CN114480502A - 用于将多核苷酸玻璃体内递送到视网膜视锥的组合物和方法 - Google Patents
用于将多核苷酸玻璃体内递送到视网膜视锥的组合物和方法 Download PDFInfo
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Abstract
本发明提供用于将多核苷酸玻璃体内递送到锥状光感受器的方法和组合物。所述方法的方面包括将包含相关多核苷酸的重组腺相关病毒注射到眼睛玻璃体中。这些方法和组合物尤其可用于治疗与视锥功能障碍和/或死亡相关的眼部病症。
Description
本申请是申请日2016年3月2日,申请号:201680013575.4,发明名称为“用于将多核苷酸玻璃体内递送到视网膜视锥的组合物和方法”的中国发明专利申请的分案申请。
相关申请的交叉参考
本申请要求2015年3月2日提交的美国临时申请第62/127,194号和2015年3月17日提交的美国临时申请第62/134,466号的优先权;所述申请中的每一个以全文引用的方式并入本文中。
关于序列表的声明
以文本格式代替纸本拷贝提供与本申请相关的序列表,且在此以引用的方式并入本说明书中。含有序列表的文本文件的名称为AVBI_006_02WO_ST25.txt。所述文本文件为74KB,创建于2016年3月1日,且以电子方式经由EFS-Web提交。
技术领域
本发明涉及视网膜病症的基于病毒的基因疗法。
背景技术
光感受器为在视网膜中发现的专门类型神经元,其能够侦测光且将光信号转化成电信号。在视网膜中存在两种类型光感受器:杆状光感受器,其对光更敏感且因此在昏暗照明中支持视觉;以及锥状光感受器,其对光的特定波长敏感且因此支持颜色感知,且其与视杆相比,更快地对刺激作出反应,因此与视杆相比,感知图像中的更精细细节和更快速的变化,且因此支持较高视敏度视觉。
多种视觉障碍与锥状光感受器的存活力或功能损失相关,其包括例如与视锥内缺陷,即视锥本征缺陷相关的那些,如斯塔加特氏黄斑营养不良(Stargardt's maculardystrophy)、视锥营养不良、视锥-视杆营养不良、脊髓小脑失调类型7和巴迪特-别铎综合症-1(Bardet-Biedl syndrome-1);以及颜色视觉障碍,包括全色盲、蓝色视锥全色弱和红色盲(protan)、绿色盲(deutan)和蓝色盲(tritan)缺陷;以及与影响中心黄斑的视网膜病症相关的那些,如年龄相关性黄斑变性、黄斑毛细血管扩张症、色素性视网膜炎、糖尿病性视网膜病变、视网膜静脉闭塞、青光眼、索斯比氏眼底营养不良(Sorsby's fundusdystrophy)、成人卵形黄斑营养不良、贝氏病(Best's disease)和X-链视网膜劈裂症(retinoschisis)。预期这些视锥细胞病症可通过向锥状光感受器递送治疗基因治疗,当通过锥状光感受器表达时,所述基因补充和“挽救”视锥细胞活力和/或功能不足。
锥状光感受器的最高密度存在于位于视网膜黄斑中心1.5mm凹陷处。称作“中央凹(fovea centralis)”或“中央凹部(foveal pit)”的此区域负责锐利中央视觉(也被称为中央凹视觉),其为人类中视觉细节最重要的活动,如阅读和驾驶所必需。中央凹由两个子区域组成:小凹,其为凹部中心处视网膜的直径0.35mm无视杆区域;以及小窝,其为包围小凹且形成凹部斜率的视网膜的直径1.5mm视锥富集区域。包围中央凹的是近窝区,其形成凹陷边缘且由视网膜的所有细胞、锥状光感受器(以相对于中央凹减少的数量表示)构成。近窝区之外为中心凹周,其为含有甚至更低密度视锥的视网膜区域。因为中央窝的视锥细胞构成视网膜中的锥状光感受器的绝大部分,所以这些细胞为针对视锥相关病症(Oster 1935)治疗递送的治疗基因的理想的目标接受者。
已通过采用病毒载体,如腺相关病毒(AAV)或慢病毒在将基因递送到视网膜细胞方面取得一定成功。然而,这些载体必须通过视网膜下注射投与,其为干扰视网膜结构且具有对通常已因待治疗病症受损的视网膜组织产生额外损伤的风险的程序。一个替代方案为将病毒载体玻璃体内递送到视网膜,即,通过将载体注射到眼睛的玻璃体中且希望载体渗透视网膜并转导视网膜细胞。然而,如所属领域所展现,中央窝视锥细胞众所周知地对通过玻璃体内递送到视网膜的病毒载体的转导具有抗性。
因此,在所属领域中需要当从眼睛的玻璃体递送时以高效率转导视锥细胞的病毒载体。本发明处理这些问题。
发明内容
提供用于将多核苷酸玻璃体内递送到锥状光感受器的方法和组合物。所述方法的方面包括将包含相关多核苷酸的重组腺相关病毒注射到眼睛玻璃体中。这些方法和组合物尤其可用于治疗与视锥功能障碍和/或死亡相关的眼部病症。
附图说明
本发明依据以下详细说明,结合附图阅读会得到充分了解。应强调的是,根据惯例,附图的各种特征未按比例绘制。相反,为了清晰起见,各种特征的尺寸经过任意扩大或缩小。附图中包括以下诸图。
图1说明玻璃体内递送的AAV2变体AAV2-7m8如何与玻璃体内递送的AAV2相比更高效地转导灵长类动物的中央凹和近窝区中的视网膜细胞。以50μL的体积将5×1011AAV2.CMV.GFP的载体基因组(左上方);AAV-2.5T.CMV.GFP(右上方)(Excoffon K.J.,等人2009.《美国国家科学院院刊(Proc.Natl.Acad.Sci.U.S.A.)》106:3865-3870);(左下方)AAV2-7.8.CMV.GFP(Dalkara D,等人《科学转化医学(Sci Transl Med.)》2013年6月12日;5(189):189ra76);或AAV-ShH10.CMV.GFP(右下方)Klimczak RR等人《公共科学图书馆·综合(PLoS One.)》2009年10月14日;4(10):e7467)注射到非洲绿猴的玻璃体中,且通过活体内OCT荧光成像在8周后观测到GFP表达。
图2说明AAV2-7m8衣壳如何稳固地转导灵长类动物的中央窝视锥。(a-b)将AAV2-7m8.MNTC.GFP注射到狒狒的中央玻璃体中且(a)5周和(b)8周后通过眼底荧光观测到表达。(c和d)在低放大率(c)和高放大率(d)下,在用AAV2-7m8.MNTC.GFP注射之后大约6个月中央窝的15微米部分内的天然GFP荧光。
图3说明在玻璃体内注射递送MNTC.GFP的AAV-7m8之后小鼠视网膜的视锥中的稳固性和视锥特异性基因表达。(a-b)经由玻璃体内注射,在小鼠接收5.04×1010个载体基因组的玻璃体内注射之后11周GFP荧光的实例。(c-e)在注射之后14周收集视网膜以便组织学处理且用抗体使视锥外段标记有L/M视蛋白(红色)。在(c)中,断开红色通道,因此仅可见天然GFP,(d)为与红色通道相同的图像以允许目测视锥外段。如果并非所有视锥是通过病毒转导,那么(c)和(d)的比较显示大部分。(e)从显示锥状光感受器轮廓的不同角度,与c和d相同的视网膜的图像。
图4A-4B说明通过蒙古沙鼠(Mongolian gerbil)视网膜的视锥中的pMNTC调节卡匣引导的基因表达。在CMV、pR2.1或MNTC启动子的控制下,以5μL的体积将1×1010-2×1010个携带GFP的病毒的载体基因组注射到蒙古沙鼠的玻璃体中,且通过眼底荧光成像,在指定时间点目测GFP表达。(a)在玻璃体内投与之后4周目测的AAV2-7m8.CMV.GFP和AAV2-7m8.MNTC.GFP引导的GFP表达。用AAV2-7m8.CMV.GFP注射沙鼠12-10、12-11和12-12,同时用AAV2-7m8.MNTC.GFP注射沙鼠12-13、12-14和12-15。OD,眼睛右侧(右眼)。OS,眼睛左侧(左眼)。(b)4和8周后,如通过眼底荧光成像所检测,AAV2-7m8.pR2.1.GFP和AAV2-7m8.MNTC.GFP引导的GFP的表达。
图5A-5D表明pMNTC调节卡匣在灵长类动物中央窝视锥中提供与视锥启动子pR2.1相比更稳固的基因表达。以50μL的体积将AAV2-7m8.MNTC.GFP或AAV2-7m8.pR2.1.GFP的5×1011个载体基因组注射到如所指定的非洲绿猴的玻璃体中(AAV2-7m8.MNTC.GFP注入动物271和472;AAV2-7m8.pR2.1.GFP注入动物500和509)。针对GFP,在(a)2周、(b)4周、(c)8周和(d)12周,使用眼底荧光摄影机(a、b、c、d)或自体荧光海德堡光学OCT(HeidelbergSpectralis OCT)(a,b;8周和12周数据未示出),活体内目测视网膜。OD,眼睛右侧(右眼)。OS,眼睛左侧(左眼)。
图6A-6D表明经优化pMNTC元件中的每一个对观测到的更稳固表达的贡献。(a)pMNTC和pR2.1表达卡匣。(b)实验表达卡匣,其中pMNTC中的各元件逐个被pR2.1中对应的元件置换。(c、d)如通过IVIS成像注射后(c)4周和(d)8周所检测,荧光素酶转基因在玻璃体内注射有测试品中的每一个(n=6-8个眼睛/构建物)的沙鼠视网膜中的表达。“7m8.CMV”充当阳性对照。
图7说明通过非人类灵长类(NHP)中的pR2.1调节卡匣引导的视锥特异性基因表达。以50μL的体积将5×1011个AAV2-7m8.pR2.1.GFP的载体基因组注射到非洲绿猴的玻璃体中。通过8μm视网膜横截面的立体荧光显微术观测到GFP转基因表达。用抗GFP抗体(绿色;鸡多克隆;艾博抗(Abcam)目录号13970)染色GFP;用对视蛋白视锥(红色;鸡多克隆;艾博抗号5405)具有特异性的抗L/M视蛋白抗体染色视蛋白视锥细胞;用抗视紫质抗体(1D4粉色;小鼠单克隆;艾博抗号5417)染色视杆细胞;且用Dapi(蓝色/所有细胞核;英杰(Invitrogen)REF号D21490)染色细胞核。GFP染色与L/M视蛋白染色(但不与视紫质染色)共定位。横跨光感受器层,GFP转基因表达存在于L/M-视蛋白视锥中,但在视杆中未观测到GFP转基因表达。箭头指示针对GFP和视蛋白两者双重染色的说明性视锥细胞。
具体实施方式
提供用于将多核苷酸玻璃体内递送到锥状光感受器的方法和组合物。所述方法的方面包括将包含相关多核苷酸的重组腺相关病毒注射到眼睛玻璃体中。这些方法和组合物尤其可用于治疗与视锥功能障碍和/或死亡相关的眼部病症。本领域的普通技术人员在阅读以下更完整地描述的组合物和方法详情之后,将对本发明的这些和其它目的、优势及特征变得显而易见。
在描述本发明方法和组合物之前,应理解本发明不限于所描述的特定方法或组合物,因为这当然可变化。还应理解,本文所使用的术语仅出于描述特定实施例的目的,而不希望具有限制性,原因是本发明的范围仅由所附权利要求书限定。
在提供数值范围的情况下,应理解还专门披露所述范围的上限与下限之间的每个中间值,直到下限单位的十分之一(除非上下文另外明确规定)。所陈述的范围内的任何所陈述值或中间值与那个所述范围内的任何其它所陈述值或中间值之间的每个更小范围涵盖于本发明中。这些更小范围的上限和下限可以独立地包括或不包括于所述范围内,且本发明中还涵盖其中任一限值包括于更小范围内、两个限值均不包括于更小范围内或两个限值均包括于更小范围内的每个范围(除了所述范围内专门排除的任何限值之外)。在所陈述范围包含界限值中的一者或两者的情况下,排除所包含的那些界限值中的任一者或两者的范围也包含于本发明中。
除非另外定义,否则本文所使用的所有技术和科学术语均具有与本发明所属领域的一般技术人员通常所理解相同的含义。虽然与本文所描述的类似或等效的任何方法和材料均可以用于本发明的实践或测试,但现在描述一些潜在且优选的方法和材料。
本文提及的所有公开案均以引入的方式并入本文中,以公开且描述与所列公开案相关的方法和/或材料。应理解,在存在抵触的范围内,本发明取代了所并入公开案的任何公开内容。
如所属领域的技术人员在阅读本发明之后将显而易见,本文中所描述和说明的每个个别实施例具有离散的组件和特征,所述特征可容易与其它若干实施例中的任一个的特征分离或与其组合而不脱离本发明的范围或精神。任何所叙述方法均可以所叙述事件的顺序或以逻辑上可能的任何其它顺序来进行。
应进一步注意,权利要求书可经起草而排除任何任选的元件。因而,这陈述意图与对所主张元件的引述结合而充当使用如“仅仅(solely)”、“仅(only)”以及其类似术语的排他性术语或使用“负性”限制的前提基础。
必须指出,除非上下文另外明确规定,否则如本文和所附权利要求书中所使用,单数形式“一(a/an)”和“所述(the)”包括复数个提及物。因此,举例来说,提及“细胞”包括多个此类细胞且提及“多核苷酸”包括提及一种或多种多核苷酸和其当量,例如所属领域的技术人员已知的核酸序列等等。
提供本文中讨论的公开案仅仅用于其在本申请的申请日之前的公开内容。不应将本文中的任何内容理解为承认本发明无权凭借先前发明而先于所述公开案。此外,所提供的公开日期可以不同于可能需要独立确认的实际公开日期。
定义
如本文所使用的“载体”是指包含多核苷酸或与多核苷酸缔合的大分子或大分子缔合物且其可用于介导多核苷酸递送到细胞。说明性载体包括例如质粒、病毒载体(病毒或其病毒基因组)、脂质体和其它基因递送媒剂。
“病毒”意指包含病毒衣壳和病毒基因组的病毒粒子。举例来说,腺相关病毒是指包含至少一种腺相关病毒衣壳蛋白或其变体和衣壳化腺相关病毒载体基因组或其变体的病毒粒子。
病毒“衣壳”意指病毒的蛋白质壳体。病毒衣壳典型地包含由称作原聚体的蛋白质制成的若干寡聚结构次单元。衣壳包封或“衣壳化”病毒的基因材料或“基因组”。在一些病毒中,包封衣壳,意指衣壳涂布有已知为病毒包膜的脂膜。
病毒“基因组”(本文中可互换地称作“病毒基因组”、“病毒载体DNA”和“病毒DNA”),意指多核苷酸序列在其末端包含至少一个和一般两个病毒末端重复序列(例如反向末端重复序列(ITR)、长末端重复序列(LTR))。
“重组病毒基因组”意指在其末端包含异源核酸序列和至少一个和一般两个病毒末端重复序列的病毒基因组。“重组病毒”意指包含重组病毒基因组的病毒粒子。
如本文所使用,术语“异源”意指从一种实体衍生出来的,所述实体在基因型上截然不同于正被比较的实体的其余部分。举例来说,通过基因工程技术引入到衍生自不同物种,例如病毒基因组的质粒或载体中的多核苷酸为异源多核苷酸。作为另一实例,从启动子的天然编码序列中去除启动子且可操作地连接到不是天然序列的编码序列上的为异源启动子。作为第三实例,异源基因产物,例如RNA、蛋白质为通常不由在其中进行表达的细胞编码的基因产物。
关于本发明的病毒,如本文所使用的术语“复制缺陷型”是指无法独立地复制和封装其基因组的病毒。举例来说,当个体细胞感染有重组病毒粒子时,异源基因在经感染细胞中表达;然而,归因于经感染细胞不具有AAV rep和cap基因和附属功能基因的事实,重组病毒不能够进一步复制。
术语“AAV”为腺相关病毒的缩写。当在本文中使用时,术语AAV可用于指病毒自身或其衍生物,例如病毒衣壳、病毒基因组等。除非另外需要,否则术语“AAV”涵盖所有亚型、天然存在形式和重组形式两者和其变体。
“天然存在”或“野生型”AAV意指包含由自然界中存在的病毒衣壳蛋白质组成的病毒衣壳的任何腺相关病毒或其衍生物。天然存在的AAV的非限制性实例包括AAV 1型(AAV-1)、AAV 2型(AAV-2)、AAV 3型(AAV-3)、AAV 4型(AAV-4)、AAV 5型(AAV-5)、AAV 6型(AAV-6)、AAV 7型(AAV-7)、AAV 8型(AAV-8)、AAV9、AAV10、AAV11、AAV12、rh10、禽类AAV、牛类AAV、犬类AAV、马类AAV、灵长类AAV、非灵长类AAV和绵羊类AAV。“灵长类AAV”是指感染灵长类动物的AAV,“非灵长类AAV”是指感染非灵长类哺乳动物的AAV,“牛类AAV”是指感染牛哺乳动物的AAV等。
“AAV变体”或“变体AAV”意指包括包含变体或突变体AAV衣壳蛋白的AAV病毒粒子。变体AAV衣壳蛋白质的实例包括AAV衣壳蛋白质,其相对于对应的亲本AAV衣壳蛋白,即由其衍生的AAV衣壳蛋白、野生型AAV衣壳蛋白等包含至少一个氨基酸差异(例如氨基酸取代、氨基酸插入、氨基酸缺失),其中变体AAV衣壳蛋白不由天然存在的AAV衣壳蛋白中存在的氨基酸序列组成。除了在结构上,即在序列层级,不同于对应的亲本AAV之外,AAV变体可在功能上不同于对应的亲本AAV。换句话说,相对于对应的亲本AAV衣壳蛋白包含至少一个氨基酸差异的变体衣壳蛋白可赋予AAV变体对应亲本AAV不具有的功能特征。举例来说,AAV变体可具有不同细胞向性,即针对特定类型细胞的不同亲和性和/或感染特定类型细胞的能力,例如AAV变体可以与亲本AAV相比增加(或降低)的亲和性结合到细胞,例如视网膜细胞,和/或以与亲本AAV相比增加(或降低)的效率感染/转导细胞,例如视网膜细胞以使得细胞群体的更多(或更少)细胞转导/感染有相同效价病毒粒子。作为第二实例,AAV变体可具有对宿主动物产生的抗体更大(或更小)的亲和性,例如AAV变体可以更大(或更小)亲和性结合到中和抗体且在更大(或更小)程度上从宿主组织清除。
“重组AAV”或“rAAV”意指包括在其病毒基因组中包含异源多核苷酸序列的任何AAV。一般来说,异源多核苷酸通过至少一个且一般通过两个天然存在的或变体AAV反向末端重复序列(ITR)侧接。术语rAAV载体涵盖rAAV载体粒子和rAAV载体质粒两者。因此,举例来说,包含异源多核苷酸序列的rAAV将为包括通常不包括于天然存在的野生型AAV,例如转基因(例如非AAV RNA编码多核苷酸序列、非AAV蛋白质编码多核苷酸序列)、非AAV启动子序列、非AAV聚腺苷酸化序列等中的核酸序列的rAAV。
如本文所使用,术语“表达载体”是指包含编码相关基因产物的区域的载体且用于影响基因产物在预期靶细胞中的表达。表达载体还包含可操作地连接到编码区域以促进目标中蛋白质的表达的控制元件。控制元件和其可操作地连接以用于表达的基因的组合有时称为“表达卡匣”,其中许多是本领域中已知和可获得的,或可由本领域中可获得的组件容易地构建。
如本文所使用,术语“表达”是指编码序列,例如内源性基因、异源基因在细胞中的转录和/或转译。
如本文所使用,术语“基因”或“编码序列”是指编码基因产物且涵盖天然存在的多核苷酸序列和cDNA两者的多核苷酸序列。基因可包括或可不包括编码区之前和之后的区域,例如5'非转译的(5'UTR)或“前导”序列和3'UTR或“尾随”序列或个别编码片段(外显子)之间的插入序列(内含子)。
如本文所使用,术语“基因产物”是指多核苷酸序列的所需表达产物,如多肽、肽、蛋白质或RNA,包括例如核糖核酸酶、短干扰RNA(siRNA)、miRNA或小发夹RNA(shRNA)。术语“多肽”、“肽”和“蛋白质”在本文中可互换使用以指任何长度的氨基酸的聚合物。术语还涵盖已经改性的氨基酸聚合物;例如双硫键形成、糖基化、脂化、磷酸化或与标记组分共轭。
如本文所使用,术语“可操作地连接(operatively linked或operably linked)”是指单一多核苷酸上基因元件的并列,其中所述元件处于准许其以预期方式操作的关系中。举例来说,如果启动子帮助引发编码序列转录,那么启动子可操作地连接到编码区域。只要维持此函数关系,在启动子与编码区域之间可能存在插入残基。控制元件,例如启动子、增强子等与其可操作地连接以用于表达的基因的组合有时称为“表达卡匣”,其中许多是本领域中已知和可获得的,或可由本领域中可获得的组件容易地构建。
“启动子”一般意指引导RNA聚合酶结合且从而促进RNA合成的DNA序列,即,足以直接转录的极少序列。启动子和对应的蛋白质或多肽表达可为普遍存在的,意指广泛范围的细胞、组织和物种的强活性或细胞类型特异性、组织特异性或物种特异性。启动子可为“组成型”,意指持续活性,或“诱导型”,意指启动子可通过生物或非生物因子的存在或不存在活化或去活。
“增强子”一般意指刺激,即促进或增强相邻基因转录的顺式作用调节元件。“静止子”意指例如通过主动地干扰一般转录因子组装体或通过抑制其它调节元件,例如与基因相关的增强子抑制,即减少或抑制相邻基因转录的顺式作用调节元件。增强子可在距离编码序列和经转录区域的位置下游至多几千个碱基对(kb)的距离上,在任一方向上起作用(即,可与编码序列相关)。增强子序列影响启动子依赖性基因表达且可位于天然基因的5'或3'区域。增强子序列可或可不与启动子序列邻接。同样地,增强子序列可或可不紧邻基因序列。举例来说,增强子序列可为来自启动子和/或基因序列的数千个碱基对。
