用本公开的病毒载体和/或衣壳而无需采用“流体力学”技术。现有技术载体的组织递送(例如，向肌肉)经常通过流体力学技术(例如，大容量的静脉内/静脉内施用)来增强，这增加了脉管系统中的压力并促进了所述载体穿过内皮细胞屏障的能力。在特定实施方案中，可以在不存在流体力学技术，诸如高容量输注和/或升高的血管内压力(例如大于正常收缩压，例如血管内压力相对于正常收缩压小于或等于5％、10％、15％、20％、25％增加)的情况下施用本公开的病毒载体和/或衣壳。此类方法可以减少或避免与流体力学技术相关联的副作用，诸如水肿、神经损伤和/或筋膜室综合征。向心肌的施用包括向左心房、右心房、左心室、右心室和/或隔膜的施用。病毒载体和/或衣壳可以通过静脉内施用、动脉内施用(诸如主动脉内施用)、直接心脏注射(例如，注入左心房、右心房、左心室、右心室)和/或冠状动脉灌注来递送至心肌。向膈肌的施用可以通过任何合适的方法，包括静脉内施用、动脉内施用和/或腹膜内施用来进行。还可以通过递送包含病毒载体和/或衣壳的储库来实现递送至靶组织。在代表性实施方案中，将包含病毒载体和/或衣壳的储库植入骨骼肌、心肌和/或膈肌组织中，或者可使组织与包含病毒载体和/或衣壳的薄膜或其他基质接触。此类可植入的基质或底物描述于美国专利号7,201,898中。在特定实施方案中，向骨骼肌、膈肌和/或心肌施用根据本公开的病毒载体和/或病毒衣壳(例如，以治疗和/或预防肌营养不良症、心脏病[例如，pad或充血性心力衰竭])。在代表性实施方案中，本公开用于治疗和/或预防骨骼肌、心肌和/或膈肌的病症。在代表性实施方案中，提供了一种在有需要的受试者中治疗和/或预防肌营养不良症的方法，所述方法包括：向哺乳动物受试者施用治疗或预防有效量的本公开的病毒载体，其中所述病毒载体包含编码抗肌萎缩蛋白、小型抗肌萎缩蛋白、微型抗肌萎缩蛋白、肌肉生长抑制素前肽、卵泡抑素、激活素ii型可溶性受体、igf-1、抗炎多肽(诸如iκb显性突变体)、肌长蛋白、肌营养相关蛋白、微型抗肌萎缩蛋白、层粘连蛋白-α2、α-肌聚糖、β-肌聚糖、γ-肌聚糖、δ-肌聚糖、igf-1、针对肌肉生长抑制素或肌肉生长抑制素前肽的抗体或抗体片段和/或针对肌肉生长抑制素的rnai的异源核酸。在特定实施方案中，可如本文其他地方所述地向骨骼肌、膈肌和/或心肌施用所述病毒载体。可替代地，可实践本公开以将核酸递送至骨骼肌、心肌或膈肌，所述骨骼肌、心肌或膈肌用作产生通常在血液中循环的多肽(例如酶)或功能性rna(例如，rnai、微型rna、反义rna)或用于全身递送至其他组织以治疗和/或预防病症(例如，代谢性病症，诸如糖尿病[例如胰岛素]、血友病[例如，因子ix或因子viii]、粘多糖贮积症[例如，sly综合征、胡尔勒综合征、舍氏综合征、胡尔勒-舍氏综合征、亨特氏综合征、沙费利波综合征a、沙费利波综合征b、沙费利波综合征c、沙费利波综合征d、莫奎欧氏综合征、马洛托-拉米综合征等]，或溶酶体贮积症，诸如高雪氏病[葡萄糖脑苷脂酶]或法布里病[α-半乳糖苷酶a]，或糖原贮积症，诸如庞贝病[溶酶体酸α葡萄糖苷酶])的平台。本文描述了用于治疗和/或预防代谢性病症的其他合适的蛋白质。肌肉作为表达目标核酸的平台的用途描述于美国专利公布号us2002/0192189中。因此，一方面，本公开还涵盖一种在有需要的受试者中治疗和/或预防代谢性病症的方法，所述方法包括：向受试者的骨骼肌施用治疗或预防有效量的本公开的病毒载体，其中所述病毒载体包含编码多肽的异源核酸，其中所述代谢性病症是所述多肽缺乏和/或缺陷的结果。本文描述了说明性代谢性病症和编码多肽的异源核酸。任选地，所述多肽是分泌的(例如，在其天然状态下是分泌的多肽或已被工程化为例如通过与本领域已知的分泌信号序列可操作地缔合来分泌的多肽)。不受限于本公开的任何特定理论，根据此实施方案，向骨骼肌的施用可导致所述多肽分泌到全身循环中并递送至靶组织。本文更详细地描述了将病毒载体递送至骨骼肌的方法。还可以实践本公开以产生用于全身递送的非编码rna，诸如反义rna、rnai或其他功能性rna(例如，核酶)。本公开还提供了一种在有需要的受试者中治疗和/或预防先天性心力衰竭或pad的方法，所述方法包括向哺乳动物受试者施用治疗或预防有效量的本公开的病毒载体，其中所述病毒载体包含编码例如肌浆内网ca2+-atp酶(serca2a)、血管生成因子、磷酸酶抑制剂i(i-1)及其片段(例如i1c)、针对受磷蛋白的rnai；受磷蛋白抑制性或显性负分子(诸如受磷蛋白s16e)、调节受磷蛋白基因的锌指蛋白、β-2-肾上腺素能受体、β-2-肾上腺素能受体激酶(bark)、pi3激酶、calsarcan、β-肾上腺素能受体激酶抑制剂(parkct)、蛋白磷酸酶1的抑制剂1及其片段(例如i1c)、s100a1、小白蛋白、腺苷酸环化酶6型、实现g蛋白偶联受体激酶2型敲低的分子(诸如截短的组成性活性barkct)、pim-1、pgc-iα、sod-1、sod-2、ec-sod、激肽释放酶、hif、胸腺素p4、mir-1、mir-133、mir-206、mir-208和/或mir-26a的异源核酸。注射剂可以常规形式，以液体溶液或混悬液、适用于在注射前在液体中溶解或混悬的固体形式或乳剂形式来制备。可替代地，可以局部而不是全身的方式，例如以储库或缓释制剂的方式施用本公开的病毒载体和/或病毒衣壳。此外，病毒载体和/或病毒衣壳可以粘附在可手术植入的基质上递送(例如，如美国专利公布号us-2004-0013645-a1所述)。可通过任何合适的手段，任选地通过施用受试者吸入的包含病毒载体和/或病毒衣壳的可吸入颗粒的气溶胶悬浮液，向受试者的肺施用本文公开的病毒载体和/或病毒衣壳。所述可吸入颗粒可以是液体或固体。如本领域技术人员已知的，包含病毒载体和/或病毒衣壳的液体颗粒的气溶胶可以通过任何合适的手段，诸如使用压力驱动的气溶胶雾化器或超声雾化器来产生。参见例如美国专利号4,501,729。包含病毒载体和/或衣壳的固体颗粒的气溶胶同样可以使用任何固体微粒药物气溶胶发生器，通过制药领域已知的技术来产生。病毒载体和病毒衣壳可施用于cns的组织(例如，脑、眼)，并且可以有利地导致病毒载体或衣壳的分布比在不存在本公开的情况下所观察到的分布更广泛。在特定实施方案中，可以施用本文所述的递送载体以治疗cns的疾病，包括遗传性病症、神经退行性病症、精神病和肿瘤。说明性cns的疾病包括但不限于cns的肾上腺脊髓神经病(amn)、阿尔茨海默氏病、安格曼综合征(angelmansyndrome)、帕金森氏病、亨廷顿氏病、卡纳万氏病、利氏病(leigh’sdisease)、雷弗素姆氏病(refsumdisease)、图雷特综合征(tourettesyndrome)、原发性侧索硬化、肌萎缩性脊髓侧索硬化症、进行性肌萎缩症、皮克氏病、肌营养不良症、多发性硬化症、重症肌无力、宾斯旺格氏病(binswanger’sdisease)、脊髓或头部受伤所致的创伤、泰萨克斯病(gm2神经节苷脂沉积症)、莱施-尼汉病、mc4r肥胖症、异染性脑白质营养不良(mld)、mpsi(胡尔勒/舍氏)、mpsiiia(沙费利波a)、尼曼皮克c1、雷特综合征(rettsyndrome)、脊髓性肌萎缩症(sma)、aadc缺乏症、单基因肌萎缩性脊髓侧索硬化症(als)、α甘露糖苷贮积症、阿尔茨海默氏病、天冬氨酰葡萄糖胺尿症、德拉韦综合征(dravetsyndrome)、巨轴索神经病、球形细胞样脑白质病(krabbe)、glut1缺乏症、gm1神经节苷脂沉积症、婴儿神经性脑膜脂霉素病(infantileneuronalceroidlipfuscinosis)(incl，batten)、少年神经性脑膜脂霉素病(jncl，batten)、晚发性婴儿神经性脑膜脂霉素病(lincl，batten)、mpsii(亨特氏)、mpsiiib(沙费利波b)、mpsiiic(沙费利波c)、mpsiva(莫奎欧氏综合征)、mpsvi(马洛托-拉米)、过氧化物酶体生物发生病症(泽尔韦格氏综合征(zellwegersyndrome)谱)、山德霍夫氏病(sandhoffdisease)(gm2神经节苷脂沉积症)、莱施-尼汉病(lesch-nyhandisease)、癫痫、脑梗塞、精神病(包括情绪障碍)(例如，抑郁症、双相情感障碍、持续性情感障碍、继发性情绪障碍)、精神分裂症、药物依赖性(例如酒精中毒和其他物质依赖性)、神经症(例如焦虑症、强迫症、躯体形式障碍、分离性障碍、悲伤、产后抑郁症)、精神病(psychosis)(例如幻觉和妄想)、痴呆、偏执狂、注意力缺损症、性心理障碍、睡眠障碍、疼痛障碍、饮食或体重障碍(例如肥胖症、恶病质、神经性厌食症和暴食症(bulemia))以及癌症和肿瘤(例如垂体瘤)。cns的病症包括涉及视网膜、后路和视神经的眼科病症。例如，此类病症包括色素性视网膜炎、糖尿病视网膜病变和其他视网膜退行性疾病、葡萄膜炎、年龄相关性黄斑变性、视神经炎、莱伯氏先天性黑蒙症(leber’scongenitalamaurosis)、莱伯氏遗传性视神经病变(leber’shereditaryopticneuropathy)、全色盲(achromatopsia)、x连锁视网膜劈裂症、视神经炎、脉络膜炎、视神经萎缩、视锥营养不良、视网膜病变、视网膜母细胞瘤、青光眼、巴德-毕氏综合征(bardet-biedlsyndrome)、乌谢尔综合征(ushersyndrome)、无虹膜、弗里德赖希氏共济失调(friedreich’sataxia)、卵黄状黄斑营养不良、视网膜母细胞瘤、斯塔加特病(stargardtdisease)、夏科-马利-杜斯氏病(charcot-marie-toothdisease)、富克斯氏营养不良(fuch’sdystrophy)、丙酸血症或色盲(colorblindness)。因此，在一些实施方案中，本公开提供了治疗受试者的眼科病症或缺陷的方法，其包括向受试者施用本公开的病毒载体，其中所述病毒载体包含编码有效治疗眼科病症或缺陷的治疗性蛋白或治疗性rna的核酸分子。在此方法的一些实施方案中，病毒载体通过玻璃体内、视网膜下、结膜下、球后、前房内和/或脉络膜上途径施用。大多数(如果不是全部的话)眼科疾病和病症与以下三种适应症中的一种或多种相关联：(1)血管生成、(2)炎症和(3)变性。本公开的递送载体可以用于递送抗血管生成因子；抗炎因子；延迟细胞变性、促进细胞保留或促进细胞生长的因子以及前述各项的组合。例如，糖尿病视网膜病变的特征在于血管生成。糖尿病视网膜病变可以通过眼内(例如，在玻璃体中)或眼周(例如，在眼球筋膜囊下区域(sub-tenon’sregion))递送一种或多种抗血管生成因子来治疗。一种或多种神经营养因子也可以眼内(例如，玻璃体内)或眼周共递送。葡萄膜炎涉及炎症。一种或多种抗炎因子可以通过眼内(例如，玻璃体或前房)施用本公开的递送载体来施用。相比之下，色素性视网膜炎的特征在于视网膜变性。在代表性实施方案中，色素性视网膜炎可以通过眼内(例如玻璃体施用)编码一种或多种神经营养因子的递送载体来治疗。年龄相关性黄斑变性涉及血管生成和视网膜变性两者。此病症可以通过在眼内(例如玻璃体)施用编码一种或多种神经营养因子的本发明的递送载体和/或眼内或眼周(例如在眼球筋膜囊下区域)施用编码一种或多种抗血管生成因子的本发明的递送载体来治疗。青光眼的特征在于眼压升高和视网膜神经节细胞丧失。青光眼的治疗包括使用递送载体施用一种或多种保护细胞使其免于兴奋毒性损害的神经保护剂。此类药剂包括眼内，任选地玻璃体内递送的n-甲基-d-天冬氨酸(nmda)拮抗剂、细胞因子和神经营养因子。在其他实施方案中，本公开可用于治疗癫痫发作，例如减少癫痫发作的发作、发生率或严重性。癫痫发作的治疗方法的功效可以通过行为(例如，晃动、眼或嘴的抽搐)和/或电图手段(大多数癫痫发作具有标志性的电图异常)来评定。因此，本公开还可以用于治疗癫痫，其以随着时间推移的多次癫痫发作为标记。在一个代表性实施方案中，使用本公开的递送载体向脑施用生长激素抑制素(或其活性片段)以治疗垂体瘤。根据此实施方案，编码生长激素抑制素(或其活性片段)的递送载体通过微输注来施用于垂体。同样地，此类治疗可用于治疗肢端肥大症(垂体生长激素分泌异常)。生长激素抑制素的核酸序列(例如，genbank登录号j00306)和氨基酸序列(例如，genbank登录号p01166；含有加工过的活性肽生长激素抑制素28和生长激素抑制素14)是本领域已知的。在特定实施方案中，所述载体可以包含如美国专利号7,071,172所述的分泌信号。在本公开的代表性实施方案中，向cns(例如，向脑或眼)施用病毒载体和/或病毒衣壳。病毒载体和/或衣壳可以被引入到脊髓、脑干(延髓、脑桥)、中脑(下丘脑、丘脑、上丘脑、脑垂腺、黑质、松果体)、小脑、端脑(纹状体、大脑(包括枕叶、颞叶、顶叶和额叶)、皮质、基底神经节、海马和门扁桃体)、边缘系统、新皮质、纹状体、大脑和下丘中。病毒载体和/或衣壳也可以施用于眼部的不同区域，诸如视网膜、角膜和/或视神经。病毒载体和/或衣壳可以被递送到脑脊髓液中(例如，通过腰椎穿刺)，用于更分散地施用递送载体。在已干扰血-脑屏障的情况下(例如，脑肿瘤或脑梗塞)，病毒载体和/或衣壳可以进一步在血管内施用于cns。病毒载体和/或衣壳可以通过本领域已知的任何途径施用于cns的所需区域，所述途径包括但不限于鞘内、眼内、脑内、脑室内、静脉内(例如，在糖诸如甘露醇存在下)、鼻内、耳内、眼内(例如玻璃体内、视网膜下、前房)和眼周(例如眼球筋膜囊下区域)递送以及肌肉内递送并逆行递送至运动神经元。在特定实施方案中，病毒载体和/或衣壳通过直接注射(例如立体定向注射)以液体制剂的形式施用于cns中的所需区域或筋膜室。在其他实施方案中，病毒载体和/或衣壳可以通过局部应用于所需区域或通过鼻内施用气溶胶制剂来提供。向眼部的施用可以通过局部应用液滴来进行。作为另一种替代方案，病毒载体和/或衣壳可以作为固体的缓释制剂施用(参见，例如美国专利号7,201,898)。在另外的实施方案中，病毒载体可以用于逆行运输以治疗和/或预防涉及运动神经元的疾病和病症(例如，肌萎缩性脊髓侧索硬化症(als)、脊髓性肌萎缩症(sma)等)。例如，病毒载体可被递送至肌肉组织，所述病毒载体可从所述肌肉组织迁移到神经元中。包括在下面的示例仅出于说明目的，并不旨在限制本发明。编号的实施方案以下编号的实施方案包含在本公开的范围内。1.