在本发明的含义内,“终止信号序列”可为使RNA聚合酶終止转录的任何基因元件,例如聚腺苷酸化信号序列。聚腺苷酸化信号序列为RNA转录物核酸内切酶裂解继而共同序列AATAAA聚腺苷酸化所必需的识别区域。聚腺苷酸化信号序列提供“聚腺苷酸位点”,即将通过转录后聚腺苷酸化添加腺嘌呤残基的RNA转录物上的位点。
在上下文中,术语“相同”或“一致性”百分比是指当比较和比对最大对应性时相同或具有相同指定百分比氨基酸残基或核苷酸的两种或更多种核苷酸序列,如使用本文所描述的序列对比算法中的一种(例如史密斯-沃特曼算法(Smith-Waterman algorithm))或通过目视检验所测量。
如本文所使用,术语“序列一致性”是指当使用序列比对程序进行比对时两个或更多个比对序列中的核苷酸之间的一致性程度。术语“同源性%”在本文中可与本文中的术语“一致性%”互换使用且是指当使用序列比对程序进行比对时两个或更多个比对序列之间的核酸或氨基酸序列一致性水平。举例来说,如本文所使用,80%同源性意指与通过规定的算法测定的80%序列一致性相同的事物,且相应地给定序列的同源物具有在给定序列的长度上大于80%序列一致性。可通过比对序列,使用多种公开可用的比对算法工具,例如Smith和Waterman,《应用数学进展(Adv.Appl.Math.)》2:482(1981)的局部同源算法、Needleman和Wunsch,《分子生物学杂志(J Mol.Biol.)》48:443(1970)的同源比对算法、Pearson和Lipman,《美国国家科学院院刊(Proc.Nat'l.Acad.Sci.USA)》85:2444(1988)的相似性方法探索、这些算法(威斯康星遗传学软件包(Wisconsin Genetics SoftwarePackage),遗传学计算机组(Genetics Computer Group),575《科学博士(Science Dr.)》,威斯康星州麦迪逊(Madison,Wis.))的计算机化实施方案中的任一种测定序列一致性,通过BLAST算法,Altschul等人,《分子生物学杂志》215:403-410(1990),其中软件为经由美国国家生物技术信息中心(www.ncbi.nlm.nih.gov/)为公开可用的,或通过目视检验(一般参见Ausubel等人,下文)。
术语“互补序列”和“互补”是指能够在反向平行核苷酸序列中的互补碱基残基之间氢键形成后彼此配对的两个反向平行核苷酸序列。
当在本文中的多核苷酸或多肽的情况下使用时,术语“天然”是指自然界中可见;即,存在于野生型病毒或细胞的基因组中的多核苷酸或多肽序列。
当在本文中的多核苷酸或多肽的情况下使用时,术语“变体”是指与天然序列或任何其它天然序列具有小于100%序列一致性的天然多核苷酸或多肽的突变体。此类变体可在对应的天然基因或基因产物序列中包含一种或多种取代、缺失或插入。术语“变体”还包括天然基因或基因产物和其突变体的片段,例如在对应的天然基因或基因产物片段中包含一种或多种取代、缺失或插入的片段。在一些实施例中,变体保留天然基因产物的功能活性,例如如所属领域中已知的配体结合、受体结合、蛋白质信号传导等。
当提及本发明的重组蛋白或多肽时,术语“片段”意指具有为与对应的全长蛋白质或多肽的氨基酸序列相同的部分(但并非全部)的氨基酸序列的多肽,其保留对应的全长蛋白质或多肽的功能或活动中的至少一种。片段优选地包括全长蛋白质或多肽的至少20-100个邻接氨基酸残基。
如本文所使用,术语“生物活性(biological activity和biologically active)”是指归因于特定基因产物,例如培养物中或活体内的细胞系中的RNA或蛋白质的活性。举例来说,RNAi分子的“生物活性”是指分子抑制多肽从靶聚核苷酸序列产生的能力。
如本文所使用,术语“拮抗剂”是指用以抑制靶分子活性的分子。拮抗剂包括两种结构拮抗剂,其通过例如直接结合到靶标或使其受体失活来抑制靶分子的活性;以及功能拮抗剂,其例如降低生物系统中的靶标产生或提高生物系统中的靶标的抑制剂产生。
如本文所使用的术语“投与”或“引入”是指出于将多核苷酸递送到细胞或个体的细胞和或器官的目的,使细胞、组织或个体与载体接触。此类投与或引入可活体内、活体外或离体进行。用于表达基因产物的载体可通过以下引入到细胞中:转染,其典型地意指通过物理手段将异源DNA插入到细胞中(例如磷酸钙转染、电穿孔、微注射或脂质体转染);感染,其典型地是指借助于感染物,即病毒引入;或转导,其典型地意指用病毒稳定感染细胞或借助于病毒剂(例如噬菌体)将基因材料从一种微生物转移到另一种微生物。
如本文所使用的“转化”或“转染”是指通过载体将异源DNA递送到细胞,例如哺乳动物细胞、昆虫细胞、细菌细胞等的内部。用于“转化”细胞的载体可为质粒、小环DNA或其它媒剂。典型地,取决于用于将异源DNA(即,载体)投与、引入或插入到细胞中的手段,细胞称为“经转导”、“经感染”;“经转染”或“经转化”。术语“经转染”和“经转化”在本文中可互换使用以指通过非病毒方法,例如电穿孔、氯化钙转染、脂质体转染等引入异源DNA,例如当制备适用于本发明方法中的本发明病毒载体时。术语“经转导”和“经感染”在本文中可互换使用以指在病毒粒子的情况下将异源DNA引入到细胞中。
如本文所使用的术语“宿主细胞”是指已经载体转导、感染、转染或转化的细胞。载体可为质粒、病毒粒子、噬菌体等。如温度、pH等培养条件为先前与选用于表达的宿主细胞一起使用的那些且将为所属领域的技术人员显而易见的。应了解,术语“宿主细胞”是指初始经转导、感染、转染或转化细胞和其后代。
如本文所使用,“治疗”基因是指当表达时赋予存在其的细胞或组织或其中表达基因的哺乳动物有益作用的基因。有益作用的实例包括改善病况或疾病的标志或症状,预防或抑制病况或疾病或赋予所需特征。治疗基因包括校正细胞或哺乳动物中的基因不足的基因。
术语“治疗(treatment、treating)”等在本文中一般用于意指获得所需药理学和/或生理学作用。所述作用就完全或部分预防疾病或其症状来说可为预防性的,例如降低在个体中发生疾病或其症状的可能性,和/或就部分或完全治愈疾病和/或可归因于所述疾病的不良作用来说可为治疗性的。如本文所使用的“治疗”覆盖哺乳动物的疾病的任何治疗,且包括:(a)预防疾病在可能易患疾病但尚未诊断患有所述疾病的个体中发生;(b)抑制疾病,即,遏制其发展;或(c)缓解疾病,即,使疾病消退。可在疾病起始或损伤之前、期间或之后投与治疗剂。发展中的疾病的治疗为备受关注的,其中治疗稳定或减少患者的非所需临床症状。此类治疗合乎需要地在受感染的组织功能完全缺失之前进行。本发明疗法将合乎需要地在疾病的有症状阶段期间且在一些情况下在疾病的有症状阶段之后投与。
术语“个体(individual、subject)”、“宿主”和“患者”在本文中可互换使用且是指需要诊断、治疗或疗法的任何哺乳动物个体,包括(但不限于)人类和非人类灵长类动物,包括猿猴和人类;哺乳动物比赛动物(例如马);哺乳动物农场动物(例如绵羊、山羊等);哺乳动物宠物(狗、猫等);以及啮齿动物(例如小鼠、大鼠等);尤其人类。
本文所使用的术语仅出于描述特定实施例的目的且无意限制本发明。如本文所使用,除非上下文另外明确指示,单数形式“一(a、an)”以及“所述”意欲还包括复数形式。此外,就具体实施方式和/或权利要求书中使用术语“包括(including、includes)”、“具有(has、with)”或其变化形式的程度而言,此类术语意欲以类似于术语“包含”的方式是包含性的。
“包含”意指在例如组合物、方法、套组等中需要所叙述的元件,但可包括其它元件以在权利要求书的范畴内形成例如组合物、方法、套组等。举例来说,“包含”编码可操作地连接到启动子的治疗性多肽的基因的表达卡匣为表达卡匣,其除基因和启动子外还可包括其它元件,例如聚腺苷酸化序列、增强子元件、其它基因、连接子结构域等。
“基本上由……组成”意指将例如所描述的组合物、方法、套组等的范畴限制于并不实质上影响例如组合物、方法、套组等的基本和新颖特征的指定材料或步骤。举例来说,“基本上由”编码可操作地连接到启动子和聚腺苷酸化序列的治疗性多肽的基因“组成”的表达卡匣可包括额外序列,例如连接子序列,只要其并不实质上影响基因的转录或转译。作为另一实例,“基本上由”所叙述的序列“组成”的变体多肽片段具有在基于衍生其的全长天然多肽的序列的界限处所叙述的序列加或减约10个氨基酸残基的氨基酸序列,例如比所叙述的界限氨基酸残基少10、9、8、7、6、5、4、3、2或1个残基,或比所叙述的界限氨基酸残基多1、2、3、4、5、6、7、8、9或10个残基。
“由……组成”意指排除权利要求书中未指定的任何元件、步骤或成分的组合物、方法或套组。举例来说,“由”编码可操作地连接到启动子和聚腺苷酸化序列的治疗性多肽的基因“组成”的表达卡匣仅由启动子、编码治疗性多肽的多核苷酸序列和聚腺苷酸化序列组成。作为另一实例,“由”所叙述的序列“组成”的多肽仅含有所叙述的氨基酸序列。
术语“约”或“大约”意指在如由所属领域的一般技术人员测定的具体值的可接受的偏差范围内,其将部分取决于所述值如何测量或测定,即,测量系统的限制。举例来说,根据所属领域中的实践,“约”可意指在1或大于1个标准差内。替代地,“约”可意指至多给定值的20%,优选至多10%,更优选至多5%,且更优选仍至多1%的范围。替代地,尤其相对于生物学系统或方法,术语可意指在数量级内,优选地在值的5倍内,且更优选在2倍内。除非另外陈述,否则在本申请和权利要求书中描述特定值的情况下,术语“约”意指在应假定的特定值的可接受的偏差范围内。
方法和组合物
在本发明的一些方面中,提供用于将多核苷酸递送到锥状光感受器的方法和组合物。如上文所论述,本文中可互换称为“视锥细胞”、“视网膜视锥”和最简单地“视锥”为眼睛视网膜中的感光细胞的两种亚型中的一种,另一种为杆状光感受器。锥状光感受器可容易地在多种物理、生物化学和功能特征方面与杆状光感受器区别开来。举例来说,锥状光感受器包含形状如锥状的外部链段区域,而杆状光感受器包含形状如杆状的外部链段。锥状光感受器表达杆状光感受器不表达的多种蛋白质,包括例如L-视蛋白(OPN1LW,其核酸和氨基酸序列可见于基因库登录号:NM_020061.5)、M-视蛋白(OPN1MW,其核酸和氨基酸序列可见于基因库登录号:NM_000513.2)或S-视蛋白(OPN1SW,其核酸和氨基酸序列可见于基因库登录号:NM_001708.2);而杆状光感受器表达锥状光感受器不表达的多种蛋白质,例如视紫质(RHO,其核酸和氨基酸序列可见于基因库登录号:NM_000539.3)和视杆衍生的视锥存活力因子(RDCVF,也称为NXNL1,其核酸和氨基酸序列可见于基因库登录号:NM_138454.1)。功能上,锥状光感受器与杆状光感受器的不同之处在于锥状光感受器负责颜色视觉且在相对较亮光中作用最佳,而杆状光感受器在较低光水平下支持视觉且在昏暗光中作用最佳;可基于此差异使用网膜电图(ERG)或颜色ERG(cERG)区别视锥和视杆。最终,锥状光感受器可通过其在视网膜中的位置区别于杆状光感受器。如上文所论述,锥状光感受器的绝大部分(所有其L-锥状光感受器和M-锥状光感受器)密集地填充在位于视网膜黄斑中心的1.5mm凹坑中,称作中央凹,其中其余的L-锥状光感受器和M-锥状光感受器和S-锥状光感受器散射在近窝区、中心凹周和外周视网膜中。相比之下,小凹中不包括杆状光感受器且中央窝中表示不充分,实际上主要见于近窝区、中心凹周和外周视网膜。
如上文所论述,在本发明之前,在所属领域中共同理解,锥状光感受器,且中央窝中的更尤其L-锥状光感受器和M锥状光感受器对通过从玻璃体递送的AAV转导具有抗性。然而,如本文中的工作实例所展现,中央窝视锥事实上可通过玻璃体内递送,使用本发明的方法和组合物转导。在一些实施例中,通过本发明方法和组合物转导的锥状光感受器存在于视网膜的任何地方,即黄斑(中央窝、近窝区、中心凹周)或边缘。在一些实施例中,锥状光感受器存在于中央凹中。在某些实施例中,锥状光感受器为中央窝视锥,即,其为存在于中央窝内的L-视锥或M-视锥,此为从距离中央凹中心约0.175mm横跨到距离中央凹中心约0.75mm的中央凹区域。
rAAV病毒粒子
在实践本发明方法时,相关多核苷酸通过将包含相关多核苷酸作为其基因组内的异源序列的重组病毒粒子注射到眼睛玻璃体中递送到锥状光感受器。在一些情况下,重组病毒粒子为重组腺相关病毒(rAAV)粒子。在一些实施例中,rAAV为野生型血清型;即,其包含由自然界中存在的病毒衣壳蛋白质组成的病毒衣壳。在其它实施例中,rAAV为AAV血清型变体,即,其包含变体AAV衣壳蛋白,即,相对于对应的亲本AAV衣壳蛋白包含至少一个氨基酸差异的AAV衣壳蛋白,例如野生型AAV衣壳蛋白,且不由天然存在的AAV衣壳蛋白中存在的氨基酸序列组成。
如本申请的工作实例中所展现,包含变体AAV衣壳蛋白(在GH环中,或更尤其在GH环的次环IV中包含至少一个氨基酸差异)的rAAV病毒粒子表明当玻璃体内递送时,相对于包含野生型AAV衣壳蛋白的rAAV病毒粒子,锥状光感受器的感染力提高。“提高的感染力”意指与野生型AAV衣壳蛋白相比,变体rAAV病毒粒子能够更好地转导靶细胞。可通过观测到更多多核苷酸递送到各细胞且更多细胞在组织中转导观测到AAV转导细胞的能力提高,使得递送到各细胞和组织的多核苷酸的量增加。因此,在本发明的一些方面中,提供将相关多核苷酸递送到锥状光感受器的改进方法,所述改进包含将有效量的rAAV变体递送到眼睛玻璃体,所述rAAV变体包含i)变体AAV衣壳蛋白,其相对于对应的亲本AAV衣壳蛋白,例如野生型AAV衣壳蛋白包含至少一个氨基酸差异,且不由天然存在的AAV衣壳蛋白中存在的氨基酸序列组成,和ii)相关多核苷酸作为病毒基因组内的异源序列。
本发明中备受关注的为相对于对应的亲本AAV衣壳蛋白,在AAV衣壳蛋白的GH环或“环IV”中包含至少一个氨基酸差异的rAAV变体。GH环或环IV意指在AAV衣壳蛋白VP1的果冻卷β-筒体的G链与H链之间产生的环,如例如Xie等人(2002)PNAS 99(16):10405-10410、vanVliet等人(2006)《分子治疗(Mol.Ther.)》14:809;Padron等人(2005)《病毒学杂志(J.Virol.)》79:5047;以及Shen等人(2007)《分子治疗》15:1955中所描述。在一些情况下,至少一个氨基酸差异在GH环的次环4内,即,GH环的溶剂可及部分,基本上由AAV1 VP1(SEQID NO:1)的约氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5 VP1(SEQID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ ID NO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQ ID NO:8)的约氨基酸573到614、AAV9VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614或约其变体的对应的氨基酸范围组成。在某些情况下,至少一个氨基酸差异在基本上由AAV1 VP1的氨基酸581-596、AAV2 VP1的580-595、AAV3 VP1的581-596、AAV4的579-594、AAV5 VP1的570-585、AAV6 VP1的581-596、AAV7 VP1的582-597、AAV8 VP1的583-598、AAV9VP1的581-596、AAV10 VP1的583-598组成的氨基酸范围内或在其变体的对应的氨基酸范围内。所属领域的技术人员将知道,基于比较各种AAV血清型的衣壳蛋白质的氨基酸序列,其中氨基酸“对应于AAV2的VP1的氨基酸570-611”,例如将在任何给定AAV血清型的衣壳蛋白中。
在一些实施例中,至少一个氨基酸差异为在AAV衣壳蛋白的GH环中的两个氨基酸之间插入肽,例如在AAV1 VP1(SEQ ID NO:1)的约氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQ ID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5 VP1(SEQ ID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ IDNO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQID NO:8)的约氨基酸573到614、AAV9 VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614之间或约其变体的对应的氨基酸范围;例如在AAV1VP1的氨基酸581-596、AAV2 VP1的580-595、AAV3 VP1的581-596、AAV4的579-594、AAV5 VP1的570-585、AAV6 VP1的581-596、AAV7 VP1的582-597、AAV8 VP1的583-598、AAV9 VP1的581-596、AAV10 VP1的583-598内或在其变体的对应的氨基酸范围内的两个氨基酸与之间。举例来说,插入部位可在AAV2 VP1的氨基酸580与581、氨基酸581与582、氨基酸582与583、氨基酸583与584、氨基酸584与585、氨基酸585与586、氨基酸586与587、氨基酸587与588、氨基酸588与589、氨基酸589与590、氨基酸590与591、氨基酸591与592、氨基酸592与593、氨基酸593与594或氨基酸594与595或另一AAV VP1或其变体中的对应的氨基酸之间。
在本发明的一些实施例中备受关注的为包含肽插入的rAAV变体,如PCT公开案第WO 2012/145601号中所公开,其全部公开内容以引用的方式并入本文中。这些rAAV变体包含长度为5到11个氨基酸的肽插入,即,插入肽包含5个氨基酸、6个氨基酸、7个氨基酸、8个氨基酸、9个氨基酸、10个氨基酸或11个氨基酸。
一个备受关注的示例性肽为式I的肽:
Y1Y2X1X2X3X4X5X6X7Y3Y4(SEQ ID NO:20)
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn和Lys;
X2选自Gly、Glu、Ala和Asp;
X3选自Glu、Thr、Gly和Pro;
X4选自Thr、Ile、Gln和Lys;
X5选自Thr和Ala;
X6选自Arg、Asn和Thr;
X7(如果存在)选自Pro和Asn。
在某些实施例中,X1和/或X7不存在。
备受关注的第二示例性肽为式II的肽:
Y1Y2X1X2X3X4X5X6X7Y3Y4(SEQ DI NO:21)
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1-X4中的每一个为任何氨基酸;
X5为Thr
X6为Arg;以及
X7为Pro。
在某些实施例中,Y1-Y4中的任何一个或多个不存在。
备受关注的第三示例性肽为式III的肽:
Y1Y2X1X2X3X4X5X6X7Y3Y4(SEQ ID NO:22)
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu和Asn;
X2(如果存在)选自Gly和Glu;
X3选自Glu和Thr;
X4选自Thr和Ile;
X5为Thr;
X6为Arg;以及
X7为Pro。
在某些实施例中,Y1-Y4、X1和X2中的任何一个或多个不存在。
备受关注的第四示例性肽为式IV的肽:
Y1Y2X1X2X3X4X5X6X7Y3Y4(SEQ ID NO:23)
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn、Arg、Ala、Ser和Lys;
X2选自Gly、Glu、Ala、Val、Thr和Asp;
X3选自Glu、Thr、Gly、Asp或Pro;
X4选自Thr、Ile、Gly、Lys、Asp和Gln;