一种重组腺相关病毒(aav)衣壳蛋白，其中所述衣壳蛋白包含在所述aav衣壳蛋白的表面暴露环中的取代，其中所述取代具有seqidno：14、15、16、17、18、19、20、21、22、187、188、189、190、191、192、193或194中任一者的序列。2.如实施方案1所述的重组aav衣壳蛋白，其中所述取代具有seqidno：14、17、19或22中任一者的序列。3.如实施方案1或2所述的重组aav衣壳蛋白，其中所述衣壳蛋白包含与aav1、aav2、aav3、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12、aavrh.8、aavrh.10、aavrh32.33、aavrh74、牛aav和禽aav中任一者的衣壳蛋白具有至少80％序列同一性的氨基酸序列。4.如实施方案1-3中任一项所述的重组aav衣壳蛋白，其中所述衣壳蛋白包含与seqidno：11-12、23-49或195-254中任一者具有至少90％序列同一性的氨基酸序列。5.如实施方案1-3中任一项所述的重组aav衣壳蛋白，其中所述衣壳蛋白包含seqidno：11-12、23-49或195-254中任一者的氨基酸序列。6.如实施方案5所述的重组aav衣壳蛋白，其中所述衣壳蛋白包含seqidno.32、35、37或40中任一者的氨基酸序列。7.如实施方案1-3中任一项所述的重组aav衣壳蛋白，其中所述氨基酸取代置换了对应于seqidno.11的氨基酸位置591-596或seqidno.12的氨基酸590-595的区域中的氨基酸。8.一种重组aav衣壳蛋白，其中所述衣壳蛋白包含取代，所述取代包含在天然aav衣壳蛋白中不存在的六个氨基酸的序列(x1-x2-x3-x4-x5-x6)，其中x2是v且x5是l(seqidno：186)。9.如实施方案8所述的重组aav衣壳蛋白，其中所述取代置换了对应于seqidno.11的氨基酸位置591-596或seqidno.12的氨基酸590-595的区域中的氨基酸。10.如实施方案8或9所述的重组aav衣壳蛋白，其中所述取代是在所述aav衣壳蛋白的表面暴露环中。11.如实施方案8-10中任一项所述的重组aav衣壳蛋白，其中x1不是t、x3不是d、x4不是r并且x6不是t。12.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是k、g、f、i、h或r。13.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x3是r、l、h、g或n。14.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x4是d、a、s或v或r。15.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x6是f、r、p、n或q。16.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是k、x3是r、x4是d并且x6是f。17.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是r、x3是l、x4是a并且x6是r。18.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是r、x3是h、x4是a并且x6是r。19.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是r、x3是h、x4是s并且x6是r。20.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是g、x3是g、x4是v并且x6是p。21.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是f、x3是n、x4是a并且x6是n。22.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是i、x3是r、x4是s并且x6是n。23.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是h、x3是l、x4是r并且x6是n。24.如实施方案8-11中任一项所述的重组aav衣壳蛋白，其中x1是r、x3是l、x4是a并且x6是q。25.如实施方案8-24中任一项所述的重组aav衣壳蛋白，其中所述aav衣壳蛋白的aav血清型选自aav1、aav2、aav3、aav4、aav5、aav6、aav7、aav8、aav9、aav10、aav11、aav12、aavrh.8、aavrh.10、aavrh32.33、aavrh74、牛aav和禽aav。26.一种重组aav衣壳蛋白，其包含seqidno：11-12、23-49或195-254中任一者的氨基酸序列。27.如实施方案26所述的重组aav衣壳蛋白，其包含seqidno.32、35、37或40的氨基酸序列。28.一种核苷酸序列，其编码如实施方案1至27中任一项所述的aav衣壳蛋白。29.如实施方案28所述的核苷酸序列，其中所述核苷酸序列是dna序列。30.如实施方案28所述的核苷酸序列，其中所述核苷酸序列是rna序列。31.一种表达载体，其包含如实施方案28-30中任一项所述的核苷酸序列。32.一种细胞，其包含如实施方案28至30中任一项所述的核苷酸序列或如实施方案31所述的表达载体。33.一种重组aav病毒载体，其包含如实施方案1至27中任一项所述的衣壳蛋白。34.如实施方案33所述的重组aav病毒载体，其中与包括不包含所述取代的衣壳蛋白的aav病毒载体相比，所述aav病毒载体关于靶组织具有增强的转导概况。35.如实施方案34所述的重组aav病毒载体，其中所述靶组织是眼组织。36.如实施方案33-35中任一项所述的重组aav病毒载体，其还包含被所述衣壳蛋白衣壳化的货物核酸。37.如实施方案36所述的重组aav病毒载体，其中所述货物核酸编码治疗性蛋白或rna。38.如实施方案36或37所述的重组aav病毒载体，其中所述货物核酸编码一种或多种以下蛋白质或与其结合的抗体：囊性纤维化跨膜调节蛋白(cftr)、抗肌萎缩蛋白、肌肉生长抑制素前肽、卵泡抑素、激活素11型可溶性受体、igf-i、iκb显性突变体、肌长蛋白、肌营养相关蛋白、小型肌营养相关蛋白、因子viii、因子ix、因子x、促红细胞生成素、血管抑素、内皮抑素、过氧化氢酶、酪氨酸羟化酶、超氧化物歧化酶、瘦素、ldl受体、脂蛋白脂肪酶、鸟氨酸转氨甲酰酶、β-球蛋白、α-球蛋白、血影蛋白、α-1-抗胰蛋白酶、腺苷脱氨酶、次黄嘌呤鸟嘌呤磷酸核糖转移酶、β-葡萄糖脑苷脂酶、鞘磷脂酶、溶酶体己糖胺酶a、支链酮酸脱氢酶、rpe65蛋白、α-干扰素、β-干扰素、γ-干扰素、白介素2、白介素4、粒细胞-巨噬细胞集落刺激因子、淋巴毒素、肽生长因子、神经营养因子、生长激素、胰岛素、胰岛素样生长因子1或胰岛素样生长因子2、血小板源性生长因子、表皮生长因子、成纤维细胞生长因子、神经生长因子、神经营养因子3或神经营养因子4、脑源性神经营养因子、rankl、vegf、胶质源性生长因子、转化生长因子α或转化生长因子β、溶酶体酸α-葡萄糖苷酶、α-半乳糖苷酶a、肿瘤坏死生长因子可溶性受体、s100a1、小白蛋白、腺苷酸环化酶6型、pp1的serca2a抑制剂1或其片段、截短的组成性活性barkct、irap、抗肌肉生长抑制素蛋白、天冬氨酸酰化酶、曲妥珠单抗、甘丙肽、神经肽y、血管抑制蛋白2、胸苷激酶、胞嘧啶脱氨酶、白喉毒素、肿瘤坏死因子、p53、rb、wt-1、trail、rs1、opsin、tkr-β、c3、cfh和/或fas配体。