X5选自Thr、Ser、Val和Ala;
X6选自Arg、Val、Lys、Pro、Thr和Asn;以及
X7选自Pro、Gly、Phe、Asn和Arg。
在某些实施例中,Y1-Y4和X1中的任何一个或多个不存在。
具有这些式的备受关注的示例性插入肽包括包含序列LGETTRP(SEQ ID NO:11)和NETITRP(SEQ ID NO:12)或其变体的肽。在一些情况下,插入肽在氨基末端处和/或在羧基末端处具有1到4个间隔子氨基酸(Y1-Y4)。适合的间隔子氨基酸包括(但不限于)白氨酸、丙氨酸、甘氨酸和丝氨酸。举例来说,在一些情况下,插入肽具有氨基酸序列:LALGETTRPA(SEQID NO:13);LANETITRPA(SEQ ID NO:14),作为另一实例,在一些情况下,插入肽具有氨基酸序列AALGETTRPA(SEQ ID NO:15)或AANETITRPA(SEQ ID NO:16),作为又一实例,在一些情况下,插入肽具有氨基酸序列GLGETTRPA(SEQ ID NO:17)或GNETITRPA(SEQ ID NO:18)。
在一些实施例中,除相对于对应的亲本AAV衣壳蛋白,GH环或其子区域中的约5到11个氨基酸的插入外,本发明rAAV病毒粒子衣壳不包括任何氨基酸取代、插入或缺失。在其它实施例中,相比于亲本AAV衣壳蛋白,除如上文所描述的GH环或其子区域中的约5到11个氨基酸的插入外,本发明rAAV病毒粒子衣壳可包括1到约25个氨基酸插入、缺失或取代。举例来说,多种氨基酸序列改变已公开于所属领域中,其中的任一种可包括于本发明rAAV中。在一些实施例中,本发明rAAV病毒粒子衣壳为嵌合衣壳,例如所述衣壳包含第一AAV血清型的AAV衣壳的一部分和第二血清型的AAV衣壳的一部分;且相对于对应的亲本AAV衣壳蛋白,在GH环或其子区域中包含约5个氨基酸到约11个氨基酸的插入。
在一些实施例中,本发明rAAV病毒粒子包含衣壳蛋白,其包含与对应的亲本衣壳蛋白的VP1衣壳蛋白具有80%或更多的序列一致性,例如与对应的亲本衣壳蛋白具有85%或更多、90%或更多、95%或更多或97C%一致性或更多的氨基酸序列,以及相对于对应的亲本AAV衣壳蛋白,GH环其或子区域中的约5到11个氨基酸的插入。举例来说,与SEQ ID NO:19中描述的7m8 VP1序列具有80%或更多的序列一致性,例如与7m8 VP1序列85%一致性或更多,90%一致性或更多,或95%一致性或更多,在一些情况下与提供于SEQ ID NO:19中的氨基酸序列具有97%一致性或更多,98%一致性或更多,或至少约99%序列一致性。
本发明组合物涵盖且可用于本发明方法中的rAAV变体可照此通过测定其转导锥状光感受器,例如中央窝锥状光感受器的功效容易地验证。举例来说,可产生包含AAV病毒基因组的病毒粒子,所述病毒基因组包含表达卡匣,其包含包装到本发明rAAV中的可操作地连接到如所属领域中已知的视锥启动子的GFP和注射到哺乳动物眼睛,例如小鼠、大鼠、兔、沙鼠、仓鼠、松鼠或灵长类,例如非人类灵长类的眼睛中的病毒粒子。当经由玻璃体内注射投与时,相比于包含对应的亲本AAV衣壳蛋白的AAV病毒粒子的锥状光感受器感染力,本发明涵盖的rAAV病毒粒子将典型地展现锥状光感受器的感染力提高至少2倍、至少5倍、至少10倍、至少15倍、至少20倍、至少25倍、至少50倍,在一些情况下,超过50倍,例如至少60倍、至少70倍、至少80倍、至少90倍,例如100倍或更多。换句话说,与包含对应的亲本AAV衣壳蛋白的AAV病毒粒子相比,适用于本发明方法中的rAAV病毒粒子将感染多至少10倍,多至少15倍,多至少20倍,多至少50倍,在一些情况下多超过50倍锥状光感受器,例如多至少60倍、至少70倍、至少80倍、至少90倍,例如100倍锥状光感受器。
在一些实施例中,所述方法可进一步包含检测锥状光感受器中递送的多核苷酸的存在的步骤。可采用用于检测多核苷酸存在的任何适宜方法。举例来说,可使用例如PCR、Next Gen测序等检测多核苷酸,或可通过例如RT-PCR、北方墨点、RNA酶保护、西方墨点、ELISA、免疫组织化学等检测由多核苷酸编码的基因产物的表达。这些方法尤其适合于临床前研究。在临床研究中,可优选通过检测功能基因产物的存在,即,通过检测基因产物对个体中的锥状光感受器的存活力或功能的影响来检测多核苷酸的存在。举例来说,如果由多核苷酸编码的基因产物提高锥状光感受器的存活力,那么可通过例如眼底摄影、光学相干性断层摄影术(OCT)、适应性光学装置(AO)等作为检测多核苷酸存在的方式来检测锥状光感受器的存活力提高。如果由多核苷酸编码的基因产物改变锥状光感受器的活性,那么可通过例如网膜电图(ERG)和颜色ERG(cERG);颜色视觉测试,如假同色板(石原(Ishihara)板、哈迪-兰德-里特(Hardy-Rand-Ritter)多色板)、方斯沃斯-蒙赛尔(Farnsworth-Munsell)100色调测试、方斯沃斯面板D-15、城市大学测试、科尔讷规则(Kollner's rule)等;以及视敏度测试,如ETDRS字母测试、斯内伦(Snellen)视敏度测试等作为检测递送的多核苷酸的存在的方式来检测锥状光感受器的改变的活性。
如上文所论述,在一些实施例中,通过本发明组合物和方法递送的多核苷酸通过递送到达的锥状光感受器表达。换句话说,在本发明的一些方面中,提供用于在锥状光感受器中表达基因产物的方法,所述方法包含将编码相关基因产物的多核苷酸递送到锥状光感受器。如所属领域的一般技术人员将充分理解,相关多核苷酸的视锥细胞的表达典型地需要可操作地连接到启动子的相关多核苷酸。如所属领域的一般技术人员还将了解,存在可获得此的多种方法。举例来说,可将多核苷酸递送到宿主细胞,即,可操作地连接到启动子的锥状光感受器。换句话说,包含相关多核苷酸的病毒基因组还包含启动子,其中启动子可操作地连接到多核苷酸以形成表达卡匣。作为另一实例,可将多核苷酸递送到宿主细胞,即,锥状光感受器,其通过将多核苷酸整合到宿主基因组中的启动子序列侧接。换句话说,包含相关多核苷酸的病毒基因组包含侧接相关多核苷酸的序列,其与侧接宿主细胞启动子的3'端的序列同源且促进相关多核苷酸重组到宿主基因组中以使得其可操作地连接到宿主细胞启动子。重组病毒基因组的其它布置可用于确保所属领域的一般技术人员将容易地预想相关多核苷酸表达;参见例如美国申请公开案第2013/0280222号,其全部公开内容以引用的方式并入本文中。
因此,在一些情况下,rAAV包含的病毒基因组包含可操作地连接到相关多核苷酸的启动子。在一些情况下,启动子为普遍存在的启动子,即,其为在广泛范围的细胞、组织和物种中为活性的启动子。在其它情况下,启动子为视锥启动子。视锥启动子意指在锥状光感受器中为活性的启动子,即,促进可操作地连接的多核苷酸的锥状光感受器表达。可用于本发明组合物中的视锥启动子的非限制性实例包括如美国临时申请第61/954,330号和第62/127,185号中所公开的pMNTC启动子;如例如美国申请第2013/0317091号中所公开的pR2.1启动子或其变体(例如pR1.7、pR1.5、pR1.1等);或如美国申请第2014/0275231号中所公开的合成IRBP/GNAT2启动子;其全部公开内容以引用的方式并入本文中。在其它情况下,rAAV包含的病毒基因组包含与宿主基因组中的靶整合位点具有同源性的两个序列:与整合位点的区域5'同源且位于病毒基因组上的多核苷酸的5'的第一序列;以及与整合位点的区域3'同源且位于病毒基因组上的多核苷酸的3'的第二序列,其中靶整合位点为3'且可操作地连接到宿主启动子,例如视锥启动子,例如L-视蛋白启动子、M-视蛋白启动子。。
在一些实施例中,相对于如采用野生型或其它亲本衣壳时观测到的表达,转导增强。增强意指相对于使用野生型或其它亲本衣壳蛋白将观测到的水平和通常对视锥存活力和/或功能具有影响的量,个体锥状光感受器中的转导提高、增加或扩增例如至少2倍、至少5倍、至少10倍、至少15倍、至少20倍、至少25倍、至少50倍,在一些情况下,超过50倍,例如至少60倍、至少70倍、至少80倍、至少90倍,例如100倍,以例如向个体提供治疗效益。
预期本发明变体rAAV的视锥细胞增强的转导导致多核苷酸,例如通过变体rAAV递送到那些细胞的表达卡匣的表达增强。可在多种方法中观测到本发明的rAAV的多核苷酸的增强的表达。举例来说,与通过亲本rAAV递送的多核苷酸将检测到的表达相比,可通过在使变体rAAV与视锥细胞接触之后更早,例如提早7天,提早2周,提早3周,提早4周,提早8周,提早12周,或更早检测到多核苷酸表达来观测到增强的表达。增强表达也可观测为每个细胞基因产物量的增加。举例来说,每个视锥细胞的基因产物量可能增加2倍或更多,例如增加3倍或更多,增加4倍或更多,增加5倍或更多,或增加10倍或更多。增强的表达也可观测为表达可检测到水平的变体rAAV携带的多核苷酸的视锥细胞的数目增加。举例来说,表达可检测水平的多核苷酸的视锥细胞的数目可能增加2倍或更多,例如增加3倍或更多,增加4倍或更多,增加5倍或更多,或增加10倍或更多。作为另一实例,本发明的多核苷酸可相比于亲本rAAV促进更大百分比细胞中的多核苷酸的可检测水平;例如在亲本rAAV可促进一定区域中的例如小于5%视锥细胞中的可检测水平的多核苷酸表达的情况下,本发明的rAAV促进所述区域中5%或更多视锥细胞的可检测水平的表达;例如10%或更多,15%或更多,20%或更多,25%或更多,30%或更多,35%或更多,40%或更多,或45%或更多,在一些情况下,50%或更多,55%或更多;60%或更多,65%或更多,70%或更多,或75%或更多,例如80%或更多,85%或更多,90%或更多或95%或更多的所接触的视锥细胞将表达可检测水平的基因产物。增强的表达也可观测视锥细胞的存活力和/或功能改变,例如如使用评定工具,如眼底摄影、OCT、适应性光学装置、cERG、颜色视觉测试、视敏度测试等所测量,如所属领域中已知且如本文所描述。
在一些实施例中,所述方法可进一步包含检测锥状光感受器中的多核苷酸的表达的步骤。在此类实施例中,可采用用于检测多核苷酸表达的如所属领域中已知或本文所描述的任何适宜方法,包括例如检测基因产物,即,经编码的RNA或蛋白质,例如通过RT-PCR、北方墨点、RNA酶保护、西方墨点、ELISA、免疫组织化学等;检测基因产物对锥状光感受器的存活力的影响,例如通过眼底摄影、光学相干性断层摄影术(OCT)、适应性光学装置(AO);或检测基因产物对视锥功能的影响,例如网膜电图(ERG)、颜色视觉测试、视敏度测试等,其中的任一种可用于本发明方法中。
包含本发明的相关多核苷酸的rAAV病毒粒子可使用任何适宜方法、如所属领域的技术人员已知的AAV包装细胞和包装技术产生。举例来说,AAV表达载体(即,包含rAAV基因组以及适用于克隆例如细菌基因组元件中的元件(例如复制起点、可选择标记物等)的质粒)可转染到哺乳动物生产细胞中。还转染到哺乳动物生产细胞中的为AAV辅助构建物,即,包含可在生产细胞中表达的AAV REP和CAP编码区的质粒,其补充AAV表达载体不具有的AAV辅助功能。经双转染的生产细胞随后经辅助病毒,例如腺病毒感染,或经包含辅助病毒附属基因(其促进AAV载体复制)的质粒(例如区域VA、E2A、E4)转染以便促进有效rAAV病毒产生。生产细胞随后经培养以产生rAAV,且使用所属领域中已知的标准技术纯化和配制AAV载体。
作为另一实例,AAV表达载体可包装为杆状病毒且引入到昆虫生产细胞,例如Sf9细胞中。还通过另一杆状病毒引入到昆虫细胞中的为AAV REP和CAP基因。杆状病毒(为病毒)包含编码有效rAAV病毒产生所必需的附属功能的基因。相应地,在通过两种杆状病毒感染昆虫细胞后,生产细胞可经培养以产生rAAV,且使用所属领域中已知的标准技术纯化和配制AAV载体。
这些和其它方法的实例可见于例如美国专利第5,436,146号、第5,753,500号、第6,040,183号、第6,093,570号和第6,548,286号中,其以全文引用的方式明确并入本文中。其它组合物和包装方法描述于Wang等人(US 2002/0168342)中,其也以全文引用的方式并入本文中。
可在生产本发明载体时采用所属领域中所使用的用于制造rAAV病毒粒子的任何适宜宿主细胞,包括例如哺乳动物细胞、昆虫细胞、微生物和酵母,例如SF-9、293、A549、HeLa细胞等。在一些情况下,宿主细胞为包装细胞,其中AAV rep和cap基因稳定地保持在宿主细胞中。在一些情况下,宿主细胞为生产细胞,其中稳定地保持和包装AAV载体基因组。
医药组合物和单元剂量
在一些实施例中,将需要例如基因疗法用途以将本发明rAAV配制为医药组合物。在某些实施例中,医药组合物包含本文所描述的载体或病毒粒子(例如rAAV)和一种或多种药学上可接受的载剂、稀释剂或赋形剂。适用的医药组合物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。对于静脉内投与,适合的载体包括生理盐水、抑菌水或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物必须为无菌的且流动性应达到能够简单注射的程度。其必须在制造和储存条件下为稳定的且必须被保存以免微生物(例如细菌和真菌)的污染活动。载剂可为含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)以及其合适的混合物的溶剂或分散介质。可例如通过使用涂层(例如卵磷脂)、在分散液情况下通过维持所需粒度以及通过使用表面活性剂来维持适当流动性。微生物活动的预防可通过各种抗细菌和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等来实现。在许多情况下,优选在组合物中包括等渗剂,例如糖、多元醇(如甘露糖醇、山梨糖醇)、氯化钠。内部组合物的延长吸收可通过在组合物中包括延迟吸收的药剂(例如单硬脂酸铝和明胶)实现。
无菌溶液可通过如下方法来制备:视需要将所需量的活性化合物与上文列举的成分中的一种或其组合并入适当溶剂中,接着过滤灭菌。一般来说,通过将活性化合物并入含有碱性分散介质和来自上文所列举的那些成分的所需其它成分的无菌媒剂中来制备分散液。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法是真空干燥和冷冻干燥,这产生了活性成分加上来自其先前无菌过滤溶液的任何其它所希望的成分的粉末。
在一个实施例中,活性化合物用将保护化合物免于从身体快速消除的载剂,如控制释放配制物,包括植入物和微封装递送系统来制备。可使用生物可降解的生物相容性聚合物,如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯以及聚乳酸。用于制备此类配制物的方法将为所属领域的技术人员显而易见的。材料也可在商业上获得。脂质体悬浮液(包括靶向经针对病毒抗原的单克隆抗体感染的细胞的脂质体)也可用作医药学上可接受的载剂。这些物质可根据所属领域的技术人员已知的方法制备,例如如美国专利第4,522,811号中所描述。
本发明的医药组合物涵盖任何医药学上可接受的盐、酯或此类酯的盐或任何其它化合物,其在投与到包含人类的动物后能够提供(直接或间接)生物活性代谢物或其残余物。相应地,举例来说,本发明还涉及本发明化合物的前药和医药学上可接受的盐、此类前药的医药学上可接受的盐和其它生物等效物。
术语“前药”指示以在身体或其细胞内通过内源性酶或其它化学物质的作用和/或条件转化成活性形式(即,药物)的非活性形式制备的治疗剂。
术语“医药学上可接受的盐”是指本发明化合物的生理学上和医药学上可接受的盐:即,保持母体化合物的所需生物活性且并不赋予其非所需毒理学作用的盐。
用金属或胺,如碱金属和碱土金属或有机胺形成医药学上可接受的碱加成盐。用作阳离子的金属包含钠、钾、镁、钙等。胺包含N-N'-二苯甲基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因(procaine)(参见例如Berge等人,“医药盐(Pharmaceutical Salts),”《药学科学杂志(J.Pharma Sci.)》,1977,66,119)。所述酸性化合物的碱加成盐通过使游离酸形式与足够量的所需碱接触来制备,从而以常规方式产生所述盐。游离酸形式可通过使盐形式与酸接触且以常规方式分离游离酸而再生。游离酸形式与其各别盐形式的略微不同之处在于某些物理特性,如在极性溶剂中的溶解度,但另外出于本发明的目的,所述盐等效于其各别游离酸。
如本文所使用,“医药加成盐”包含本发明的组合物的组分中的一种的酸形式的医药学上可接受的盐。这些包含胺的有机或无机酸盐。优选的酸盐为盐酸盐、乙酸盐、水杨酸盐、硝酸盐和磷酸盐。其它适合的医药学上可接受的盐为所属领域的技术人员熟知的且包含多种无机和有机酸的碱性盐,如无机酸,例如盐酸、氢溴酸、硫酸或磷酸;有机羧酸、磺酸、磺酸基或磷酸基酸或经N取代的氨基磺酸,例如乙酸、丙酸、乙醇酸、琥珀酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、乳酸、草酸、葡糖酸、葡萄糖二酸、葡糖醛酸、柠檬酸、苯甲酸、肉桂酸、杏仁酸、水杨酸、4-氨基水杨酸、2-苯基苯甲酸、2-乙酰氧基苯甲酸、恩波酸、烟碱酸或异烟酸;以及氨基酸,如涉及自然界中的蛋白质的合成的20个α-氨基酸,例如谷氨酸或天冬氨酸以及苯乙酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙烷-1,2-二磺酸、苯磺酸4-甲基苯磺酸、萘-2-磺酸、萘-1,5-二磺酸、2-磷酸甘油酸或3-磷酸甘油酸、葡萄糖-6-磷酸盐、N-环己基氨基磺酸(形成环己基氨基磺酸盐)或其它酸有机化合物,如抗坏血酸。化合物的也可用医药学上可接受的阳离子制备医药学上可接受的盐。适合的医药学上可接受的阳离子为所属领域的技术人员熟知的且包含碱性、碱土、铵和季铵阳离子。碳酸盐或氢碳酸盐也为可能的。对于寡核苷酸,医药学上可接受的盐的优选实例包含但不限于:(I)用阳离子形成的盐,所述阳离子如钠、钾、铵、镁、钙;聚酰胺,如精胺和亚精胺等;(II)用无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸硫酸、磷酸、硝酸等;(III)用有机酸形成的盐,所述有机酸如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡糖酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、棕榈酸、褐藻酸、多聚谷氨酸、萘磺酸、甲磺酸、对甲苯磺酸、萘二磺酸、聚半乳糖醛酸等;以及(IV)由元素阴离子形成的盐,如氯、溴和碘。
本发明的医药组合物包含但不限于溶液、乳液和含有脂质体的配制物。这些组合物可由多种组分产生,所述组分包含但不限于预先形成的液体、自乳化固体和自乳化半固体。
本发明的某些组合物还在配制物中并入载体化合物。如本文所使用,“载体化合物”或“载体”可指核酸或其类似物,其为惰性的(即,本身不具有生物活性),但通过降低具有生物活性的核酸的生物利用率的活体内方法(通过使生物活性核酸降解或促进从循环去除其)识别为核酸。核酸和载体化合物(典型地具有过量后一物质)的共投与可导致在肝脏、肾脏或其它额外循环容器中回收的核酸的量实质上减少,这可能归因于共同受体的载体化合物与核酸之间的竞争。举例来说,当其与多聚肌苷酸、硫酸葡聚糖、聚肌胞苷酸或4-乙酰氨基-4'异硫氰基-芪-2,2'二磺酸共投与时,可减少肝脏组织中的部分硫代磷酸酯寡核苷酸的回收(Miyao等人,《反义研究和开发(Antisense Res.Dev.)》,1995,5,115-121;Takakura等人,《反义和核酸药物开发(Antisense&Nucl.Acid Drug Dev.)》,1996,6,177-183)。
本发明重组AAV可并入到医药组合物中以用于投与到哺乳动物患者,尤其人类。病毒粒子可在无毒性、惰性、医药学上可接受的水性载体中,优选地在3到8范围内,更优选6到8范围内的pH下配制。此类无菌组合物将包含含有编码溶解于水性缓冲液(在复原后具有可接受的pH)中的治疗性分子的核酸的载体或病毒粒子。
在一些实施例中,本文所提供的医药组合物包含治疗有效量的载体或病毒粒子,其与医药学上可接受的载剂和/或赋形剂,例如生理盐水、磷酸盐缓冲盐水、磷酸盐和氨基酸、聚合物、多元醇、糖、缓冲剂、防腐剂和其它蛋白质混杂。示例性氨基酸、聚合物和糖等为辛基苯氧基聚乙氧基乙醇化合物、聚乙二醇单硬脂酸酯化合物、聚氧化乙烯脱水山梨糖醇脂肪酸酯、蔗糖、果糖、右旋糖、麦芽糖、葡萄糖、甘露糖醇、葡聚糖、山梨糖醇、肌醇、半乳糖醇、木糖醇、乳糖、海藻糖、牛或人类血清白蛋白、柠檬酸酯、乙酸酯、林格氏和汉克氏溶液(Ringer's and Hank's solution)、半胱氨酸、精氨酸、肉碱、丙氨酸、甘氨酸、赖氨酸、缬氨酸、白氨酸、聚乙烯吡咯烷酮、聚乙烯和二醇。优选地,此配制物在4℃下稳定至少六个月。
在一些实施例中,本文所提供的医药组合物包含缓冲液,如磷酸盐缓冲盐水(PBS)或磷酸钠/硫酸钠、tris缓冲液、甘氨酸缓冲液、无菌水和所属领域的一般技术人员已知的其它缓冲剂,如Good等人(1966)《生物化学(Biochemistry)》5:467所描述的那些。缓冲液(其中医药组合物包含腺病毒载体递送系统中所含有的肿瘤遏制基因)的pH可在6.5到7.75,优选7到7.5,且最优选7.2到7.4范围内。
在一些实施例中,本文所提供的医药组合物包含提高悬浮液粘度的物质,如羧甲基纤维素钠、山梨糖醇或葡聚糖,其量为约1%-10%,如1%、2%、3%、4%、5%、6%、7%、8%、9%或10%。
医药组合物可与投与说明书一起包括于容器、包装或分配器中。
在一些情况下,例如对于眼内、经口或非经肠投与,可能尤其有利的为为了易于投与和剂量均一性以单位剂型配制医药组合物。如本文所使用的单位剂型是指适合作为单一剂量用于待治疗个体的物理离散单位;每个单位含有与所需药物载剂结合,经计算以产生所需治疗效果的预定数量的活性化合物。本发明的单位剂型的规格由活性化合物的独特特征和打算实现的特定治疗效果,和混配此类活性化合物用于治疗个体的领域中固有的局限性规定且直接取决于这些因素。
在一些情况下,单位剂量的本发明的医药组合物可以pfu(空斑形成单位)测量。在一些情况下,本发明的医药组合物的单位剂量的pfu可为约1×108到约5×1010pfu。在一些情况下,本发明的医药组合物的单位剂量的pfu为至少约1×108、2×108、3×108、4×108、5×108、6×108、7×108、8×108、9×108、1×109、2×109、3×109、4×109、5×109、6×109、7×109、8×109、9×109、1×1010、2×1010、3×1010、4×1010和5×1010pfu。在一些情况下,本发明的医药组合物的单位剂量的pfu为至多约1×108、2×108、3×108、4×108、5×108、6×108、7×108、8×108、9×108、1×109、2×109、3×109、4×109、5×109、6×109、7×109、8×109、9×109、1×1010、2×1010、3×1010、4×1010和5×1010pfu。
在一些情况下,本发明的病毒载体可测量为载体基因组。在一些情况下,本发明的医药组合物的单位剂量为1×108个载体基因组或更多,例如1×109、1×1010、1×1011、1×1012或1×1013个载体基因组或更多,在某些情况下,1×1014个载体基因组或更多,且通常不超过1×1015个载体基因组。在一些实施例中,本发明的医药组合物的单位剂量为至多约1×1015个载体基因组,例如1×1014个载体基因组或更少,例如1×1013、1×1012、1×1011、1×1010或1×109个载体基因组或更少,在某些情况下,1×108个载体基因组且典型地不低于1×108个载体基因组。在一些情况下,本发明的医药组合物的单位剂量为1×1010到1×1011个载体基因组。在一些情况下,本发明的医药组合物的单位剂量为1×1010到3×1012个载体基因组。在一些情况下,本发明的医药组合物的单位剂量为1×109到3×1013个载体基因组。在一些情况下,本发明的医药组合物的单位剂量为1×108到3×1014个载体基因组。
在一些情况下,本发明的医药组合物的单位剂量可使用感染倍率(MOI)测量。在一些情况下,MOI可指载体或病毒基因组与核可递送到的细胞的比率或整倍数。在一些情况下,MOI可为1×106。在一些情况下,MOI可为1×105-1×107。在一些情况下,MOI可为1×104-1×108。在一些情况下,本发明的重组病毒为至少约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。在一些情况下,本发明的重组病毒为1×108到3×1014MOI。在一些情况下,本发明的重组病毒为至多约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。
在一些方面中,医药组合物包含约1×108到约1×1015个重组病毒,约1×109到约1×1014个重组病毒,约1×1010到约1×1013个重组病毒,约1×10109到约3×1012个重组病毒或约1×1011到约3×1012个重组病毒。
投与方法
本发明的医药组合物可通过任何适宜方法,例如眼内、静脉内、腹膜内等投与到个体眼睛。在一些情况下,投与为眼内的,例如通过玻璃体内注射或视网膜下注射。可通过以下简单概述说明用于经由玻璃体内注射或视网膜下视网膜下注射递送载体的一般方法。这些实例仅意图说明方法的某些特征且决不意图为限制性的。
在优选实施例中,玻璃体内递送本发明rAAV。对于玻璃体内投与,载体可以悬浮液形式递送。首先,将局部麻醉剂施用到眼睛表面,继而局部消毒溶液。在具有或不具有仪器的情况下,眼睛保持敞开,且用例如较短的狭窄30号针头,在直接观测下将载体注射通过巩膜进入个体眼睛的玻璃体腔室。玻璃体内投与一般为良好耐受的。在程序结束时,在注射位点处有时轻微发红。存在偶发性压痛,但大部分患者并未报导有任何疼痛。在此程序之后不需要眼睛贴片或眼罩,且活动不受限制。有时,抗生素滴眼剂指定若干天以帮助防止感染。
在一些实施例中,视网膜下递送本发明rAAV。对于视网膜下投与,可在直接观测下使用操作显微镜,以视网膜下注射的悬浮液形式递送载体。此程序可涉及玻璃体切除术,继而使用精细插管,经由一种或多种较小视网膜切开术,将载体悬浮液注射到视网膜下空间中。
简单来说,输液插管可缝合在适当的位置以在整个操作期间通过输注(例如生理盐水)维持正常球体积。使用适当的孔尺寸(例如20到27号)的插管进行玻璃体切除术,其中去除的玻璃体凝胶体积通过输注生理盐水或其它等渗溶液从输液插管替换。有利地进行玻璃体切除术,因为(1)去除其皮层(后部玻璃体膜)有助于通过插管穿透视网膜;(2)其去除和用流体(例如生理盐水)替换产生空间以容纳载体的眼内注射,和(3)其受控制的去除降低视网膜泪液和计划外的视网膜脱离的可能性。
在实践本发明方法时,以能有效地将相关多核苷酸递送到5%或更多个体锥状光感受器的量,将本发明rAAV病毒粒子递送到眼睛,例如10%或更多,20%或更多,30%或更多,40%或更多,或50%或更多个体锥状光感受器,例如60%或更多,70%或更多,80%或更多,或90%或更多个体锥状光感受器,在一些情况下,95%或更多,98%或更多,或100%个体锥状光感受器以个别向个体提供治疗效益。换句话说,在投与后,5%或更多个体锥状光感受器,例如10%或更多,20%或更多,30%或更多,40%或更多,或50%或更多,在一些情况下,60%或更多,70%或更多,80%或更多,或90%或更多,例如95%、98%或100%视锥将包含足够量的相关多核苷酸以影响视锥存活力和/或功能,例如治疗或防止病症。在一些实施例中,经转导的锥状光感受器将位于整个视网膜中。在一些实施例中,经转导的锥状光感受器将为中央窝和小凹中的视锥。在一些实施例中,经转导的锥状光感受器将为中央窝视锥,即位于中央窝中的L-视锥或M-视锥。
典型地,有效量将为约1×108个载体基因组或更多的本发明rAAV,例如1×109、1×1010、1×1011、1×1012或1×1013个载体基因组或更多,在某些情况下,1×1014个载体基因组或更多且通常不超过1×1015个载体基因组。在一些情况下,递送的载体基因组的量为至多约1×1015个载体基因组,例如1×1014个载体基因组或更少,例如1×1013、1×1012、1×1011、1×1010或1×109个载体基因组或更少,在某些情况下1×108个载体基因组且典型地不低于1×108个载体基因组。在一些情况下,递送的载体基因组的量为1×1010到1×1011个载体基因组。在一些情况下,递送的载体基因组的量为1×1010到3×1012个载体基因组。在一些情况下,递送的载体基因组的量为1×109到3×1013个载体基因组。在一些情况下,递送的载体基因组的量为1×108到3×1014个载体基因组。
在一些情况下,待投与的医药组合物的量可使用感染倍率(MOI)测量。在一些情况下,MOI可指载体或病毒基因组与核可递送到的细胞的比率或整倍数。在一些情况下,MOI可为1×106。在一些情况下,MOI可为1×105-1×107。在一些情况下,MOI可为1×104-1×108。在一些情况下,本发明的重组病毒为至少约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。在一些情况下,本发明的重组病毒为1×108到3×1014MOI。在一些情况下,本发明的重组病毒为至多约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。
在一些方面中,医药组合物的量包含约1×108到约1×1015个重组病毒,约1×109到约1×1014个重组病毒,约1×1010到约1×1013个重组病毒,约1×1010到约3×1012个重组病毒或约1×1011到约3×1012个重组病毒。
效用
用于将多核苷酸玻璃体内递送到锥状光感受器和更尤其中央窝视锥的方法和组合物可更多用于研究和医学。
举例来说,此类方法和组合物可用于研究中以测试活体内通过多核苷酸编码的基因产物的功能,以例如更好地理解锥状光感受器的功能和/或基因产物是否将影响锥状光感受器的存活力和/或功能。
如上文所提及,本文统称为“本发明组合物”的本发明rAAV可用于在动物的视锥细胞中,例如在动物的中央窝视锥中表达转基因。举例来说,本发明组合物可用于研究中以例如测定基因对视锥细胞活力和/或功能的作用。作为另一实例,本发明组合物可用于医学中以例如治疗视锥细胞病症。因此,在本发明的一些方面中,提供用于在视锥细胞中表达基因的方法,所述方法包含使视锥细胞与本发明组合物接触。在一些实施例中,接触活体外进行。在一些实施例中,接触活体内进行,即,向个体投与本发明组合物。
对于视锥细胞与本发明rAAV活体外接触的实例,细胞可来自任何哺乳动物物种,例如啮齿动物(例如小鼠、大鼠、沙鼠、松鼠)、兔、猫、犬、山羊、绵羊、猪、马、牛、灵长类动物、人类。细胞可来自现有细胞系,例如WERI细胞、661W细胞,或其可为原代细胞,其中“原代细胞”、“原代细胞系”和“原代培养物”在本文中可互换使用以指已衍生自个体且允许活体外生长培养物的有限数目的继代,即分裂物的细胞和细胞培养物。举例来说,原代培养物为可已传代0次、1次、2次、4次、5次、10次或15次,但不足以通过危机阶段的培养物。典型地,本发明的原代细胞系活体外保持少于10次继代。
如果细胞为原代细胞,那么其可通过任何适宜方法从哺乳动物收集,例如整个外植体、活检体等。适当的溶液可用于所收集的细胞的分散液或悬浮液。此类溶液一般将为平衡盐溶液,例如标准生理食盐水、PBS、汉克氏平衡盐溶液等,其适宜地补充有胎牛血清或其它天然存在的因子以及低浓度(一般为5-25mM)的可接受的缓冲液。适宜缓冲剂包括HEPES、磷酸盐缓冲剂、乳酸盐缓冲剂等。可紧接着使用所述细胞,或其可储存、冷冻较长时间段,解冻且能够再使用。在此类情况下,细胞将通常冷冻在10%DMSO、50%血清、40%缓冲培养基或如所属领域中常用的一些其它此类溶液中以在此类冷冻温度下保存细胞且以如所属领域中通常已知的方式解冻以便解冻经冷冻培养的细胞。
为了促进转基因表达,本发明rAAV将与细胞接触约30分钟到24小时或更多,例如1小时、1.5小时、2小时、2.5小时、3小时、3.5小时、4小时、5小时、6小时、7小时、8小时、12小时、16小时、18小时、20小时、24小时等。可向本发明细胞提供本发明rAAV一次或多次,例如一次、两次、三次、或大于三次,且所述细胞允许与试剂一起培育各接触事件后一定时间量,例如16-24小时,其后用新鲜培养基替换所述培养基且进一步培养细胞。接触细胞可存在于提高细胞存活率的任何培养基中和任何培养条件下。举例来说,细胞可悬浮于适宜的任何适当的营养物培养基中,如伊斯科夫氏改性的DMEM或RPMI 1640,其补充有胎牛血清或热灭活山羊血清(约5-10%)、L-谷氨酰胺、硫醇(尤其2-巯基乙醇)和抗生素,例如青霉素和链霉素。培养物可含有对细胞具有反应性的生长因子。如本文所定义,生长因子为能够经由对跨膜受体的特异性作用促进培养物或完整组织中的细胞的存活率、生长和/或分化的分子。生长因子包括多肽和非多肽因子。
典型地,提供有效量的本发明rAAV以使转基因在细胞中表达。如本文中其它处所论述,可容易地凭经验,例如通过检测转基因基因产物的存在或水平,通过检测对视锥细胞的存活力或功能的作用等来测定有效量。典型地,与衍生其衣壳的亲本rAAV的相同量相比,本发明rAAV的作用量将促进更多转基因在视锥细胞中表达。典型地,相对于亲本rAAV表达,表达将增强2倍或更多,例如3倍、4倍或5倍或更多,在一些情况下,10倍、20倍或50倍或更多,例如100倍。
在一些实施例中,如当转基因为可选择标记物时,对于包含通过从其余的群体分离经修饰的细胞的转基因的那些,细胞群体可为富集的。可通过适于所使用的可选择标记物的任何适宜分离技术进行分离。举例来说,如果转基因为荧光标记,那么可通过荧光激活细胞分选术分离细胞,而如果转基因为细胞表面标记物,那么可通过亲和性分离技术,例如磁性分离、亲和色谱法、用连接到固体基质的亲和试剂进行“淘选”或其它适宜技术,从异源群体分离细胞。提供准确分离的技术包括荧光活化细胞分选器,其可具有不同复杂度,如多种颜色通道、较低角度和钝角光散射检测通道、阻抗通道等。可针对死亡的细胞,通过采用与死亡的细胞相关的染料(例如碘化丙锭),选择细胞。可采用不会过度危害细胞存活力的任何技术。以此方式获得包含转基因的细胞高度富集的细胞组合物。“高度富集的”意指经基因修饰的细胞将为70%或更多,75%或更多,80%或更多,85%或更多,90%或更多细胞组合物,例如约95%或更多或98%或更多细胞组合物。换句话说,组合物可为经基因修饰细胞的基本上纯组合物。
对于视锥细胞与本发明rAAV活体内接触的实例,个体可为任何哺乳动物,例如啮齿动物(例如小鼠、大鼠、沙鼠)、兔、猫、犬、山羊、绵羊、猪、马、牛或灵长类动物。在某些实施例中,个体为始狭鼻猴类的灵长类动物。如所属领域中已知,狭鼻猴为高等灵长类动物的两个细分部中的一个(另一个为新世界猴)且包括旧世界猴和猿,其之后进一步分成低等猿或长臂猿和大猿,由猩猩、大猩猩、黑猩猩、倭黑猩猩和人类组成。在另一优选实施例中,灵长类动物为人类。
本发明rAAV可通过任何适合的方法投与到个体视网膜。举例来说,可经由玻璃体内注射或视网膜下注射眼内投与本发明组合物。可通过以下简单概述说明用于经由玻璃体内注射或视网膜下视网膜下注射递送载体的一般方法。这些实例仅意图说明方法的某些特征且决不意图为限制性的。
对于视网膜下投与,可在直接观测下使用操作显微镜,以视网膜下注射的悬浮液形式递送本发明rAAV。典型地,将通过此类方法投与1到200μL,例如50μL、100μL、150μL或200μL,但通常不超过200μL体积的本发明组合物。此程序可涉及玻璃体切除术,继而使用精细插管,经由一种或多种较小视网膜切开术,将载体悬浮液注射到视网膜下空间中。简单来说,输液插管可缝合在适当的位置以在整个操作期间通过输注(例如生理盐水)维持正常球体积。使用适当的孔尺寸(例如20到27号)的插管进行玻璃体切除术,其中去除的玻璃体凝胶体积通过输注生理盐水或其它等渗溶液从输液插管替换。有利地进行玻璃体切除术,因为(1)去除其皮层(后部玻璃体膜)有助于通过插管穿透视网膜;(2)其去除和用流体(例如生理盐水)替换产生空间以容纳载体的眼内注射,和(3)其受控制的去除降低视网膜泪液和计划外的视网膜脱离的可能性。
对于玻璃体内投与,本发明rAAV可以悬浮液形式递送。首先,将局部麻醉剂施用到眼睛表面,继而局部消毒溶液。在具有或不具有仪器的情况下,眼睛保持敞开,且用例如较短的狭窄30号针头,在直接观测下将rAAV注射通过巩膜进入个体眼睛的玻璃体腔室。典型地,可通过玻璃体内注射,在不去除玻璃体的情况下,将1到100μL,例如25μL、50μL或100μL且通常不超过100μL体积的本发明组合物递送到眼睛。替代地,可进行玻璃体切除术,且整个体积的玻璃体凝胶通过本发明组合物输注置换。在此类情况下,高达约4mL本发明组合物可递送到例如人类眼睛。玻璃体内投与一般为良好耐受的。在程序结束时,在注射位点处有时轻微发红。存在偶发性压痛,但大部分患者并未报导有任何疼痛。在此程序之后不需要眼睛贴片或眼罩,且活动不受限制。有时,抗生素滴眼剂指定若干天以帮助防止感染。
本发明方法和/或组合物可用于医学中以在锥状光感受器中表达治疗性多核苷酸,作为治疗或预防视网膜病症的疗法。术语“治疗(treatment、treating)”等在本文中一般用于意指获得所需药理学和/或生理学作用。所述作用就完全或部分预防疾病或其症状来说可为预防性的,例如降低在个体中发生疾病或其症状的可能性,和/或就部分或完全治愈疾病和/或可归因于所述疾病的不良作用来说可为治疗性的。如本文所使用的“治疗”覆盖哺乳动物的疾病的任何治疗,且包括:(a)预防疾病在可能易患疾病但尚未诊断患有所述疾病的个体中发生;(b)抑制疾病,即,遏制其发展;或(c)缓解疾病,即,使疾病消退。可在疾病起始或损伤之前、期间或之后投与治疗剂。发展中的疾病的治疗为备受关注的,其中治疗稳定或减少患者的非所需临床症状。此类治疗合乎需要地在受感染的组织功能完全缺失之前进行。本发明疗法将合乎需要地在疾病的有症状阶段期间且在一些情况下在疾病的有症状阶段之后投与。
存在可使用本发明方法和/或组合物治疗或预防的多种视网膜病症。备受关注的为视锥相关病症;即,与视锥存活力损失和/或视锥功能下降相关的病症。如上文所论述,锥状光感受器负责颜色视觉和较高视敏度中央凹视觉且密集地填充在位于视网膜黄斑中心的1.5mm凹坑(称作中央凹)中。与此一致,黄斑典型地显示与视锥功能障碍和存活力相关的病症且影响颜色视觉和较高视敏度视觉。视锥相关病症的非限制性实例包括视杆-视锥营养不良;视锥-视杆营养不良;进行性视锥营养不良;色素性视网膜炎(RP);斯塔加特氏病;黄斑毛细血管扩张症、雷伯氏遗传性光学神经病、贝氏病;成人卵形黄斑营养不良;X-链视网膜劈裂症;颜色视觉障碍,如蓝色视锥全色弱、全色盲、不完全全色盲、红色盲缺陷、绿色盲缺陷和蓝色盲缺陷;以及影响中央黄斑的视网膜病症,如年龄相关性黄斑变性、湿性年龄相关性黄斑变性、地图状萎缩、黄斑毛细血管扩张症、色素性视网膜炎、糖尿病性视网膜病变、视网膜静脉闭塞、青光眼、索斯比氏眼底营养不良、成人卵形黄斑营养不良、贝氏病和X-链视网膜劈裂症。
斯塔加特氏黄斑营养不良。斯塔加特氏黄斑营养不良也称为斯塔加特氏病和眼底黄色斑点病,其为造成进行性视觉损失通常到法定失明的程度的幼年型黄斑变性的遗传性形式。症状发作通常在六岁与三十岁之间(平均约16-18岁)出现。若干基因(包括ABCA4、CNGB3、ELOVL4、PROM1)突变与所述病症相关。症状典型地在二十岁之前产生,且包括波浪状视觉、盲点、模糊、颜色视觉减弱和难以适应暗光。斯塔加特氏病的主要症状为视敏度损失,其在20/50到20/200范围内。另外,患有斯塔加特氏病的那些对眩光敏感;阴天可稍微缓解。当黄斑受损时,视觉最显著减弱,其可通过眼底测验观测到。