39.如实施方案36或37所述的重组aav病毒载体，其中所述货物核酸编码基因编辑分子。40.如实施方案39所述的重组aav病毒载体，其中所述基因编辑分子是核酸酶。41.如实施方案39或40所述的重组aav病毒载体，其中所述基因编辑分子是cas9核酸酶。42.如实施方案39或40所述的重组aav病毒载体，其中所述基因编辑分子是cpf1核酸酶。43.如实施方案39所述的重组aav病毒载体，其中所述基因编辑分子是指导rna。44.一种药物组合物，其包含如实施方案33至43中任一项所述的重组aav病毒载体。45.如实施方案44所述的药物组合物，其中所述组合物还包含药学上可接受的载体。46.一种治疗有需要的患者的方法，其包括向所述患者施用治疗有效量的如实施方案33至43中任一项所述的重组aav病毒载体或如实施方案44或45所述的药物组合物。47.如实施方案46所述的方法，其中所述患者患有眼睛疾病或病症。48.如实施方案47所述的方法，其中所述眼睛疾病或病症包括色素性视网膜炎、黄斑变性、视神经炎、莱伯氏先天性黑蒙症、莱伯氏遗传性视神经病变、全色盲、x连锁视网膜劈裂症、视神经炎、脉络膜炎、视神经萎缩、视锥营养不良、视网膜病变、视网膜母细胞瘤、青光眼、巴德-毕氏综合征、乌谢尔综合征、无虹膜、弗里德赖希氏共济失调、卵黄状黄斑营养不良、视网膜母细胞瘤、斯塔加特病、夏科-马利-杜斯氏病、富克斯氏营养不良、丙酸血症或色盲。49.如实施方案46-48中任一项所述的方法，其中所述患者是哺乳动物。50.如实施方案49所述的方法，其中所述患者是人类。51.一种将核酸分子引入到细胞中的方法，其包括使所述细胞与如实施方案33至43中任一项所述的重组aav病毒载体接触。52.如实施方案32-43中任一项所述的aav病毒载体，其用作药物。53.如实施方案32-43中任一项所述的aav病毒载体，其用于治疗方法中。实施例实施例1.靶向眼组织的aav载体的组合工程化和选择用于产生靶向眼组织(即，rpe和/或视网膜)的aav突变体的方法如下。第一步骤涉及例如使用冷冻电子显微镜鉴定在aav衣壳表面上的构象3d表面暴露环。然后使用其中每个密码子均被核苷酸nnk取代的简并引物和通过gibson组装和/或多步骤pcr组合在一起的基因片段对表面暴露环内的所选残基进行诱变。将含有突变的抗原基序的简并文库的衣壳编码基因克隆到野生型aav基因组中，以置换原始的cap编码dna序列，从而得到质粒文库。然后将质粒文库用腺病毒辅助质粒转染到293生产细胞系中，以产生aav衣壳文库，然后可以对其进行选择。通过dna测序确认aav文库的成功产生。为了选择具有期望转导概况的新aav病毒株，将aav文库在非人灵长类动物中进行多轮感染。在每个阶段，将目标组织从动物受试者中分离。对从目标组织中收获的细胞裂解物进行测序，以鉴定成功转导了目标靶组织的aav载体分离物。在非人灵长类动物中进行了多轮感染后，将来自每个诱变区域的分离序列以所有排列和组合来组合。作为非限制性特定实例，如上文所述，对aav衣壳蛋白上的表面暴露环进行诱变，以产生aav载体的简并文库。然后，将简并文库在非人灵长类动物中进行第一轮感染(图1a、图2a)。具体地说，通过玻璃体内注射将文库施用到灵长类动物的眼睛。在感染后第7天收获视网膜色素上皮(rpe)，并对其进行测序，以鉴定单个aav分离物(图1b、图2b)。然后将在第一轮进化期间分离的aav(图2b)通过玻璃体内注射重新引入到第二种非人灵长类动物中。在感染后第7天收获视网膜色素上皮(rpe)(图3a)和视网膜(图4a)，并对其进行测序，以鉴定单个aav分离物。将在rpe中第二轮进化期间分离的aav通过玻璃体内注射重新引入到第三种非人灵长类动物中，并且将在视网膜中第二轮进化期间分离的aav通过玻璃体内注射重新引入到第四种非人灵长类动物中。在感染后第7天从第三种灵长类动物收获rpe(图3b)，并且在感染后第7天从第四种灵长类动物收获视网膜(图4b)，并对其进行测序，以鉴定单个aav分离物。表7中提供了在rpe和/或视网膜中鉴定出的各种分离株的描述。这些分离株在非人灵长类动物体内特异性靶向并感染rpe和/或视网膜。表7.从rpe和/或视网膜分离的重组aav的表面环取代置换表面环序列的序列全衣壳序列kvrdlf(seqidno：14)seqidnos：32，41rvlalr(seqidno：15)seqidnos：33，42rvhalr(seqidno：16)seqidnos：34，43rvhslr(seqidno：17)seqidnos：35，44gvgvlp(seqidno：18)seqidnos：36，45fvnaln(seqidno：19)seqidnos：37，46ivrsln(seqidno：20)seqidnos：38，47hvlrln(seqidno：21)seqidnos：39，48rvlalq(seqidno：22)seqidnos：40，49rvrglr(seqidno：187)seqidnos：195，203kvrtlr(seqidno：188)seqidnos：196，204mvgnlv(seqidno：189)seqidnos：197，205rvlglr(seqidno：190)seqidnos：198，206kvaglc(seqidno：191)seqidnos：199，207ivrplv(seqidno：192)seqidnos：200，208kvrgla(seqidno：193)seqidnos：201，209rvrglg(seqidno：194)seqidnos：202，210实施例2.重组aav载体转导培养物中的细胞为了确认从实施例1的非人灵长类动物rpe和/或视网膜中分离的各种aav载体通常是否具有感染性并能够转导培养物中的细胞，制备了包装有荧光素酶转基因的各种aav载体，其中每个aav载体包含含有表7中列出的一个取代的衣壳序列。使aav载体与维持在标准培养条件下的u87细胞(原发性胶质母细胞瘤细胞系)接触。以10，000vg/细胞的感染复数(moi)来感染细胞。48小时后，将细胞裂解，使裂解物与生物发光底物接触，并测量rfu。如图5所示，所有测试的aav载体都能够成功地转导培养物中的u87细胞，从而导致其包装的转基因(荧光素酶)在细胞中表达。此数据证实了重组aav载体具有感染性并且可用于将转基因递送至目标细胞。前述内容是对本发明的说明，并且不应解释为对本发明进行限制。本发明由以下权利要求及其中包括的权利要求的等效物限定。序列表<110>stridebio公司(stridebio,inc.)麦科伊·丹尼尔(mccoy,daniel)贝瑞·加勒特·e(berry,garrette.)<120>靶向眼组织的病毒载体<130>strd-007/01wo331843-2046<150>62/652,108<151>2018-04-03<160>259<170>patentinversion3.5<210>1<211>736<212>prt<213>依赖病毒腺相关病毒1(dependovirusadeno-associatedvirus1)<400>1metalaalaaspglytyrleuproasptrpleugluaspasnleuser151015gluglyileargglutrptrpaspleulysproglyalaprolyspro202530lysalaasnglnglnlysglnaspaspglyargglyleuvalleupro354045glytyrlystyrleuglypropheasnglyleuasplysglyglupro505560valasnalaalaaspalaalaalaleugluhisasplysalatyrasp657075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rpmetgluproalatyrglnargpheleu1510<210>168<211>8<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>168aspproargalathrproglyser15<210>169<211>12<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>169pheargproasnargalaglnasptyrasnthrasn1510<210>170<211>9<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>170cysthrlysasnsertyrleumetcys15<210>171<211>11<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<220><221>misc_feature<222>(2)..(2)<223>xaa可为r或q<220><221>misc_feature<222>(3)..(3)<223>xaa可为l或r<220><221>misc_feature<222>(5)..(5)<223>xaa可为g或n<220><221>misc_feature<222>(6)..(7)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(8)..(8)<223>xaa可为a或v<220><221>misc_feature<222>(9)..(9)<223>xaa可为任何天然存在的氨基酸<400>171cysxaaxaathrxaaxaaxaaglyxaaglycys1510<210>172<211>9<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>172cysproilegluaspargprometcys15<210>173<211>12<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>173hisglutrpsertyrleualaprotyrprotrpphe1510<210>174<211>9<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>174metcysprolyshisproleuglycys15<210>175<211>15<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>175argmettrpproserserthrvalasnleuseralaglyargarg151015<210>176<211>20<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>176seralalysthralavalserglnargvaltrpleuproserhisarg151015glyglyglupro20<210>177<211>20<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>177lysserarggluhisvalasnasnseralacysproserlysargile151015thralaalaleu20<210>178<211>4<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>178gluglyphearg1<210>179<211>6<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>179alaglyleuglyvalarg15<210>180<211>15<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>180glythrargglnglyhisthrmetargleuglyvalseraspgly151015<210>181<211>15<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>181ilealaglyleualathrproglytrpserhistrpleualaleu151015<210>182<211>7<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>182sermetserilealaargleu15<210>183<211>7<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>183histhrphegluproglyval15<210>184<211>15<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>184asnthrserleulysargileserasnlysargileargarglys151015<210>185<211>15<212>prt<213>人工序列(artificialsequence)<220><223>靶向肽序列<400>185leuargilelysarglysargarglysarglyslysthrarglys151015<210>186<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(1)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(2)..(2)<223>xaa为v<220><221>misc_feature<222>(3)..(4)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(5)..