视锥营养不良。视锥营养不良(COD)为通过视锥细胞损失表征的遗传性眼部病症。视锥营养不良的最常见症状为视觉损失(发作年龄在少年晚期到六十多岁范围内)、对亮光敏感和不佳颜色视觉。视敏度通常逐渐降低,但其可快速降低到20/200;随后,在更严重的情况下,其下降到“屈指可数”的视觉。使用颜色测试板(HRR系列)的颜色视觉测试揭示两个红色-绿色和蓝色-黄色板的多个错误。据相信,营养不良为原发性的,因为视锥功能的主观和客观异常在检眼镜检查改变可见之前发现。然而,视网膜色素上皮(RPE)快速变得相关,导致主要涉及黄斑的视网膜营养不良。经由检眼镜的眼底测验在视锥营养不良早期基本上正常,且明确的黄斑改变通常在可见损失之后存在。检眼镜检查检验期间可见的最常见类型黄斑病灶具有公牛眼外观且由包围中央较深区域的萎缩性色素上皮的圆环状区域组成。在另一较不常见的视锥营养不良形式中,黄斑区域中的多斑色素结块的后极存在相当扩散的萎缩。罕见地,在早期阶段可见患者脉络膜毛细血管层和较大脉络膜血管萎缩。荧光素血管造影(FA)为疑似患有视锥营养不良的某人的检查中的适用的附加设备,如其可检测对于检眼镜来说过于微妙可见的视网膜的早期改变。因为眼底改变的广谱和在早期进行诊断的困难,视网膜电图(ERG)仍为进行所述诊断的最佳测试。通过当在光线充足的室内(亮光ERG)进行测试时减少的单闪和闪烁响应指定ERG的异常视锥功能。若干基因(包括GUCA1A、PDE6C、PDE6H和RPGR)突变与所述病症相关。
视锥-视杆营养不良。视锥-视杆营养不良(CRD或CORD)为属于色素性视网膜病群组的遗传性视网膜营养不良。CRD的特征在于眼底检验可见的视网膜色素沉积物,主要位于黄斑区域和两种视锥和视杆细胞损失。相比于由杆状光感受器的原发性损失和随后锥状光感受器的继发性损失产生的视杆-视锥营养不良(RCD),CRD反映事件的相对顺序:涉及原发性视锥,或有时通过同时损失视锥和视杆两者。症状包括中央视场中降低的视敏度、颜色视觉缺陷、厌光和降低的灵敏度,继而外周视觉和夜间失明的进行性损失。若干基因(包括ADAM9、PCDH21、CRX、GUCY2D、PITPNM3、PROM1、PRPH2、RAX2、RIMS1、RPGR和RPGRIP1)突变与所述病症相关。
脊髓小脑失调类型7。脊髓小脑失调为进行性、退行性、遗传性疾病,其特征为缓慢进行性步态失调且通常与手、话语和眼睛动作协调不佳相关。存在多种类型SCA,其中脊髓小脑失调类型7(SCA-7)与大部分其它SCA的不同之处在于除协调不佳外可能存在的视觉问题。SCA-7与ATXN7/SCA7基因中的常染色体主导突变相关。当疾病在40岁之前显露时,视觉问题而非协调不佳典型地为疾病的最早迹象。早期症状包括难以分辨颜色和中央视力降低。另外,可检测到共济失调(失调、眼睛动作减缓和感觉或反射轻微改变)症状。随着疾病发展,动作控制损失、话语不清和难以吞咽变得显著。
巴迪特-别铎综合症-1。巴迪特-别铎综合症-1(BBS-1)为具有可变表达度和家族内和之间观测到的广泛范围的临床可变性的多效性病症。主要临床特征为视杆-视锥营养不良,其中儿童发作视觉损失在夜间失明之前;轴后多指;躯体肥胖症,其在发展初期期间显示且在整个成虫期中仍成问题;一些但并非所有个体的特定学习困难;雄性生殖腺发育不全和复杂的雌性泌尿生殖畸形;以及肾脏功能障碍,其为罹病率和死亡率的主要病因。视觉损失为巴迪特-别铎综合症的主要特征中的一个。夜视问题在儿童中期前变得显而易见,继而在外周视觉中产生盲点。随时间推移,这些盲点增大且合并以产生隧道视觉。患有巴迪特-别铎综合症的大多数人还产生模糊的中央视觉(视敏度不佳)且在青春期或成人期早期之前变得法定失明。巴迪特-别铎综合症可由已知或疑似在纤毛功能中起关键作用的至少14种不同基因(通常称作BBS基因)突变产生,其中BBS1和BBS10突变为最常见的。
全色盲。全色盲或视杆单色视觉为其中个体体验完全失去颜色感知以使得个体仅看到黑色、白色和灰色阴影的病症。其它症状包括降低的视敏度、畏光、眼球震颤、较小中央暗点和偏注视。通过其畏光活动和/或其眼球震颤,首先在约六个月大的儿童中常常注意到所述病症。眼睛动作的视敏度和稳定性一般在生命前6-7年期间改良(但保持接近20/200)。CNGB3、CNGA3、GNAT2、PDE6C和PDE6HI突变与所述病症相关。
不完全全色盲。不完全全色盲类似于全色盲,但外显率更小。在不完全全色盲中,除呈降低的形式外,症状类似于完全全色盲的那些。患有不完全全色盲的个体视敏度降低,而具有或不具有眼球震颤或畏光。此外,这些个体仅显示视锥细胞功能的部分削弱,但再次保留视杆细胞功能。
蓝色视锥全色弱。蓝色视锥(S视锥)单色视觉(BCM)为罕见的X-链先天性固定视锥功能障碍综合症,影响大约1/100,000个体。患有BCM的受感染的雄性在视网膜中不具有功能性较长波长敏感性(L)或中等波长敏感性(M)视锥,这归因于L和M-视蛋白基因的基因座处的突变。从出生起严重影响颜色鉴别,且视觉来源于其余的受保护S视锥和杆状光感受器。BCM典型地呈现视敏度降低(6/24到6/60)、摆动式眼球震颤、畏光,且患者通常患有近视。视杆特异性和最大网膜电图(ERG)通常不显示明确的异常,而无法检测30Hz视锥ERG。单闪亮光ERG通常为可记录的,尽管较小且较迟,且S视锥ERG受到良好保护。
颜色视觉缺陷。颜色视觉缺陷(CVD)或色盲为失去在普通照明条件下查看颜色或感知色差的能力或降低。罹患色盲的个体可使用多种颜色视觉测试中的任一种鉴别,所述测试例如颜色ERG(cERG)、假同色板(石原板、哈迪-兰德-里特多色板)、方斯沃斯-蒙赛尔100色调测试、方斯沃斯面板D-15、城市大学测试、科尔讷规则等。颜色视觉缺陷的实例包括红色盲缺陷、绿色盲缺陷和蓝色盲缺陷。红色盲缺陷包括第一色盲(protanopia)(对红光不敏感)和红色觉变常(对红光的敏感度降低),且与L-视蛋白基因(OPN1LW)突变相关。绿色盲缺陷包括第二色盲(对绿光不敏感)和绿色觉变常(对绿光的敏感度降低),且与M-视蛋白基因(OPN1MW)突变相关。蓝色盲缺陷包括第三色盲(对蓝光不敏感)和蓝色觉变常(对蓝光的敏感度降低),且与S-视蛋白基因(OPN1SW)突变相关。
年龄相关性黄斑变性。年龄相关性黄斑变性(AMD)为超过50岁的人视觉损失的主导原因中的一个。AMD主要影响中央视觉,其为如阅读、驾驶和辨识面部的详细任务所需的。此病状的视觉损失由黄斑中的光感受器逐渐减少产生。侧面(外周)视觉和夜视一般不受影响。
研究人员已描述两种主要类型的年龄相关性黄斑变性,已知为干式或“非渗出性”形式和湿式或“渗出性”或“新生血管性”形式,这两个可通过递送本发明rAAV中包装的转基因来治疗。
干式AMD的特征在于在视网膜色素上皮与黄斑的底层脉络膜之间堆积黄色沉积物,称作脉络膜小疣,其可通过眼底摄影观测到。此导致视觉的缓慢进行性损失。病状典型地影响两个眼睛视觉,但在另一眼睛之前,视觉损失通常在一个眼睛中进行。其它改变可包括色素变化和RPE萎缩。举例来说,在称作中央地图状萎缩或“GA”的某些情况下,观测到视网膜色素上皮萎缩和眼睛中央部分中光感受器的后续损失。干式AMD已与CD59和互补序列级联中的基因突变相关。
湿式AMD为干式AMD的进展状态,且在接近10%干式AMD患者中发生。病理学改变包括视网膜色素上皮细胞(RPE)功能障碍、在RPE下采集的流体和黄斑区域中的脉络膜新生血管(CNV)。在严重情况下可能发生流体泄漏、RPE或神经视网膜从破裂血管脱离和出血。湿式AMD的症状可包括视觉畸变,如呈现波浪状或扭曲的直线、看起来不平衡的门道或街道标志或与其实物相比呈现较小或更远的物件;中央视觉降低;颜色强度或亮度降低;以及视野中的轮廊分明的模糊光点或盲点。发作可为急剧的且快速恶化。诊断可包括使用阿姆斯勒网格(Amsler grid)测试个体中央视觉(黄斑变性可引起网格中的直线呈现淡化、破损或变形)缺陷,使用荧光素血管造影片观测血管或视网膜异常,且使用光学相干性断层摄影术检测视网膜膨胀或泄漏血管。产生CNV时涉及多种细胞因子,其中有血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)、色素上皮衍生因子(PEDF)、低氧症诱导型因子(HIF)、血管生成素(Ang)和其它细胞因子、丝裂原活化蛋白质激酶(MAPK)等。
黄斑毛细血管扩张症。黄斑毛细血管扩张症(MacTel)为黄斑的近中央凹区域中的病理扩张血管(毛细血管扩张症)的形式。由于液体填充的胞囊发展,组织退化且视网膜结构有疤痕,其损害感光细胞的营养且永久地破坏视觉。存在两种类型MacTel:1型和2型。2型黄斑毛细血管扩张症为双侧疾病,在中,40岁和以上的个人中其患病率最近显示高达0.1%。活组织显微镜检查可显示降低的视网膜透明度、结晶沉积物、轻度膨胀毛细管、钝化微静脉、视网膜色素斑、中央窝萎缩和新生血管性复合物。荧光素血管造影显示早期中的小凹和晚期中的扩散高荧光对于毛细血管扩张毛细管来说主要为暂时的。高分辨率光学相干性断层摄影术(OCT)可揭示内部链段-外部链段边界的光感受器破坏、内部或外部视网膜水平面处的高反射性空腔和后期视网膜萎缩。在1型黄斑毛细血管扩张症中,疾病几乎始终在一个眼睛中发生,这将其与2型区分开来。尽管MacTel不通常引起完全失明,但其通常引起中央视觉损失,这在10-20岁的时段内对于阅读和驾驶视觉为所需的。
色素性视网膜炎。色素性视网膜炎(RP)为遗传性病症群组,其特征为可能导致中央视觉损失的进行性外周视觉损失和夜视困难(夜盲症)。RP的呈现迹象和症状变化,但传统迹象和症状包括夜盲症(夜间失明,最常为RP中的最早症状);视觉损失(通常为外周的,但在晚期情况下,中央视觉损失);以及闪光幻觉(看到闪光)。因为RP为多种遗传性疾病的集合,在物理发现中存在显著可变性。眼部检验涉及评定视敏度和瞳孔反应以及前段、视网膜和眼底评估。在一些情况下,RP为综合症的一个方面,例如还与听觉损失相关的综合症(尤塞氏综合症(Usher syndrome)、瓦尔登布尔氏综合症(Waardenburg syndrome)、雷夫苏姆氏病(Refsum disease));卡恩斯-塞尔综合症(Kearns-Sayre syndrome)(外部眼肌麻痹、上睑下垂、心肌梗死和色素性视网膜病);无β脂蛋白血症(脂肪吸收障碍、脂溶性维生素缺陷、脊髓小脑退化和色素性视网膜退化);粘多糖病(例如贺氏综合症(Hurlersyndrome)、谢氏综合症(Scheie syndrome)、沙费利波综合症(Sanfilippo syndrome));巴迪特-别铎综合症(多指、躯体肥胖症、肾脏功能障碍、身材矮小症和色素性视网膜病);以及神经元蜡样脂褐质沉积症(痴呆症、癫痫和色素性视网膜病;婴儿形式已知为詹-比二氏病(Jansky-Bielschowsky disease),幼年型形式为沃-施-巴病(Vogt-Spielmeyer-Battendisease),且成人形式为库夫斯综合症(Kufs syndrome)。色素性视网膜炎最常与RHO、RP2、RPGR、RPGRIP1、PDE6A、PDE6B、MERTK、PRPH2、CNGB1、USH2A、ABCA4、BBS基因突变相关。
糖尿病性视网膜病变。糖尿病性视网膜病变(DR)为由糖尿病并发症引起的视网膜损伤,其可最终导致失明。不希望受理论所束缚,据相信,高血糖症诱导的壁内周细胞死亡和基底膜增厚导致血管壁功能不全。这些损害改变血液-视网膜阻挡层形成且还使得视网膜血管变得更可渗透。
糖尿病性视网膜病变存在两个阶段:非增生性糖尿病性视网膜病变(NPDR)和增生性糖尿病性视网膜病变(PDR)。非增生性糖尿病性视网膜病变为糖尿病性视网膜病变的第一阶段且通过眼底测验和同时共存的糖尿病诊断。在视觉降低的情况下,可进行荧光素血管造影以观察眼睛后血管和可能存在的任何视网膜缺血。患有糖尿病的所有人处于罹患NPDR的风险下,且因此,将为本发明载体的预防性治疗的候选物。增生性糖尿病性视网膜病变为糖尿病性视网膜病变的第二阶段,其特征为视网膜的新血管生成、玻璃体出血和模糊视觉。在一些情况下,纤维血管增生造成牵引型视网膜脱离。在一些情况下,血管也可生长到眼睛前房角度且引起新生血管性青光眼。患有NPDR的个体处于罹患PDR的增加的风险下,且因此,将为本发明载体的预防性治疗的候选物。
糖尿病黄斑水肿。糖尿病黄斑水肿(DME)为糖尿病性视网膜病变的晚期视觉受限并发症,其影响几乎30%已患有至少20年糖尿病的患者且归因于DR主要负责视觉损失。其由视网膜微血管改变产生,损害血液-视网膜阻挡层,引起血浆成分泄漏到周围视网膜中且因此视网膜水肿中。不希望受理论所束缚,据相信,高血糖症、细胞信号传导路径的持续改变和具有白细胞介导的损伤的慢性微血管发炎导致慢性视网膜微血管损伤,其触发VEGF眼内水平提高,之后提高脉管渗透性。
处于罹患DME风险下的患者包括已长时间患有糖尿病和经历重度高血压(高血压)、液体潴留、低白蛋白血症或高脂质血症中的一种或多种的那些。如果病状允许未经治疗而进展,那么DME的共同症状为模糊视觉、飞蚊症、双重视觉和最终失明。DME通过眼底检验诊断为在黄斑中心的2个圆盘直径内视网膜增厚。可采用的其它方法包括光学相干性断层摄影术(OCT)以检测视网膜膨胀、囊样水肿和浆液性视网膜脱离;荧光素血管造影,其区别且定位相对于扩散泄漏的病灶区域,从而如果激光凝固用于治疗水肿,那么导引激光凝固安置;以及颜色立体眼底相片,其可用于评估视网膜中的长期改变。也可测量视敏度,尤其遵循黄斑水肿进程且在投与本发明医药组合物后观测其治疗。
视网膜静脉闭塞。视网膜静脉闭塞(RVO)为排出血液视网膜的循环部分堵塞。堵塞可在毛细管中备份压力,其可导致出血以及流体和血液其它成分泄漏。
青光眼。青光眼为描述导致光学神经损伤,通常与眼睛中增加的流体压力(眼内压)(IOP)相关的眼部(眼睛)病症群组的术语。病症可大致分成两个主要类别:“开角型”和“闭角型”(或角闭型)青光眼。在美国,开角型青光眼占90%的青光眼情况。其无痛且不具有急性发作。仅有迹象为逐渐进行性视场损失和光学神经改变(在眼底检验上增加的杯与盘比率)。在美国,闭角型青光眼占少于10%的青光眼情况,但在其它国家(尤其亚洲国家)占多达一半的青光眼情况。约10%闭角型患者存在急性闭角型危机,其特征为突然眼痛、光晕、红眼、极高眼内压(>30mmHg)、恶心和呕吐、突然降低的视觉和固定的中度扩张瞳孔。在一些情况下,其还与椭圆形瞳孔相关。调节由DLK、NMDA、INOS、CASP-3、Bcl-2或Bcl-xl编码的蛋白质的活性可治疗所述病状。
索斯比氏眼底营养不良。索斯比氏眼底营养不良为与TIMP3基因突变相关的常染色体主导的视网膜疾病。临床上,发现早期中度外周脉络膜小疣和颜色视觉缺陷。一些患者抱怨夜间失明。最常,呈现症状为突然视敏度损失,显示生命第三个十年到第四个十年,这归因于不可治疗的黄斑下新血管形成。组织学上,在布鲁赫氏膜(Bruch's membrane)水平面处积聚含有30μm厚材料的融合脂质。
卵形黄斑营养不良。卵形黄斑营养不良为可能产生进行性视觉损失的基因眼睛病症。卵形黄斑营养不良与位于黄斑之下的细胞中的脂肪黄色色素(脂褐质)堆积相关。随时间推移,此物质的异常积聚可能损伤对于清楚的中央视觉来说关键的细胞。因此,患有此病症的人通常失去其中央视觉,且其视力可能变得模糊或变形。卵形黄斑营养不良典型地不影响侧面(外周)视觉或在夜间查看的能力。
研究人员已描述具有类似特征的卵形黄斑营养不良的两种形式。早发型形式(已知为贝氏病)通常在儿童中出现;症状发作和视觉损失严重程度大幅变化。其与VMD2/BEST1基因突变相关。成人发作形式(成人卵形黄斑营养不良)随后开始,通常在中年期中,且往往会产生随时间推移缓慢恶化的视觉损失。其与PRPH2基因突变相关。卵形黄斑营养不良的两种形式各自具有可在眼睛检验期间检测到的黄斑特征改变。
视杆-视锥营养不良。视杆-视锥营养不良为视杆功能障碍的进行性疾病家族,其导致夜间失明和外周视场宽阔区域损失,其为普遍问题或至少与视锥功能障碍一般严重时存在。扇贝定界的陷窝萎缩可见于视网膜的赤道部中。黄斑仅通过临床检验适度地涉及,但中央视网膜薄化见于所有情况中。色觉障碍早期为温和的且通常变得更严重。视场适当地严重收缩,但在较年轻的个体中存在典型的环形暗点。外周视网膜含有‘白点’且通常类似于视网膜炎点状闪辉症中可见的视网膜改变。色素性视网膜炎为包括在此定义下的疾病的大组,且整体上进行评估以影响大约1/3,500人。取决于所使用的分类标准,约60-80%所有色素性视网膜炎患者具有视网膜疾病的轮廓鲜明的视杆-视锥营养不良图案,且当考虑其它综合症形式时,约50-60%所有视网膜炎眼点属于视杆-视锥营养不良非综合症类别中。
雷伯氏先天性黑蒙。雷伯氏先天性黑蒙(LCA)为典型地在生命的第一年中变得明显的视网膜的严重营养不良。视觉功能通常不佳且通常伴有眼球震颤、迟缓或几乎不存在瞳孔反应、畏光、高度远视和圆锥形角膜。视敏度罕见地优于20/400。特征研究结果为弗兰切斯基眼部数字标志,包含戳眼、按压眼睛和摩擦眼睛。眼底外观为极其可变的。尽管视网膜可首先呈现正常,常常在儿童后期观测到暗示色素性视网膜炎的色素性视网膜病。网膜电图(ERG)在特征上“无法检测到”或严重低于正常的。已知17种产生LCA的基因突变:GUCY2D(基因座名称:LCA1)、RPE65(LCA2)、SPATA7(LCA3)、AIPL1(LCA4)、LCA5(LCA5)、RPGRIP1(LCA6)、CRX(LCA7)、CRB1(LCA8)、NMNAT1(LCA9)、CEP290(LCA10)、IMPDH1(LCA11)、RD3(LCA12)、RDH12(LCA13)、LRAT(LCA14)、TULP1(LCA15)、KCNJ13(LCA16)和IQCB1。一起,评估这些基因突变以解释超过一半的所有LCA诊断。已报导LCA的至少一种其它疾病基因座,但基因不为已知的。
X-链视网膜劈裂症。X-链视网膜劈裂症(XLRS)的特征在于涉及生命第一个十年,在一些情况下早在三个月时发作的对称双侧黄斑。眼底检验显示黄斑中的劈裂(视网膜的神经纤维层裂开)区域,有时给出辐轮图案的效果。大约50%个体中发生外周视网膜,主要颞下劈裂。感染的雄性典型地具有20/60到20/120的视觉。视敏度通常在生命第一个和第二个十年期间退化,但随后保持相对稳定直到第五个或第六个十年为止。X-链幼年型视网膜劈裂症的诊断是基于眼底发现、电生理学测试和分子基因测试结果。RS1为已知与X-链幼年型视网膜劈裂症相关的唯一基因。
受视锥细胞病症影响或处于罹患视锥细胞病症的风险下的个体可容易地使用用以检测如所属领域中已知的病症的症状的技术鉴别,包括(但不限于):眼底摄影;光学相干性断层摄影术(OCT);适应性光学装置(AO);网膜电图,例如ERG、颜色ERG(cERG);颜色视觉测试,如假同色板(石原板、哈迪-兰德-里特多色板)、方斯沃斯-蒙赛尔100色调测试、方斯沃斯面板D-15、城市大学测试、科尔讷规则等;以及视敏度测试,如ETDRS字母测试、斯内伦视敏度测试、视场测试、对比敏感性测试等;如所属领域的一般技术人员将已知的。另外或替代地,受视锥细胞病症影响或处于罹患视锥细胞病症的风险下的个体可容易地使用用以检测与如所属领域中已知的视锥细胞病症相关的基因突变的技术鉴别,包括(但不限于):PCR、DNA序列分析、限制消化、DNA印迹杂交、质谱分析等。在一些实施例中,所述方法包含鉴别需要视锥细胞疗法的个体的步骤。在此类情况下,可利用用于测定个体是否具有视锥细胞病症的症状或处于罹患视锥细胞病症的风险下的任何适宜方法,例如通过检测本文所描述或所属领域中已知的症状,通过检测如本文中或如所属领域中已知的基因突变以鉴别需要视锥细胞疗法的个体。
在实践本发明方法时,本发明组合物典型地以能有效地使转基因在视锥细胞中表达的量递送到个体视网膜。在一些实施例中,所述方法包含检测转基因在视锥细胞中的表达的步骤。
存在多种检测转基因表达的方法,其中的任一种都可用于本发明实施例中。举例来说,可直接,即通过测量基因产物的量,例如在RNA水平上(例如通过RT-PCR、北方墨点、RNA酶保护);在蛋白质水平上,例如通过西方墨点、ELISA、免疫组织化学等来检测表达。作为另一实例,可间接,即通过检测基因产物对个体中的锥状光感受器的存活力或功能的影响来检测表达。举例来说,如果由转基因编码的基因产物提高视锥细胞的存活力,那么可通过检测视锥细胞的存活力改良,例如通过眼底摄影、光学相干性断层摄影术(OCT)、适应性光学装置(AO)等来检测转基因表达。如果由转基因编码的基因产物改变视锥细胞活性,那么可通过检测视锥细胞活性改变来检测转基因表达,例如通过网膜电图(ERG)和颜色ERG(cERG);功能适应性光学装置;颜色视觉测试,如假同色板(石原板、哈迪-兰德-里特多色板)、方斯沃斯-蒙赛尔100色调测试、方斯沃斯面板D-15、城市大学测试、科尔讷规则等;以及视敏度测试,如ETDRS字母测试、斯内伦视敏度测试、视场测试、对比敏感性测试等作为检测递送的多核苷酸的存在的方式。在一些情况下,可检测视锥细胞功能中的存活力提高和改变。