(5)<223>xaa为l<220><221>misc_feature<222>(6)..(6)<223>xaa可为任何氨基酸<400>186xaaxaaxaaxaaxaaxaa15<210>187<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>187argvalargglyleuarg15<210>188<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>188lysvalargthrleuarg15<210>189<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>189metvalglyasnleuval15<210>190<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>190argvalleuglyleuarg15<210>191<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>191lysvalalaglyleucys15<210>192<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>192ilevalargproleuval15<210>193<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>193lysvalargglyleuala15<210>194<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<400>194argvalargglyleugly15<210>195<211>735<212>prt<213>人工序列(artificialsequence)<220><223>重组aav衣壳<400>195metalaalaaspglytyrleuproasptrpleugluaspasnleuser151015gluglyvalargglutrptrpalaleuglnproglyalaprolyspro202530lysalaasnglnglnhisglnaspasnalaargglyleuvalleupro354045glytyrlystyrleuglyproglyasnglyleuasplysglyglupro505560valasnalaalaaspalaalaalaleugluhisasplysalatyrasp65707580glnglnleulysalaglyaspasnprotyrleulystyrasnhisala859095aspalaglupheglnglnargleuglnglyaspthrserpheglygly100105110asnleuglyargalavalpheglnalalyslysargvalleuglupro115120125leuglyleuvalgluglnalaglygluthralaproglylyslysarg130135140proleuilegluserproglnglnproaspserserthrglyilegly145150155160lyslysglylysglnproalalyslyslysleuvalphegluaspglu165170175thrglyalaglyaspglyproprogluglyserthrserglyalamet180185190seraspaspserglumetargalaalaalaglyglyalaalavalglu195200205glyglyglnglyalaaspglyvalglyasnalaserglyasptrphis210215220cysaspserthrtrpsergluglyhisvalthrthrthrserthrarg225230235240thrtrpvalleuprothrtyrasnasnhisleutyrlysargleugly245250255gluserleuglnserasnthrtyrasnglypheserthrprotrpgly260265270tyrpheasppheasnargphehiscyshispheserproargasptrp275280285glnargleuileasnasnasntrpglymetargprolysalametarg290295300vallysilepheasnileglnvallysgluvalthrthrserasngly305310315320gluthrthrvalalaasnasnleuthrserthrvalglnilepheala325330335aspsersertyrgluleuprotyrvalmetaspalaglyglnglugly340345350serleupropropheproasnaspvalphemetvalproglntyrgly355360365tyrcysglyleuvalthrglyasnthrserglnglnglnthrasparg370375380asnalaphetyrcysleuglutyrpheproserglnmetl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660665670tyrserthrglyglnvalservalglnileasptrpgluileglnlys675680685gluargserlysargtrpasnprogluvalglnphethrserasntyr690695700glyglnglnasnserleuleutrpalaproaspalaalaglylystyr705710715720thrgluproargalaileglythrargtyrleuthrhishisleu725730735<210>253<211>734<212>prt<213>人工序列(artificialsequence)<220><223>重组aav衣壳<400>253metthraspglytyrleuproasptrpleugluaspasnleuserglu151015glyvalargglutrptrpalaleuglnproglyalaprolysprolys202530alaasnglnglnhisglnaspasnalaargglyleuvalleuprogly354045tyrlystyrleuglyproglyasnglyleuasplysglygluproval505560asnalaalaaspalaalaalaleugluhisasplysalatyraspgln65707580glnleulysalaglyaspasnprotyrleulystyrasnhisalaasp859095alaglupheglnglnargleuglnglyaspthrserpheglyglyasn100105110leuglyargalavalpheglnalalyslysargvalleugluproleu115120125glyleuvalgluglnalaglygluthralaproglylyslysargpro130135140leuilegluserproglnglnproaspserserthrglyileglylys145150155160lysglylysglnproalalyslyslysleuvalphegluaspgluthr165170175glyalaglyaspglyproprogluglyserthrserglyalametser180185190aspaspserglumetargalaalaalaglyglyalaalavalglugly195200205glyglnglyalaaspglyvalglyasnalaserglyasptrphiscys210215220aspserthrtrpsergluglyhisvalthrthrthrserthrargthr225230235240trpvalleuprothrtyrasnasnhisleutyrlysargleuglyglu245250255serleuglnserasnthrtyrasnglypheserthrprotrpglytyr260265270pheasppheasnargphehiscyshispheserproargasptrpgln275280285argleuileasnasnasntrpglymetargprolysalametargval290295300lysilepheasnileglnvallysgluvalthrthrserasnglyglu305310315320thrthrvalalaasnasnleuthrserthrvalglnilephealaasp325330335sersertyrgluleuprotyrvalmetaspalaglyglngluglyser340345350leupropropheproasnaspvalphemetvalproglntyrglytyr355360365cysglyleuvalthrglyasnthrserglnglnglnthraspargasn370375380alaphetyrcysleuglutyrpheproserglnmetleuargthrgly385390395400asnasnphegluilethrtyrserpheglulysvalprophehisser405410415mettyralahisserglnserleuaspargleumetasnproleuile420425430aspglntyrleutrpglyleuglnserthrthrthrglythrthrleu435440445asnalaglythralathrthrasnphethrlysleuargprothrasn450455460pheserasnphelyslysasntrpleuproglyproserilelysgln465470475480glnglypheserlysthralaasnglnasntyrgluileproalathr485490495glyseraspserleuileglutyrgluthrhisserthrleuaspgly500505510argtrpseralaleuthrproglyproprometalathralaglypro515520525alaaspserlyspheserasnserglnleuilephealaglyprolys530535540glnasnglyasnthralathrvalproglythrleuilephethrser545550555560gluglugluleualaalathrasnalathraspthraspmettrpgly565570575asnleuproglyglyaspglnserserserasnleuprothrvalasp580585590argleuthralaleuglyalavalproglymetvaltrpglnasnarg595600605aspiletyrtyrglnglyproiletrpalalysileprohisthrasp610615620glyhisphehisproserproleuileglyglypheglyleulyshis625630635640proproproglnilepheilelysasnthrprovalproalaasnpro645650655alathrthrpheserserthrprovalasnserpheilethrglntyr660665670serthrglyglnvalservalglnileasptrpgluileglnlysglu675680685argserlysargtrpasnprogluvalglnphethrserasntyrgly690695700glnglnasnserleuleutrpalaproaspalaalaglylystyrthr705710715720gluproargalaileglythrargtyrleuthrhishisleu725730<210>254<211>735<212>prt<213>人工序列(artificialsequence)<220><223>重组aav衣壳<400>254metalaalaaspglytyrleuproasptrpleugluaspasnleuser151015gluglyvalargglutrptrpalaleuglnproglyalaprolyspro202530lysalaasnglnglnhisglnaspasnalaargglyleuvalleupro354045glytyrlystyrleuglyproglyasnglyleuasplysglyglupro505560valasnalaalaaspalaalaalaleugluhisasplysalatyrasp65707580glnglnleulysalaglyaspasnprotyrleulystyrasnhisala859095aspalaglupheglnglnargleuglnglyaspthrserpheglygly100105110asnleuglyargalavalpheglnalalyslysargvalleuglupro115120125leuglyleuvalgluglnalaglygluthralaproglylyslysarg130135140proleuilegluserproglnglnproaspserserthrglyilegly145150155160lyslysglylysglnproalalyslyslysleuvalphegluaspglu165170175thrglyalaglyaspglyproprogluglyserthrserglyalamet180185190seraspaspserglumetargalaalaalaglyglyalaalavalglu195200205glyglyglnglyalaaspglyvalglyasnalaserglyasptrphis210215220cysaspserthrtrpsergluglyhisvalthrthrthrserthrarg225230235240thrtrpvalleuprothrtyrasnasnhisleutyrlysargleugly245250255gluserleuglnserasnthrtyrasnglypheserthrprotrpgly260265270tyrpheasppheasnargphehiscyshispheserproargasptrp275280285glnargleuileasnasnasntrpglymetargprolysalametarg290295300vallysilepheasnileglnvallysgluvalthrthrserasngly305310315320gluthrthrvalalaasnasnleuthrserthrvalglnilepheala325330335aspsersertyrgluleuprotyrvalmetaspalaglyglnglugly340345350serleupropropheproasnaspvalphemetvalproglntyrgly355360365tyrcysglyleuvalthrglyasnthrserglnglnglnthrasparg370375380asnalaphetyrcysleuglutyrpheproserglnmetleuargthr385390395400glyasnasnphegluilethrtyrserpheglulysvalprophehis405410415sermettyralahisserglnserleuaspargleumetasnproleu420425430ileaspglntyrleutrpglyleuglnserthrthrthrglythrthr435440445leuasnalaglythralathrthrasnphethrlysleuargprothr450455460asnpheserasnphelyslysasntrpleuproglyproserilelys465470475480glnglnglypheserlysthralaasnglnasntyrgluileproala485490495thrglyseraspserleuileglutyrgluthrhisserthrleuasp500505510glyargtrpseralaleuthrproglyproprometalathralagly515520525proalaaspserlyspheserasnserglnleuilephealaglypro530535540lysglnasnglyasnthralathrvalproglythrleuilephethr545550555560sergluglugluleualaalathrasnalathraspthraspmettrp565570575glyasnleuproglyglyaspglnserserserasnleuprothrval580585590aspargleuthralaleuglyalavalproglymetvaltrpglnasn595600605argaspiletyrtyrglnglyproiletrpalalysileprohisthr610615620aspglyhisphehisproserproleuileglyglypheglyleulys625630635640hisproproproglnilepheilelysasnthrprovalproalaasn645650655proalathrthrpheserserthrprovalasnserpheilethrgln660665670tyrserthrglyglnvalservalglnileasptrpgluileglnlys675680685gluargserlysargtrpasnprogluvalglnphethrserasntyr690695700glyglnglnasnserleuleutrpalaproaspalaalaglylystyr705710715720thrgluproargalaileglythrargtyrleuthrhishisleu725730735<210>255<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(1)<223>xaa可为任何氨基酸，除了t<220><221>misc_feature<222>(2)..(2)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(3)..(3)<223>xaa可为任何氨基酸，除了d<220><221>misc_feature<222>(4)..(4)<223>xaa可为任何氨基酸，除了r<220><221>misc_feature<222>(5)..(5)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(6)..(6)<223>xaa可为任何氨基酸，除了t<400>255xaaxaaxaaxaaxaaxaa15<210>256<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(1)<223>xaa为k、g、f、i、h或r<220><221>misc_feature<222>(2)..(6)<223>xaa可为任何氨基酸<400>256xaaxaaxaaxaaxaaxaa15<210>257<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(2)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(3)..(3)<223>xaa为r、l、h、g或n<220><221>misc_feature<222>(4)..(6)<223>xaa可为任何氨基酸<400>257xaaxaaxaaxaaxaaxaa15<210>258<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(3)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(4)..(4)<223>xaa可为d、a、s、v或r<220><221>misc_feature<222>(5)..(6)<223>xaa可为任何氨基酸<400>258xaaxaaxaaxaaxaaxaa15<210>259<211>6<212>prt<213>人工序列(artificialsequence)<220><223>aav衣壳氨基酸取代序列<220><221>misc_feature<222>(1)..(5)<223>xaa可为任何氨基酸<220><221>misc_feature<222>(6)..(6)<223>xaa为f、r、p、n或q<400>259xaaxaaxaaxaaxaaxaa15当前第1页12