在一些实施例中,本发明方法产生治疗效益,例如预防病症发展,中断病症进展,逆转病症进展等。在一些实施例中,本发明方法包含检测已获得的治疗效益的步骤。所属领域的一般技术人员将了解,此类疗效量度将适用于改变的特定疾病,且将认识到适当的检测方法以用于测量疗效。举例来说,治疗黄斑变性的疗效可观测为黄斑变性速率降低或停止黄斑变性进展,其作用可通过例如眼底摄影、OCT或AO,通过比较本发明组合物投与之后的测试结果与本发明组合物投与之前的测试结果而观测到。作为另一实例,治疗进行性视锥功能障碍的疗效可观测到为视锥功能障碍进展速率降低,视锥功能障碍进展停止,或视锥功能改良,其作用可通过例如ERG和/或cERG;颜色视觉测试;功能适应性光学装置;和/或视敏度测试,例如通过比较本发明组合物投与之后的测试结果与本发明组合物投与之前的测试结果和检测视锥存活力和/或功能改变而观测到。作为第三实例,治疗颜色视觉缺陷的疗效可观测到为个体颜色感知,例如红色波长感知、绿色波长感知、蓝色波长感知的变化,其作用可通过例如cERG和颜色视觉测试,例如通过比较本发明组合物投与之后的测试结果与本发明组合物投与之前的测试结果和检测视锥存活力和/或功能改变而观测到。
预期本发明rAAV递送的转基因表达为稳固的。相应地,在一些情况下,可在投与后两个月或更短,例如投与后4、3或2周或更短,例如本发明组合物投与后1周,观测到转基因表达,例如如通过测量基因产物水平,通过测量疗效等所检测。还预期转基因表达随时间推移而持续。相应地,在一些情况下,可在本发明组合物投与后2个月或更短,例如4、6、8或10个月或更久,在一些情况下1年或更久,例如2、3、4或5年,在某些情况下超过5年,观测到转基因表达,例如如通过测量基因产物水平,通过测量疗效等所检测。
在某些实施例中,所述方法包含检测视锥细胞中的本发明rAAV递送的多核苷酸的表达,其中表达相对于在GH环中不包含7-10个氨基酸插入的AAV(即参考对照物,例如已插入肽的亲本rAAV)表达有所增强。典型地,相对于参考物,例如亲本rAAV的表达,表达将增强2倍或更多,例如3倍、4倍或5倍或更多,在一些情况下,10倍、20倍或50倍或更多,例如100倍,如通过例如更早的检测、更高水平的基因产物、对细胞的更强功能影响等所证明。
典型地,实现改变的有效量将为约1×108个载体基因组或更多,在一些情况下1×109、1×1010、1×1011、1×1012或1×1013个载体基因组或更多,在某些情况下,1×1014个载体基因组或更多且通常不超过1×1015个载体基因组。在一些情况下,递送的载体基因组的量为至多约1×1015个载体基因组,例如1×1014个载体基因组或更少,例如1×1013、1×1012、1×1011、1×1010或1×109个载体基因组或更少,在某些情况下1×108个载体基因组且典型地不低于1×108个载体基因组。在一些情况下,递送的载体基因组的量为1×1010到1×1011个载体基因组。在一些情况下,递送的载体基因组的量为1×1010到3×1012个载体基因组。在一些情况下,递送的载体基因组的量为1×109到3×1013个载体基因组。在一些情况下,递送的载体基因组的量为1×108到3×1014个载体基因组。
在一些情况下,待投与的医药组合物的量可使用感染倍率(MOI)测量。在一些情况下,MOI可指载体或病毒基因组与核可递送到的细胞的比率或整倍数。在一些情况下,MOI可为1×106。在一些情况下,MOI可为1×105-1×107。在一些情况下,MOI可为1×104-1×108。在一些情况下,本发明的重组病毒为至少约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。在一些情况下,本发明的重组病毒为1×108到3×1014MOI。在一些情况下,本发明的重组病毒为至多约1×101、1×102、1×103、1×104、1×105、1×106、1×107、1×108、1×109、1×1010、1×1011、1×1012、1×1013、1×1014、1×1015、1×1016、1×1017和1×1018MOI。
在一些方面中,医药组合物的量包含约1×108到约1×1015个重组病毒粒子,约1×109到约1×1014个重组病毒粒子,约1×1010到约1×1013个重组病毒粒子,约1×1011到约3×1012个重组病毒粒子。
个别剂量典型地不低于对个体产生可测量的作用所需的量,且可基于本发明组合物或其副产物的吸收、分布、代谢和分泌(“ADME”)的药物动力学和药理学和因此基于在本发明内安置组合物来测定。此包括投与途径以及剂量的考量,其可针对视网膜下(直接施用到针对局部反应主要所需的活动所在处)、玻璃体内(针对全视网膜反应,施用到玻璃体)或非经肠(通过全身性途径,例如静脉内、肌肉内等施用)施用进行调节。有效剂量和/或剂量方案可容易地凭经验根据临床前分析、安全性和升级以及剂量范围试验、个体临床医生-患者关系以及活体外和活体内分析,如本文所描述和以下实验部分中所说明的那些来判定。
本说明书中所提到和/或本申请数据表中所列出的所有以上美国专利、美国专利申请公开案、美国专利申请、外国专利、外国专利申请以及非专利出版物以其全文引用的方式并入本文中。
从上文中将了解,虽然本文中已经出于说明的目的描述了本发明的特定实施例,但可在不偏离本发明的精神和范围的情况下进行各种修改。因此,除受到所附权利要求书的限制外,本发明不受限制。
实例
提出以下实例以便向所属领域的一般技术人员完整地披露且描述如何制备和使用本发明,且并不打算限制本发明人视为其发明的范围,也不打算表示下文实验是所进行的全部或唯一实验。已努力确保关于所使用的数量(例如量、温度等)的准确性,但应当说明存在一些实验性误差和偏差。除非另外指示,否则份数是重量份,分子量是重量平均分子量,温度是以摄氏度计,且压力是大气压或接近大气压。
分子和细胞生物化学中的一般方法可见于如以下标准教科书:《分子克隆实验指南(Molecular Cloning:A Laboratory Manual)》,第3版(Sambrook等人,HaRBor实验室出版社(HaRBor Laboratory Press)2001);《精编分子生物学实验指南(Short Protocols inMolecular Biology)》,第4版(Ausubel等人编,约翰·威利父子公司(John Wiley&Sons)1999);《蛋白质方法(Protein Methods)》(Bollag等人,约翰·威利父子公司1996);《基因疗法的非病毒载体(Nonviral Vectors for Gene Therapy)》(Wagner等人编,学术出版社(Academic Press)1999);《病毒载体(Viral Vectors)》(Kaplift和Loewy编,学术出版社1995);《免疫学方法手册(Immunology Methods Manual)》(I.Lefkovits编,学术出版社1997);以及《细胞和组织培养物:生物技术中的实验室程序(Cell and Tissue Culture:Laboratory Procedures in Biotechnology)》(Doyle和Griffiths,约翰·威利父子公司1998),其公开内容以引用的方式并入本文中。本发明中提及的用于基因操作的试剂、克隆载体和套组可购自市售供应商,如伯乐(BioRad)、斯塔津(Stratagene)、英杰(Invitrogen)、西格玛-阿尔德里奇(Sigma-Aldrich)和克隆科技(ClonTech)。
实例1
背景
治疗多种锥状光感受器相关病症需要新型疗法,所述病症包括黄斑营养不良,如视锥-视杆营养不良、视锥营养不良、斯塔加特氏黄斑营养不良和全色盲;颜色视觉障碍,如红色盲、绿色盲和蓝色盲缺陷;以及中央黄斑视觉障碍,如年龄相关性黄斑变性、黄斑毛细血管扩张症、色素性视网膜炎、糖尿病性视网膜病变、视网膜静脉闭塞、青光眼、索斯比氏眼底营养不良、成人卵形黄斑营养不良、贝氏病和X-链视网膜劈裂症。因为这些视觉障碍与锥状光感受器的功能和/或存活力损失相关,所以假设可通过将治疗性基因递送到锥状光感受器以恢复视锥存活力和功能,从而可治疗这些病症。
为此设计了多核苷酸卡匣“pMNTC”,其中增强子、启动子、5'UTR、内含子、Kozak和聚腺苷酸化序列经设计以用于视锥特异性表达(图6A)。所述卡匣包括来自L-视蛋白和M-视蛋白基因组基因座的LCR增强子序列和来自M-视蛋白基因的截断启动子序列,包含转录起点位点上游约140个核苷酸。另外,所述卡匣包括基于M-视蛋白5'UTR,但经修饰以具有极少二级结构且在插入内含子且其3'端处包括额外序列的5'非翻译区(5'UTR)。所使用的内含子序列为pSI嵌合内含子,其具有来自人类β-血球蛋白基因的第一内含子的5-供体位点和分支以及来自处于免疫球蛋白基因重链可变区的前导子与主体之间的内含子的3-受体位点(Bothwell,A.L.等人(1981)重链可变区对抗体NPb家族的贡献:γ2a可变区明显的体细胞突变(Heavy chain variable region contribution to the NPb family ofantibodies:Somatic mutation evident in a gamma 2a variable region).《细胞(Cell)》24,625-37)。改变供体和受体位点以及分支点位点的序列以匹配共同序列用于剪接(Senapathy,P.,Shapiro,M.B.和Harris,N.L.(1990)《酶学方法(Meth.Enzymol.)》183,252-78)。pMNTC多核苷酸卡匣中还包括强Kozak序列和SV40聚腺苷酸化序列。
还进行实验以鉴别将转基因递送到视锥细胞的最佳AAV。出于基因疗法的目的,已使用病毒载体,如AAV和慢病毒成功实现将多核苷酸递送到视网膜细胞。然而,这些病毒必须视网膜下注射以到达非人类灵长类动物(NHP)视网膜细胞,这一过程伴随有视网膜损伤风险。破坏性更小的途径为通过玻璃体内注射进行投与。然而,在玻璃体内递送AAV或慢病毒后锥状光感受器的有效转导从未得到证明:尽管存在AAV具有以高效率转导视网膜视锥细胞的能力的报道(Merigan等人IOVS 2008,49E-摘要4514),但随后的报道对这些载体功效提出质疑(Yin等人IOVS 2011,52(5):2775-2783)。
结果
AAV2的定向进化已使得可鉴别出能够转导光感受器的病毒变体“7m8”优于野生型AAV2(Dalkara等人《科学·转化医学(Sci Transl Med)》2013)。然而,视网膜含有两种类型光感受器(视杆和视锥)且无报道证明AAV2-7m8是否可本身转导锥状光感受器和更尤其中央窝的高度视锥富集区域中的锥状光感受器。为了测试此可能性,我们通过玻璃体内注射将携带可操作地连接到GFP的普遍存在的启动子CMV的表达卡匣的AAV2-7m8递送到非洲绿猴的视网膜内。与玻璃体内递送的AAV2或所属领域中先前已显示转导视网膜细胞的其它AAV变体相比,玻璃体内递送的AAV2-7m8.CMV.GFP似乎以更高效率在灵长类动物的中央凹(中央凹部中心处视网膜的0.35mm直径无视杆区域)和近窝区(凹坑边缘)中转导视网膜细胞。所测试的AAV2-7m8和所测试的其它AAV似乎都不能够转导灵长类动物中央窝、包围小凹且形成凹部斜率的视网膜的直径1.5mm视锥富集区域的视锥(图1)。
我们随后包装在AAV2-7m8衣壳内包含可操作地连接到GFP的pMNTC的基因组,且评估此载体组合物在玻璃体内注射时在视锥细胞中活体内表达GFP转基因的能力。在总光感受器中的不同数量视网膜视锥细胞的多种物种中,包括小鼠(3%视锥)、大鼠(1%视锥)、沙鼠(13%视锥)和非人类灵长类动物(5%视锥)评估表达。与图1中的结果相反,可在整个非人类灵长类动物中央窝中检测到较强基因表达(图2)。这些数据指示,玻璃体内递送的AAV2-7m8可实际上转导视网膜视锥,且pMNTC在视锥细胞中充当稳固表达卡匣。稳固报导基因表达还见于大鼠(数据未示出)和沙鼠(图4A)的玻璃体内注射的视网膜中,其中表达水平和解剖学位置与视锥丰度和所有物种中的位置相关。
为了测定pMNTC引导表达的细胞特异性,通过使用对视锥L和M视蛋白具有特异性的抗体的免疫组织化学分析经转导的小鼠视网膜的整个支架。在由AAV2-7m8.MNTC.GFP载体(图3)表达GFP的小鼠视网膜的几乎所有视锥中仅观测到L/M视蛋白表达(其标记锥状光感受器外段),指示转基因的MNTC引导表达为高度视锥特异性的。此外,通过L/M视蛋白特异性抗体标记的80%或更多视锥外段也表达GFP转基因,指示AAV2-7m8以较高效率转导视锥(图3)。
我们还通过包装在AAV2-7m8衣壳(AAV2-7m8pR2.1.GFP载体)内包含可操作地连接到GFP的pR2.1的基因组来测定pR2.1引导表达的细胞特异性。pR2.1包含来自人类L-视蛋白基因的人类L/M视蛋白增强子(“LCR”)和启动子区。另外,pR2.1在已插入经修饰的SV40后16s内含子序列的其3'端处包含融合到额外5'UTR序列的L-视蛋白5'UTR。此后接L-视蛋白Kozak序列,其随后典型地框内连接到转基因。在卡匣的末端处为SV40聚腺苷酸尾部。在非洲绿猴(非人类灵长类动物;NHP)中玻璃体内注射之后12周评估此载体组合物在视锥细胞中活体内表达GFP转基因的能力。简单来说,NHP接受50μL 1.0×1013vg/mL AAV2-7m8pR2.1.GFP的双侧玻璃体内投与以每个眼睛产生5×1011vg的最终剂量。通过使用具有佳能6D数字成像硬件和光学OCT Plus的拓普康(Topcon)TRC-50EX视网膜摄影机,在基线和玻璃体内载体注射后4、8和12周进行视网膜检验,包括眼底颜色和荧光摄影。在12周将动物处死且处理眼睛。用鸡多克隆抗GFP抗体(艾博抗目录号13970;英国剑桥);对视蛋白视锥具有特异性的兔多克隆抗L/M视蛋白抗体(艾博抗目录号5405);1D4小鼠单克隆抗视紫质抗体(艾博抗目录号5417);以及用以使所有细胞核染色的Dapi(英杰参考号D21490)对来自NHP的经处理的视网膜的横切片进行染色。通过多光谱分析以及抗体探针和DIC(针对拓扑结构的差分干涉感染)使含有GFP标记的转基因的细胞成像。因为光学平面的扁平化堆叠穿过整个切片。使用形态和探针共定位优化转基因的细胞分析。染色GFP(转基因)与染色L/M视蛋白且不与染色视紫质共定位,指示pR2.1特异性地促进视锥细胞中的表达(图7)。在中央窝、中间和极远边缘处观测到GFP转基因信号;GFP转基因信号与L/M视蛋白、钙结合蛋白以及PNA探针共定位;观测到中央窝中明显不包括含有1D4的细胞;以及无GFP转基因阳性细胞与含有视杆或其它探针的细胞缔合。(图7)。总之,观测到GFP(转基因表达)和L/M视蛋白的双重染色细胞,但无GFP和视紫质两者双重染色的细胞,指示AAV2-7m8pR2.1.GFP载体特异性地在视锥细胞而非视杆细胞中引导表达。
我们随后将pMNTC与pR2.1促进视锥细胞中表达的能力进行比较。AAV2-7m8.MNTC.GFP和AAV2-7m8.pR2.1.GFP的病毒制剂玻璃体内活体内递送到沙鼠和非人类灵长类动物视网膜,且眼底自体荧光和OCT后2周、4周、8周和12周视网膜活体内成像。与携带pR2.1.GFP表达卡匣的沙鼠视网膜中相比,更早,更强且在用携带pMNTC.GFP表达卡匣的rAAV转导的沙鼠视网膜中的更多视锥中检测到GFP报导子表达(图4B)。同样地,相比于用pR2.1表达卡匣转导的NHP视网膜,更早且在用携带pMNTC.GFP表达卡匣的rAAV转导的非人类灵长类动物视网膜中的更多视锥中检测到GFP报导子表达(图5,n=4个眼睛)。在沙鼠和NHP两者中,在整个研究持续时间内,与pR2.1相比,由pMNTC不断地观测到更强的GFP。
为了测定pMNTC表达卡匣中的元件中的每一个对表达总体改良的贡献,克隆一系列表达构建物,其中pMNTC中的元件中的每一个逐个经来自pR2.1表达卡匣的对应元件取代。这些构建物随后包装到AAV2-7m8中且通过玻璃体内注射递送到沙鼠视网膜。通过活体内生物发光(IVIS成像系统,珀金埃尔默(PerkinElmer))(其提供横跨整个眼睛的报导子表达的定量读数)活体内4和8周后评估沙鼠视网膜。
正如预期,在pMNTC的控制下的荧光素酶报导子表达高于在pR2.1的控制下的荧光素酶报导子表达(图6A-D)。用与其具有最高序列同源性的pR2.1启动子序列置换pMNTC启动子序列降低表达(构建物pMNTC_pR2.1 L3'P),包括处于pR2.1的5'UTR更远端处的pR2.1启动子序列同样如此(构建物pMNTC_pR2.1-L5'P)。表达还通过引入到pR2.1 5'UTR中观测到的两个假起点序列(“AUG1”和“AUG2”)的pMNTC 5'UTR中而降低(构建物pMNTC_2.1-AUG1/2)。有趣地,当用其中已去除这些假起点的经修饰的pR2.1 5'UTR序列(核苷酸17变为C,nt61和62变为CA)置换pMNTC 5'UTR(pMNTC_pR2.1-5'UTR)时,表达未降低,表明pR2.1 5'UTR将促进视锥细胞中的较强表达,除了pR2.1 5'UTR元件中的假AUG。同样有趣地,与pMNTC的pSI嵌合内含子相比,pR2.1内含子似乎提供更稳固表达,表明在本发明的多核苷酸卡匣中包括pR2.1内含子可用于进一步改良视锥细胞中的表达。最后,去除L/M增强子(pR2.1和pMNTC中均可见)同样降低表达。尽管聚腺苷酸加尾似乎起初还对表达具有显著影响,但包含此pR2.1元件的pMNTC构建物的再测序显露,聚腺苷酸尾部不可操作地连接到转基因,从而解释了为何由此构建物仅观测到背景水平的表达。因此,L/M视蛋白LCR、包括M视蛋白核心启动子而非L视蛋白启动子以及排除5'UTR中的假起点都能促进使用pMNTC启动子获得的基因表达增强。
总之,我们已鉴别出一种AAV变体,所述AAV变体在GH环中包含7m8肽,其可用于将多核苷酸玻璃体内递送到视网膜视锥。同样地,我们已鉴别出多种可用于促进锥状光感受器中的较强表达的多核苷酸卡匣元件。这些发现共同表示可能有助于研发视锥相关病症的治疗剂的进步。
材料和方法
WERI-RB-1细胞中的活体外转基因表达。表达锥状光感受器色素细胞的WERI-Rb-1视网膜胚细胞瘤细胞经本发明根据Shaaban和Deeb,1998;IOVS 39(6)885-896描述的方法的多核苷酸卡匣转染。使用沿用已久的分子生物学技术,如克隆(Maniatis等人)或经由重生DNA合成,将多核苷酸卡匣转染为质粒DNA。所有调节元件都放置于卡匣中且用于驱动增强的GFP蛋白质。随后使用非病毒转染的现有技术,例如使用基于脂质的转染试剂(Altogen生物系统,NV)或脂染胺LTX(生命技术公司),将质粒DNA引入到细胞中。随后将细胞培养72小时且使用流式细胞测量术和荧光显微术测量eGFP表达。将经本发明的多核苷酸卡匣(即,经设计用于锥状光感受器表达的构建物)转染的细胞中的转基因表达与未经优化对应物(即,基于pR2.1的那些)进行比较,且发现携带改进的元件的卡匣更强。
还使用表达视锥视蛋白的其它哺乳动物细胞系(如661W细胞(Tan等人,IOVS2004;45(3)764-768))评估活体外表达。
类似地,使用已经工程改造以表达锥状光感受器特异性蛋白质的非光感受器细胞系评估活体外表达。此类系统已描述具有已经基因工程改造以表达CRX/Sp1的HEK293细胞(Khani等人,IOVS 2007;48:3954)。还使用标记基因(eGFP、dsRed、mCherry、荧光素酶)以及生理学基因(视蛋白、ACHR基因)。通过检验mRNA水平(例如通过RT-PCR)或蛋白质水平(例如通过ELISA或西方墨点)测试生理学基因。
动物护理。所有实验符合关于美国生理学会(American Physiological Society)和神经科学学会(Society for Neuroscience)采用且机构动物护理及使用委员会(Institutional Animal Care and Use Committee,IACUC)批准的动物的护理和使用的原理。
小动物研究。在小鼠、大鼠和沙鼠中活体内评估由表达盒的编码序列编码的基因产物表达。此通过活体内玻璃体内注射包含表达卡匣的rAAV制剂实现(Li等人,2008;《分子视觉(Mol Vis)》48:332-338)。应注意,可实际上进行质粒DNA的电穿孔(Matsuda/Cepko)。
小鼠研究。这一研究中所使用的小鼠为C57BL/6。用氯胺酮/甲苯噻嗪(110mg/kg腹膜内)麻醉动物。将装载有测试制品的倾斜34号一次性针头插入眼睛玻璃体中,且以1.5μl体积将5.04×1010个rAAV载体基因组注射到玻璃体中。
沙鼠和大鼠研究。在这一研究中,使用蒙古沙鼠(长爪沙鼠(Merionesunguiculatus)和棕色挪威大鼠。用10%苯肾上腺素和0.5%托品酰胺使瞳孔扩张。用腹膜内或肌肉内注射0.1-0.2mL氯胺酮/甲苯噻嗪溶液(对于大鼠,70mg/mL氯胺酮和10mg/mL甲苯噻嗪;对于沙鼠,25mg/mL氯胺酮和0.3mg/mL甲苯噻嗪)麻醉动物。在距离角膜缘约1mm的经优化上颞位置处,通过巩膜,将装载有100μL汉密尔顿(Hamilton)注射器中的测试制品的倾斜34号一次性针头插入眼睛玻璃体中。用微注射泵将5μL体积的测试制品(2×1010vgrAAV.GFP或1.15×1010vg rAAV.荧光素酶)的1×1010-2×1010个载体基因组缓慢注射到玻璃体中,其后针尖保持在所注射的眼睛中所注射的位置处10秒以便确保足够的测试制品分配。随后抽出针头。
非人类灵长类动物(NHP)研究。还在较大动物中测试多核苷酸卡匣和表达载体。此通过使用AAV,例如使用Mancuso等人的技术进行。简单来说,制得AAV卡匣,制造使表达卡匣包壳化的AAV,且在非人类灵长类动物中玻璃体内(在玻璃体中至多170μL)或视网膜下(在不同位置处至多3,100μL注射剂;可在注射之前进行玻璃体切除术)注射病毒制剂。通过报导子(GFP)、颜色ERG和/或行为测试,使用剑桥颜色测试或对经训练以在目标进入视野时进行眼急动(眼睛移动)的动物来评估表达。使用眼睛追踪器监测眼急动。在处理之前,动物经训练以进行颜色视觉测试或当其看到着色目标时进行眼急动。进行ERG以评估存在的视锥的光谱灵敏度。颜色视觉测试性能和ERG的数据提供动物为双色(色盲)的证据。对于接受携带GFP基因的载体的动物,使用眼底成像,用RetCam II或类似装置,在产生GFP激发的光下监测表达。对于接受相比于动物的内源性色素光谱灵敏度不同的光色素基因的动物,使用多焦颜色ERG监测表达以在至多106个不同视网膜位置处且通过行为测试测量光谱灵敏度。
在七氟醚后用10-15mg/kg氯胺酮使狒狒镇静。用肌肉内注射5:1氯胺酮:甲苯噻嗪混合物(0.2ml/kg 100mg/ml氯胺酮和20mg/ml甲苯噻嗪)使非洲绿猴镇静。用局部10%苯肾上腺素实现瞳孔放大。将开睑器放置于眼睛中以便于注射。施加一滴0.5%丙美卡因盐酸盐和随后5%必妥碘溶液,继而用无菌生理盐水进行冲洗。狒狒(图2)通过玻璃体内(ITV)注射接受60μl 3.4×1013vg rAAV制剂以产生每个眼睛2.02×1012vg的最终剂量。非洲绿猴通过ITV注射接受50μL 1×1013rAAV载体制剂以产生每个眼睛5×1011vg的最终剂量。使用在角膜缘后~2.5mm锯齿缘水平处颞下插入的31号0.375英寸针头(泰尔茂(Terumo)),在允许完全目测眼外和眼内针头安置的手术放大率下,投与中央玻璃体的ITV注射剂。中央玻璃体安置通过在注射时直接观测针尖确证。在ITV注射后,投与局部三重抗生素软膏。
裂隙灯活组织纤维检查。在基线筛选期间和注射后4周(第28天)、8周(56天)和12周(84天),通过裂隙灯活组织纤维检查检测各猴眼睛的前段以监测发炎。未观测到异常。
NHP尸检和眼睛处理。在玻璃体内注射后12周用戊巴比妥使动物安乐死。在眼外组织去核和修整之前,在12点钟位置处用缝合线标记眼睛。通过将组织前部移到角膜缘且通过浸没在4%多聚甲醛中固定且储存于70%乙醇中来分离后部杯。
免疫标记。在平整和剥离视网膜作为整个支架之前,使眼睛到水,随后PBS缓冲液中复水。通过GFP的立体荧光显微术(Discovery Fl V20,卡尔蔡司显微术有限责任公司(Carl Zeiss Microscopy,LLC),纽约州索恩伍德(Thornwood,NY))来使制剂成像。四分之一圆周中央窝从平坦支架剥离,安装在盖玻片下且成像为完全剪辑画面(5×平铺和缝合部,Axio Observer Z1,蔡司)。从中央窝中央处到边缘分离视网膜条带,冰冻保护在蔗糖中且冷冻在OCT中。用富集特异性视网膜细胞群体的蛋白质抗体免疫染色8μm切片,包括L/M-视蛋白和S-视蛋白、谷氨酰胺合成酶(GS)、钙结合蛋白、视紫质(1D4)、β-III微管蛋白、层粘连蛋白、花生凝集素(PNA)和/或其它。通过多光谱分析以及抗体探针和DIC(针对拓扑结构的差分干涉感染)使含有GFP标记的转基因的细胞成像,因为光学平面的扁平化堆叠穿过整个切片(Axio Observer Z1,腹板背部,蔡司)。使用形态和探针共定位优化转基因的细胞分析。
眼底检验和摄影。使用菲尼克斯微米(Phoenix Micron)IV眼底显微镜进行大鼠和沙鼠视网膜的眼睛检验和眼底摄影。所有动物接受基线筛选/摄影以确认眼部健康,且随后在指定时间点拍照以监测GFP转基因表达。通过颜色眼底摄影记录光学神经和视网膜或肉眼损害外观的任何变化,且使用荧光素过滤器的荧光眼底成像目测GFP表达。
通过使用具有佳能6D数字成像硬件和新视觉眼底图像分析系统软件和光学OCTPlus的拓普康TRC-50EX视网膜摄影机进行NHP的视网膜检验、眼底颜色和荧光摄影以及自体荧光OCT。所有动物接受基线成像。还在玻璃体内载体注射后2、4、8和12周处记录GFP表达。
IVIS成像系统。在rAAV递送后,使用IVIS成像系统,在玻璃体内注射后2、4和8周活体内定量视网膜中的荧光素酶表达。用150mg/kg荧光素(珀金埃尔默)(在15ml/kg剂量下的15mg/ml荧光素)皮下注射沙鼠。大约22分钟后,通过吸入4%异氟醚3-5分钟使动物镇静。其后紧接着将动物放置在成对成像平台上,且在对侧眼睛成像后紧接着对各动物的一个眼睛的发光进行定量。未经处理的沙鼠用作负面标准物,其中发光的背景水平典型地记录1×104个光子/秒的发光。在成像之前使用体模小鼠(生物发光成像的XPM-2珀金埃尔默体模小鼠)进行生物发光验证以确保成像系统校准。
免疫组织化学。用致死性剂量的戊巴比妥钠使小鼠安乐死且经由心脏灌注,首先用0.13M磷酸盐缓冲盐水(PBS)pH 7.2-7.4,每mL含有2个单位的肝素,继而含4%多聚甲醛(PFA)的PBS,继而含4%多聚甲醛加1%戊二醛的PBS,来固定组织。戊二醛用于保持神经视网膜连接到RPE以使得视锥外段将保持完整。在投与之前正好使各溶液升温到~37℃,且在每一阶段递送~35-40mL灌注液。当停止灌注时,将小鼠包裹在潮湿纸巾中且静置以在去核和解剖之前进一步固定2-3小时。
永久性油墨用于标志眼睛方向,去除前段,且在4%PFA中在4℃下将眼睛杯固定过夜,且随后在4℃下储存于PBS中。通过使浸泡在4%PFA中两小时的组织之间的解剖视网膜平整,且随后将其转移到培养板以便额外6小时定色来制得视网膜整个支架。然后,用含有0.03%叠氮化钠的PBS(西格马)置换PFA。
在旋转台震荡器上进行抗体标记。为了阻断非特异性标记,在4℃下用含有5%驴血清(杰克逊免疫研究(Jackson ImmunoResearch),目录号004-000-120)、1mg/ml BSA(杰克逊免疫研究,目录号001-000-161)和0.03%Triton X-100于PBS(pH 7.4)中的溶液将整个支架培育过夜。在这一研究中使用的初级抗体为1:200经稀释的兔抗红色-绿色(L/M)视蛋白(密理博(Millipore),目录号AB5405)。在PBS中洗涤样本3次各自持续30分钟,随后在4℃下用DAPI(4',6-二甲脒基-2-苯基吲哚、二盐酸盐1:10,000;英杰,目录号D-21490)加第二抗体培育过夜。L/M-视蛋白抗体的二级抗体为在抗体稀释液缓冲液(英杰,目录号A21206)中经稀释的1:200阿莱克萨(Alexa)荧光剂488标记的驴抗兔IgG(H+L)。与二级抗体一起培育,继而进行三次30分钟PBS洗涤,30分钟4%多聚甲醛后定色和三次额外30分钟PBS洗涤。最终,将视网膜切片放置在具有含2%DABCO的甘油的载片上且用盖玻片覆盖。
显微术。使用具有20×(露天)物镜和用1.5×光学变焦的摄影机组的尼康日蚀(Nikon Eclipse)E1000获得小鼠视网膜整个支架的宽视场图像。对于各样本,相隔0.5μm获取50个光学切片且在ImageJ中重建M-视蛋白Z-堆叠。定向Z-堆叠以使得外段长度在平面中,且抗体染色开始与结束之间的距离测量为外段长度估计值。此外,产生Z-堆叠的3D且可对在外部链段中具有可见的M-视蛋白的视锥的数目进行定量。
使用奥林巴斯(Olympus)FluoViewTM FV1000获得共聚焦图像片。使用20×油浸没透镜(相隔0.5μm获取40个图像)使切片成像且在ImageJ中重建Z堆叠。使用AdobePhotoshop,在图像内且横跨图像平衡通道曝露水平。对于视网膜整个支架,使用10×露天透镜获取图像且用Adobe Photoshop天然马赛克结构软件建构马赛克。
测试多核苷酸卡匣的组织特异性的实验。在此情况下,经由一种或多种投与途径,如玻璃体内、视网膜下或静脉内注射编码GFP的构建物。随后处死动物且通过qPCR(以检测指示构建物存在的DNA序列)和GFP表达(以检测主动表达构建物的区域)来分析组织。尽管DNA序列不存在指示不具有给定组织的生物分布,但DNA序列的存在与转基因表达(mRNA或蛋白质水平)的缺乏指示载体的存在,但所述组织中缺乏表达。以此方式,锥状光感受器的特异性水平可为现有的且就限制表达来说用于测定本发明的效用以靶向在未靶向组织,如光学神经、肝脏、脾脏或大脑组织中无表达的锥状光感受器细胞。玻璃体内AAV已知生物分布于如此高度表达的大脑(Provost等人),用于靶向锥状光感受器的改进的构建物将适用于限制视网膜的靶细胞表达和限制与脱靶转基因表达相关的潜在不利事件。
前述仅说明本发明的原理。应了解,所属领域的技术人员将能够设计各种布置,尽管本文中未明确地描述或展示所述布置,但其体现本发明的原理且包括于其精神和范围内。此外,本文中所引述的所有实例和条件性语言主要意图辅助读者理解本发明的原理,和由发明人所提供的概念以深化所属领域,且应将其视为并不限制此类特定所引述实例和条件。此外,引述本发明的原理、方面和实施例以及其特定实例的所有本文中的陈述都打算涵盖其结构和功能等效物。此外,希望此类等效物包括当前已知等效物和未来开发等效物两者,即,不管结构如何,执行相同功能的任何所产生元件。因此,本发明的范围并不意图限于本文中所展示和描述的示范性实施例。而是,由所附权利要求书体现本发明的范围和精神。
本文所描述的全部公开案和专利申请都以全文引用的方式并入本文中。
本发明提供了
1.一种用于在个体中将相关多核苷酸递送到锥状光感受器的方法,所述方法包含:
将有效量的包含所述相关多核苷酸的重组腺相关病毒(rAAV)变体递送到眼睛的玻璃体中。
2.根据项1所述的方法,其中所述rAAV变体包含变体AAV衣壳蛋白,其在亲本AAV衣壳蛋白的GH环中包含氨基酸肽插入。
3.根据项2所述的方法,其中所述亲本衣壳蛋白的所述GH环主要由AAV1 VP1(SEQID NO:1)的氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5 VP1(SEQID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ ID NO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQ ID NO:8)的约氨基酸573到614、AAV9VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614或其变体的对应的氨基酸范围组成。
4.根据项2所述的方法,其中所述亲本衣壳为AAV2 VP1,其中所述插入部位在AAV2VP1的氨基酸580与581、氨基酸581与582、氨基酸582与583、氨基酸583与584、氨基酸584与585、氨基酸585与586、氨基酸586与587、氨基酸587与588、氨基酸588与589、氨基酸589与590、氨基酸590与591、氨基酸591与592、氨基酸592与593、氨基酸593与594或氨基酸594与595之间。
5.根据项2所述的方法,其中所述肽具有下式:Y1Y2X1X2X3X4X5X6X7Y3Y4
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn和Lys;
X2选自Gly、Glu、Ala和Asp;
X3选自Glu、Thr、Gly和Pro;
X4选自Thr、Ile、Gln和Lys;
X5选自Thr和Ala;
X6选自Arg、Asn和Thr;
X7(如果存在)选自Pro和Asn。
6.根据项5所述的方法,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:11)。
7.根据项1所述的方法,其中所述锥状光感受器为中央窝视锥。
8.根据项1所述的方法,其中所述个体为灵长类动物。
9.一种用于在个体中在锥状光感受器中表达基因产物的方法,所述方法包含:
将有效量的包含编码所述基因产物的多核苷酸的重组腺相关病毒(rAAV)变体递送到所述眼睛的玻璃体中。
10.根据项9所述的方法,其中所述rAAV变体包含变体AAV衣壳蛋白,其在所述亲本AAV衣壳蛋白的GH环中包含氨基酸肽插入。
11.根据项10所述的方法,其中所述亲本衣壳蛋白的所述GH环主要由AAV1 VP1(SEQ ID NO:1)的氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQ ID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5VP1(SEQ ID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ ID NO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQ ID NO:8)的约氨基酸573到614、AAV9 VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614或其变体的对应的氨基酸范围组成。
12.根据项10所述的方法,其中所述亲本衣壳为AAV2 VP1,其中所述插入部位在AAV2 VP1的氨基酸580与581、氨基酸581与582、氨基酸582与583、氨基酸583与584、氨基酸584与585、氨基酸585与586、氨基酸586与587、氨基酸587与588、氨基酸588与589、氨基酸589与590、氨基酸590与591、氨基酸591与592、氨基酸592与593、氨基酸593与594或氨基酸594与595之间。
13.根据项10所述的方法,其中所述肽具有下式:Y1Y2X1X2X3X4X5X6X7Y3Y4
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn和Lys;
X2选自Gly、Glu、Ala和Asp;
X3选自Glu、Thr、Gly和Pro;
X4选自Thr、Ile、Gln和Lys;
X5选自Thr和Ala;
X6选自Arg、Asn和Thr;
X7(如果存在)选自Pro和Asn。
14.根据项13所述的方法,其中所述肽包含所述氨基酸序列LGETTRP(SEQ ID NO:11)。
15.根据项9所述的方法,其中所述多核苷酸可操作地连接到MNTC启动子。
16.根据项9所述的方法,其中所述方法进一步包含检测所述锥状光感受器中的多核苷酸的表达。
17.根据项9所述的方法,其中所述锥状光感受器为中央窝视锥。
18.根据项9所述的方法,其中所述个体为灵长类动物。
19.一种用于治疗或预防患有视锥相关视网膜病症或处于罹患视锥相关视网膜病症的风险下的个体的视锥相关视网膜病症的方法,所述方法包含:
以有效治疗或预防所述视锥相关视网膜病症的量玻璃体内投与包含治疗性多核苷酸的重组腺相关病毒(rAAV)变体。
20.根据项19所述的方法,其中所述rAAV变体包含变体AAV衣壳蛋白,其在所述亲本AAV衣壳蛋白的所述GH环中包含氨基酸肽插入。
21.根据项20所述的方法,其中所述亲本衣壳蛋白的所述GH环主要由AAV1 VP1(SEQ ID NO:1)的氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQ ID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5VP1(SEQ ID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ ID NO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQ ID NO:8)的约氨基酸573到614、AAV9 VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614或其变体的对应的氨基酸范围组成。
22.根据项20所述的方法,其中所述亲本衣壳为AAV2 VP1,其中所述插入部位在AAV2 VP1的氨基酸580与581、氨基酸581与582、氨基酸582与583、氨基酸583与584、氨基酸584与585、氨基酸585与586、氨基酸586与587、氨基酸587与588、氨基酸588与589、氨基酸589与590、氨基酸590与591、氨基酸591与592、氨基酸592与593、氨基酸593与594或氨基酸594与595之间。
23.根据项20所述的方法,其中所述肽具有下式:Y1Y2X1X2X3X4X5X6X7Y3Y4
其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn和Lys;
X2选自Gly、Glu、Ala和Asp;
X3选自Glu、Thr、Gly和Pro;
X4选自Thr、Ile、Gln和Lys;
X5选自Thr和Ala;
X6选自Arg、Asn和Thr;
X7(如果存在)选自Pro和Asn。
24.根据项20所述的方法,其中所述肽包含所述氨基酸序列LGETTRP(SEQ ID NO:11)。
25.根据项19所述的方法,其中所述视网膜病症为视锥相关病症。
26.根据项25所述的方法,其中所述视锥相关病症选自由以下组成的群组:视杆-视锥营养不良;视锥-视杆营养不良;进行性视锥营养不良;色素性视网膜炎(RP);斯塔加特氏病;黄斑毛细血管扩张症、雷伯氏遗传性光学神经病、贝氏病;成人卵形黄斑营养不良;X-链视网膜劈裂症;颜色视觉病症;年龄相关性黄斑变性;湿性年龄相关性黄斑变性;地图状萎缩;糖尿病性视网膜病变;视网膜静脉闭塞;视网膜缺血;家族性渗出性玻璃体视网膜病变(FEVR);寇特病(COATs disease);以及索斯比氏眼底营养不良。
27.根据项19所述的方法,其中所述方法进一步包含鉴别出个体患有视锥相关病症。
28.根据项19所述的方法,其中所述方法进一步包含在投与步骤后检测到视觉改良。
29.根据项19所述的方法,其中所述个体为灵长类动物。
序列表
<110> 阿德夫拉姆生物技术股份有限公司
Chalberg, Thomas W.
Neitz, Jay
Neitz, Maureen
<120> 用于将多核苷酸玻璃体内递送到视网膜视锥的组合物和方法
<130> AVBI-006/02WO
<150> 62/127,194
<151> 2015-03-02
<150> 62/134,466
<151> 2015-03-17
<160> 23
<170> PatentIn version 3.5
<210> 1
<211> 736
<212> PRT
<213> 腺相关病毒 - 1
<400> 1
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Glu Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Phe Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Ala Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys Asn Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 2
<211> 735
<212> PRT
<213> 腺相关病毒 - 2
<400> 2
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Arg Gln Ala Ala Thr
580 585 590
Ala Asp Val Asn Thr Gln Gly Val Leu Pro Gly Met Val Trp Gln Asp
595 600 605
Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr
610 615 620
Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu Lys
625 630 635 640
His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala Asn
645 650 655
Pro Ser Thr Thr Phe Ser Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln
660 665 670
Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln Lys
675 680 685
Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr
690 695 700
Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val Tyr
705 710 715 720
Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 3
<211> 736
<212> PRT
<213> 腺相关病毒 - 3
<400> 3
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Val Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Arg Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Ile Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Gly
130 135 140
Ala Val Asp Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Val Gly
145 150 155 160
Lys Ser Gly Lys Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Ala Pro Thr Ser Leu Gly Ser Asn Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Lys Leu Ser Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Arg Gly Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg Thr
435 440 445
Gln Gly Thr Thr Ser Gly Thr Thr Asn Gln Ser Arg Leu Leu Phe Ser
450 455 460
Gln Ala Gly Pro Gln Ser Met Ser Leu Gln Ala Arg Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Leu Ser Lys Thr Ala Asn Asp Asn
485 490 495
Asn Asn Ser Asn Phe Pro Trp Thr Ala Ala Ser Lys Tyr His Leu Asn
500 505 510
Gly Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Asp Asp Glu Glu Lys Phe Phe Pro Met His Gly Asn Leu Ile Phe Gly
530 535 540
Lys Glu Gly Thr Thr Ala Ser Asn Ala Glu Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln
565 570 575
Tyr Gly Thr Val Ala Asn Asn Leu Gln Ser Ser Asn Thr Ala Pro Thr
580 585 590
Thr Gly Thr Val Asn His Gln Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Met Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Thr Thr Phe Ser Pro Ala Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Asn Lys Ser Val Asn Val Asp Phe Thr Val Asp Thr Asn Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 4
<211> 734
<212> PRT
<213> 腺相关病毒 - 4
<400> 4
Met Thr Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser Glu
1 5 10 15
Gly Val Arg Glu Trp Trp Ala Leu Gln Pro Gly Ala Pro Lys Pro Lys
20 25 30
Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro Val
50 55 60
Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp Gln
65 70 75 80
Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Gln Arg Leu Gln Gly Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Leu
115 120 125
Gly Leu Val Glu Gln Ala Gly Glu Thr Ala Pro Gly Lys Lys Arg Pro
130 135 140
Leu Ile Glu Ser Pro Gln Gln Pro Asp Ser Ser Thr Gly Ile Gly Lys
145 150 155 160
Lys Gly Lys Gln Pro Ala Lys Lys Lys Leu Val Phe Glu Asp Glu Thr
165 170 175
Gly Ala Gly Asp Gly Pro Pro Glu Gly Ser Thr Ser Gly Ala Met Ser
180 185 190
Asp Asp Ser Glu Met Arg Ala Ala Ala Gly Gly Ala Ala Val Glu Gly
195 200 205
Gly Gln Gly Ala Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys
210 215 220
Asp Ser Thr Trp Ser Glu Gly His Val Thr Thr Thr Ser Thr Arg Thr
225 230 235 240
Trp Val Leu Pro Thr Tyr Asn Asn His Leu Tyr Lys Arg Leu Gly Glu
245 250 255
Ser Leu Gln Ser Asn Thr Tyr Asn Gly Phe Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Asn Trp Gly Met Arg Pro Lys Ala Met Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Thr Ser Asn Gly Glu
305 310 315 320
Thr Thr Val Ala Asn Asn Leu Thr Ser Thr Val Gln Ile Phe Ala Asp
325 330 335
Ser Ser Tyr Glu Leu Pro Tyr Val Met Asp Ala Gly Gln Glu Gly Ser
340 345 350
Leu Pro Pro Phe Pro Asn Asp Val Phe Met Val Pro Gln Tyr Gly Tyr
355 360 365
Cys Gly Leu Val Thr Gly Asn Thr Ser Gln Gln Gln Thr Asp Arg Asn
370 375 380
Ala Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly
385 390 395 400
Asn Asn Phe Glu Ile Thr Tyr Ser Phe Glu Lys Val Pro Phe His Ser
405 410 415
Met Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile
420 425 430
Asp Gln Tyr Leu Trp Gly Leu Gln Ser Thr Thr Thr Gly Thr Thr Leu
435 440 445
Asn Ala Gly Thr Ala Thr Thr Asn Phe Thr Lys Leu Arg Pro Thr Asn
450 455 460
Phe Ser Asn Phe Lys Lys Asn Trp Leu Pro Gly Pro Ser Ile Lys Gln
465 470 475 480
Gln Gly Phe Ser Lys Thr Ala Asn Gln Asn Tyr Lys Ile Pro Ala Thr
485 490 495
Gly Ser Asp Ser Leu Ile Lys Tyr Glu Thr His Ser Thr Leu Asp Gly
500 505 510
Arg Trp Ser Ala Leu Thr Pro Gly Pro Pro Met Ala Thr Ala Gly Pro
515 520 525
Ala Asp Ser Lys Phe Ser Asn Ser Gln Leu Ile Phe Ala Gly Pro Lys
530 535 540
Gln Asn Gly Asn Thr Ala Thr Val Pro Gly Thr Leu Ile Phe Thr Ser
545 550 555 560
Glu Glu Glu Leu Ala Ala Thr Asn Ala Thr Asp Thr Asp Met Trp Gly
565 570 575
Asn Leu Pro Gly Gly Asp Gln Ser Asn Ser Asn Leu Pro Thr Val Asp
580 585 590
Arg Leu Thr Ala Leu Gly Ala Val Pro Gly Met Val Trp Gln Asn Arg
595 600 605
Asp Ile Tyr Tyr Gln Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp
610 615 620
Gly His Phe His Pro Ser Pro Leu Ile Gly Gly Phe Gly Leu Lys His
625 630 635 640
Pro Pro Pro Gln Ile Phe Ile Lys Asn Thr Pro Val Pro Ala Asn Pro
645 650 655
Ala Thr Thr Phe Ser Ser Thr Pro Val Asn Ser Phe Ile Thr Gln Tyr
660 665 670
Ser Thr Gly Gln Val Ser Val Gln Ile Asp Trp Glu Ile Gln Lys Glu
675 680 685
Arg Ser Lys Arg Trp Asn Pro Glu Val Gln Phe Thr Ser Asn Tyr Gly
690 695 700
Gln Gln Asn Ser Leu Leu Trp Ala Pro Asp Ala Ala Gly Lys Tyr Thr
705 710 715 720
Glu Pro Arg Ala Ile Gly Thr Arg Tyr Leu Thr His His Leu
725 730
<210> 5
<211> 724
<212> PRT
<213> 腺相关病毒 - 5
<400> 5
Met Ser Phe Val Asp His Pro Pro Asp Trp Leu Glu Glu Val Gly Glu
1 5 10 15
Gly Leu Arg Glu Phe Leu Gly Leu Glu Ala Gly Pro Pro Lys Pro Lys
20 25 30
Pro Asn Gln Gln His Gln Asp Gln Ala Arg Gly Leu Val Leu Pro Gly
35 40 45
Tyr Asn Tyr Leu Gly Pro Gly Asn Gly Leu Asp Arg Gly Glu Pro Val
50 55 60
Asn Arg Ala Asp Glu Val Ala Arg Glu His Asp Ile Ser Tyr Asn Glu
65 70 75 80
Gln Leu Glu Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala Asp
85 90 95
Ala Glu Phe Gln Glu Lys Leu Ala Asp Asp Thr Ser Phe Gly Gly Asn
100 105 110
Leu Gly Lys Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro Phe
115 120 125
Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Thr Gly Lys Arg Ile
130 135 140
Asp Asp His Phe Pro Lys Arg Lys Lys Ala Arg Thr Glu Glu Asp Ser
145 150 155 160
Lys Pro Ser Thr Ser Ser Asp Ala Glu Ala Gly Pro Ser Gly Ser Gln
165 170 175
Gln Leu Gln Ile Pro Ala Gln Pro Ala Ser Ser Leu Gly Ala Asp Thr
180 185 190
Met Ser Ala Gly Gly Gly Gly Pro Leu Gly Asp Asn Asn Gln Gly Ala
195 200 205
Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr Trp
210 215 220
Met Gly Asp Arg Val Val Thr Lys Ser Thr Arg Thr Trp Val Leu Pro
225 230 235 240
Ser Tyr Asn Asn His Gln Tyr Arg Glu Ile Lys Ser Gly Ser Val Asp
245 250 255
Gly Ser Asn Ala Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr
260 265 270
Phe Asp Phe Asn Arg Phe His Ser His Trp Ser Pro Arg Asp Trp Gln
275 280 285
Arg Leu Ile Asn Asn Tyr Trp Gly Phe Arg Pro Arg Ser Leu Arg Val
290 295 300
Lys Ile Phe Asn Ile Gln Val Lys Glu Val Thr Val Gln Asp Ser Thr
305 310 315 320
Thr Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp
325 330 335
Asp Asp Tyr Gln Leu Pro Tyr Val Val Gly Asn Gly Thr Glu Gly Cys
340 345 350
Leu Pro Ala Phe Pro Pro Gln Val Phe Thr Leu Pro Gln Tyr Gly Tyr
355 360 365
Ala Thr Leu Asn Arg Asp Asn Thr Glu Asn Pro Thr Glu Arg Ser Ser
370 375 380
Phe Phe Cys Leu Glu Tyr Phe Pro Ser Lys Met Leu Arg Thr Gly Asn
385 390 395 400
Asn Phe Glu Phe Thr Tyr Asn Phe Glu Glu Val Pro Phe His Ser Ser
405 410 415
Phe Ala Pro Ser Gln Asn Leu Phe Lys Leu Ala Asn Pro Leu Val Asp
420 425 430
Gln Tyr Leu Tyr Arg Phe Val Ser Thr Asn Asn Thr Gly Gly Val Gln
435 440 445
Phe Asn Lys Asn Leu Ala Gly Arg Tyr Ala Asn Thr Tyr Lys Asn Trp
450 455 460
Phe Pro Gly Pro Met Gly Arg Thr Gln Gly Trp Asn Leu Gly Ser Gly
465 470 475 480
Val Asn Arg Ala Ser Val Ser Ala Phe Ala Thr Thr Asn Arg Met Glu
485 490 495
Leu Glu Gly Ala Ser Tyr Gln Val Pro Pro Gln Pro Asn Gly Met Thr
500 505 510
Asn Asn Leu Gln Gly Ser Asn Thr Tyr Ala Leu Glu Asn Thr Met Ile
515 520 525
Phe Asn Ser Gln Pro Ala Asn Pro Gly Thr Thr Ala Thr Tyr Leu Glu
530 535 540
Gly Asn Met Leu Ile Thr Ser Glu Ser Glu Thr Gln Pro Val Asn Arg
545 550 555 560
Val Ala Tyr Asn Val Gly Gly Gln Met Ala Thr Asn Asn Gln Ser Ser
565 570 575
Thr Thr Ala Pro Ala Thr Gly Thr Tyr Asn Leu Gln Glu Ile Val Pro
580 585 590
Gly Ser Val Trp Met Glu Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp
595 600 605
Ala Lys Ile Pro Glu Thr Gly Ala His Phe His Pro Ser Pro Ala Met
610 615 620
Gly Gly Phe Gly Leu Lys His Pro Pro Pro Met Met Leu Ile Lys Asn
625 630 635 640
Thr Pro Val Pro Gly Asn Ile Thr Ser Phe Ser Asp Val Pro Val Ser
645 650 655
Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Thr Val Glu Met Glu
660 665 670
Trp Glu Leu Lys Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln
675 680 685
Tyr Thr Asn Asn Tyr Asn Asp Pro Gln Phe Val Asp Phe Ala Pro Asp
690 695 700
Ser Thr Gly Glu Tyr Arg Thr Thr Arg Pro Ile Gly Thr Arg Tyr Leu
705 710 715 720
Thr Arg Pro Leu
<210> 6
<211> 736
<212> PRT
<213> 腺相关病毒 - 6
<400> 6
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Phe Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly
145 150 155 160
Lys Thr Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro Pro
180 185 190
Ala Thr Pro Ala Ala Val Gly Pro Thr Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ala
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Ala Ser Thr Gly Ala Ser Asn Asp Asn His
260 265 270
Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe
275 280 285
His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn
290 295 300
Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln
305 310 315 320
Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn Asn
325 330 335
Leu Thr Ser Thr Val Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu Pro
340 345 350
Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala
355 360 365
Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly
370 375 380
Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro
385 390 395 400
Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe
405 410 415
Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp
420 425 430
Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Asn Arg
435 440 445
Thr Gln Asn Gln Ser Gly Ser Ala Gln Asn Lys Asp Leu Leu Phe Ser
450 455 460
Arg Gly Ser Pro Ala Gly Met Ser Val Gln Pro Lys Asn Trp Leu Pro
465 470 475 480
Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Lys Thr Asp Asn
485 490 495
Asn Asn Ser Asn Phe Thr Trp Thr Gly Ala Ser Lys Tyr Asn Leu Asn
500 505 510
Gly Arg Glu Ser Ile Ile Asn Pro Gly Thr Ala Met Ala Ser His Lys
515 520 525
Asp Asp Lys Asp Lys Phe Phe Pro Met Ser Gly Val Met Ile Phe Gly
530 535 540
Lys Glu Ser Ala Gly Ala Ser Asn Thr Ala Leu Asp Asn Val Met Ile
545 550 555 560
Thr Asp Glu Glu Glu Ile Lys Ala Thr Asn Pro Val Ala Thr Glu Arg
565 570 575
Phe Gly Thr Val Ala Val Asn Leu Gln Ser Ser Ser Thr Asp Pro Ala
580 585 590
Thr Gly Asp Val His Val Met Gly Ala Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly His Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Leu
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asn Pro Pro Ala Glu Phe Ser Ala Thr Lys Phe Ala Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Val Gln Tyr Thr Ser Asn
690 695 700
Tyr Ala Lys Ser Ala Asn Val Asp Phe Thr Val Asp Asn Asn Gly Leu
705 710 715 720
Tyr Thr Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Pro Leu
725 730 735
<210> 7
<211> 737
<212> PRT
<213> 腺相关病毒 - 7
<400> 7
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asn Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Ala Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Ser Val Gly Ser Gly Thr Val Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn
210 215 220
Ala Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Ser Glu Thr Ala Gly Ser Thr Asn Asp Asn
260 265 270
Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Lys Leu Arg Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Thr Asn Asp Gly Val Thr Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Ile Gln Val Phe Ser Asp Ser Glu Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn
370 375 380
Gly Ser Gln Ser Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr Ser
405 410 415
Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ala
435 440 445
Arg Thr Gln Ser Asn Pro Gly Gly Thr Ala Gly Asn Arg Glu Leu Gln
450 455 460
Phe Tyr Gln Gly Gly Pro Ser Thr Met Ala Glu Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Phe Arg Gln Gln Arg Val Ser Lys Thr Leu Asp
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Asp Arg Phe Phe Pro Ser Ser Gly Val Leu Ile
530 535 540
Phe Gly Lys Thr Gly Ala Thr Asn Lys Thr Thr Leu Glu Asn Val Leu
545 550 555 560
Met Thr Asn Glu Glu Glu Ile Arg Pro Thr Asn Pro Val Ala Thr Glu
565 570 575
Glu Tyr Gly Ile Val Ser Ser Asn Leu Gln Ala Ala Asn Thr Ala Ala
580 585 590
Gln Thr Gln Val Val Asn Asn Gln Gly Ala Leu Pro Gly Met Val Trp
595 600 605
Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro
610 615 620
His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly
625 630 635 640
Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro
645 650 655
Ala Asn Pro Pro Glu Val Phe Thr Pro Ala Lys Phe Ala Ser Phe Ile
660 665 670
Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu
675 680 685
Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser
690 695 700
Asn Phe Glu Lys Gln Thr Gly Val Asp Phe Ala Val Asp Ser Gln Gly
705 710 715 720
Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn
725 730 735
Leu
<210> 8
<211> 738
<212> PRT
<213> 腺相关病毒 - 8
<400> 8
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 9
<211> 736
<212> PRT
<213> 腺相关病毒 9
<400> 9
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Gln Pro
20 25 30
Lys Ala Asn Gln Gln His Gln Asp Asn Ala Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Gly Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Leu Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Gln Ser Pro Gln Glu Pro Asp Ser Ser Ala Gly Ile Gly
145 150 155 160
Lys Ser Gly Ala Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Thr Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro Pro
180 185 190
Ala Ala Pro Ser Gly Val Gly Ser Leu Thr Met Ala Ser Gly Gly Gly
195 200 205
Ala Pro Val Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Gln Trp Leu Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly Gly Ser Ser Asn Asp Asn
260 265 270
Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg
275 280 285
Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn
290 295 300
Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile
305 310 315 320
Gln Val Lys Glu Val Thr Asp Asn Asn Gly Val Lys Thr Ile Ala Asn
325 330 335
Asn Leu Thr Ser Thr Val Gln Val Phe Thr Asp Ser Asp Tyr Gln Leu
340 345 350
Pro Tyr Val Leu Gly Ser Ala His Glu Gly Cys Leu Pro Pro Phe Pro
355 360 365
Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asp
370 375 380
Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe
385 390 395 400
Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Ser Tyr Glu
405 410 415
Phe Glu Asn Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu
420 425 430
Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser
435 440 445
Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln Gln Thr Leu Lys Phe Ser
450 455 460
Val Ala Gly Pro Ser Asn Met Ala Val Gln Gly Arg Asn Tyr Ile Pro
465 470 475 480
Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser Thr Thr Val Thr Gln Asn
485 490 495
Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala Ser Ser Trp Ala Leu Asn
500 505 510
Gly Arg Asn Ser Leu Met Asn Pro Gly Pro Ala Met Ala Ser His Lys
515 520 525
Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser Gly Ser Leu Ile Phe Gly
530 535 540
Lys Gln Gly Thr Gly Arg Asp Asn Val Asp Ala Asp Lys Val Met Ile
545 550 555 560
Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr Glu Ser
565 570 575
Tyr Gly Gln Val Ala Thr Asn His Gln Ser Ala Gln Ala Gln Ala Gln
580 585 590
Thr Gly Trp Val Gln Asn Gln Gly Ile Leu Pro Gly Met Val Trp Gln
595 600 605
Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile Pro His
610 615 620
Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe Gly Met
625 630 635 640
Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val Pro Ala
645 650 655
Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys Leu Asn Ser Phe Ile Thr
660 665 670
Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu Leu Gln
675 680 685
Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr Ser Asn
690 695 700
Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala Val Asn Thr Glu Gly Val
705 710 715 720
Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg Asn Leu
725 730 735
<210> 10
<211> 738
<212> PRT
<213> 腺相关病毒 10
<400> 10
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Ala Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Glu Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro
180 185 190
Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Ser Thr Gly Gly Thr Gln Gly Thr Gln Gln Leu Leu
450 455 460
Phe Ser Gln Ala Gly Pro Ala Asn Met Ser Ala Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met
530 535 540
Phe Gly Lys Gln Gly Ala Gly Arg Asp Asn Val Asp Tyr Ser Ser Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Ala Asn Thr Gly
580 585 590
Pro Ile Val Gly Asn Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 11
Leu Gly Glu Thr Thr Arg Pro
1 5
<210> 12
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 12
Asn Glu Thr Ile Thr Arg Pro
1 5
<210> 13
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 13
Leu Ala Leu Gly Glu Thr Thr Arg Pro Ala
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> LANETITRPA
<400> 14
Leu Ala Asn Glu Thr Ile Thr Arg Pro Ala
1 5 10
<210> 15
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 15
Ala Ala Leu Gly Glu Thr Thr Arg Pro Ala
1 5 10
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 16
Ala Ala Asn Glu Thr Ile Thr Arg Pro Ala
1 5 10
<210> 17
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 17
Gly Leu Gly Glu Thr Thr Arg Pro Ala
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> rAAV肽插入物
<400> 18
Gly Asn Glu Thr Ile Thr Arg Pro Ala
1 5
<210> 19
<211> 745
<212> PRT
<213> 人工序列
<220>
<223> 具有肽插入的变体VP1壳体
<400> 19
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Thr Leu Ser
1 5 10 15
Glu Gly Ile Arg Gln Trp Trp Lys Leu Lys Pro Gly Pro Pro Pro Pro
20 25 30
Lys Pro Ala Glu Arg His Lys Asp Asp Ser Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Arg Gln Leu Asp Ser Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Lys Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Pro Val Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu His Ser Pro Val Glu Pro Asp Ser Ser Ser Gly Thr Gly
145 150 155 160
Lys Ala Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln Thr
165 170 175
Gly Asp Ala Asp Ser Val Pro Asp Pro Gln Pro Leu Gly Gln Pro Pro
180 185 190
Ala Ala Pro Ser Gly Leu Gly Thr Asn Thr Met Ala Thr Gly Ser Gly
195 200 205
Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Asn Ser
210 215 220
Ser Gly Asn Trp His Cys Asp Ser Thr Trp Met Gly Asp Arg Val Ile
225 230 235 240
Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His Leu
245 250 255
Tyr Lys Gln Ile Ser Ser Gln Ser Gly Ala Ser Asn Asp Asn His Tyr
260 265 270
Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn Arg Phe His
275 280 285
Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn Asn Asn Trp
290 295 300
Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn Ile Gln Val
305 310 315 320
Lys Glu Val Thr Gln Asn Asp Gly Thr Thr Thr Ile Ala Asn Asn Leu
325 330 335
Thr Ser Thr Val Gln Val Phe Thr Asp Ser Glu Tyr Gln Leu Pro Tyr
340 345 350
Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe Pro Ala Asp
355 360 365
Val Phe Met Val Pro Gln Tyr Gly Tyr Leu Thr Leu Asn Asn Gly Ser
370 375 380
Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr Phe Pro Ser
385 390 395 400
Gln Met Leu Arg Thr Gly Asn Asn Phe Thr Phe Ser Tyr Thr Phe Glu
405 410 415
Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser Leu Asp Arg
420 425 430
Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu Ser Arg Thr
435 440 445
Asn Thr Pro Ser Gly Thr Thr Thr Gln Ser Arg Leu Gln Phe Ser Gln
450 455 460
Ala Gly Ala Ser Asp Ile Arg Asp Gln Ser Arg Asn Trp Leu Pro Gly
465 470 475 480
Pro Cys Tyr Arg Gln Gln Arg Val Ser Lys Thr Ser Ala Asp Asn Asn
485 490 495
Asn Ser Glu Tyr Ser Trp Thr Gly Ala Thr Lys Tyr His Leu Asn Gly
500 505 510
Arg Asp Ser Leu Val Asn Pro Gly Pro Ala Met Ala Ser His Lys Asp
515 520 525
Asp Glu Glu Lys Phe Phe Pro Gln Ser Gly Val Leu Ile Phe Gly Lys
530 535 540
Gln Gly Ser Glu Lys Thr Asn Val Asp Ile Glu Lys Val Met Ile Thr
545 550 555 560
Asp Glu Glu Glu Ile Arg Thr Thr Asn Pro Val Ala Thr Glu Gln Tyr
565 570 575
Gly Ser Val Ser Thr Asn Leu Gln Arg Gly Asn Leu Ala Leu Gly Glu
580 585 590
Thr Thr Arg Pro Ala Arg Gln Ala Ala Thr Ala Asp Val Asn Thr Gln
595 600 605
Gly Val Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln
610 615 620
Gly Pro Ile Trp Ala Lys Ile Pro His Thr Asp Gly His Phe His Pro
625 630 635 640
Ser Pro Leu Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile
645 650 655
Leu Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ser Thr Thr Phe Ser
660 665 670
Ala Ala Lys Phe Ala Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val
675 680 685
Ser Val Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp
690 695 700
Asn Pro Glu Ile Gln Tyr Thr Ser Asn Tyr Asn Lys Ser Val Asn Val
705 710 715 720
Asp Phe Thr Val Asp Thr Asn Gly Val Tyr Ser Glu Pro Arg Pro Ile
725 730 735
Gly Thr Arg Tyr Leu Thr Arg Asn Leu
740 745
<210> 20
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽插入式I
<220>
<221> MISC_FEATURE
<222> (1)..(2)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = Leu, Asn和Lys
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = Gly, Glu, Ala和Asp
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = Glu, Thr, Gly和Pro
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = Thr, Ile, Gln,和 Lys
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = Thr和Ala
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = Arg, Asn和Thr
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = Pro和Asn
<220>
<221> MISC_FEATURE
<222> (10)..(11)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<400> 20
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 21
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽插入式II
<220>
<221> MISC_FEATURE
<222> (1)..(2)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<220>
<221> MISC_FEATURE
<222> (3)..(6)
<223> Xaa = 任何氨基酸
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = 任何氨基酸
<220>
<221> misc_feature
<222> (10)..(11)
<223> Xaa可以是任何天然存在的氨基酸
<400> 21
Xaa Xaa Xaa Xaa Xaa Xaa Thr Arg Pro Xaa Xaa
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽插入式III
<220>
<221> MISC_FEATURE
<222> (1)..(2)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = Leu和Asn
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = Gly和Glu
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = Glu和Thr
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = Thr和 Ile
<220>
<221> MISC_FEATURE
<222> (10)..(11)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<400> 22
Xaa Xaa Xaa Xaa Xaa Xaa Thr Arg Pro Xaa Xaa
1 5 10
<210> 23
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽插入式 IV
<220>
<221> MISC_FEATURE
<222> (1)..(2)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = Leu, Asn, Arg, Ala, Ser和Lys
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa =Gly, Glu, Ala, Val, Thr 和Asp
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = Glu, Thr, Gly, Asp 和Pro
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = Thr, Ile, Gly, Lys, Asp 和Gln
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = Thr, Ser, Val 和Ala
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = Arg, Val, Lys, Pro, Thr 和Asn
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = Pro, Gly, Phe, Asn 和Arg
<220>
<221> MISC_FEATURE
<222> (10)..(11)
<223> Xaa = Ala, Leu, Gly, Ser, Thr或不存在
<400> 23
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
Claims (10)
1.一种用于在个体中将相关多核苷酸递送到锥状光感受器的方法,所述方法包含:
将有效量的包含所述相关多核苷酸的重组腺相关病毒(rAAV)变体递送到眼睛的玻璃体中。
2.根据权利要求1所述的方法,其中所述rAAV变体包含变体AAV衣壳蛋白,其在亲本AAV衣壳蛋白的GH环中包含氨基酸肽插入。
3.根据权利要求2所述的方法,其中所述亲本衣壳蛋白的所述GH环主要由AAV1VP1(SEQID NO:1)的氨基酸571-612、AAV2 VP1(SEQ ID NO:2)的约氨基酸570-611、AAV3 VP1(SEQID NO:3)的约氨基酸571-612、AAV4 VP1(SEQ ID NO:4)的约氨基酸569-610、AAV5 VP1(SEQID NO:5)的约氨基酸560-601、AAV6 VP1(SEQ ID NO:6)的约氨基酸571到612、AAV7 VP1(SEQ ID NO:7)的约氨基酸572到613、AAV8 VP1(SEQ ID NO:8)的约氨基酸573到614、AAV9VP1(SEQ ID NO:9)的约氨基酸571到612、AAV10 VP1(SEQ ID NO:10)的约氨基酸573到614或其变体的对应的氨基酸范围组成。
4.根据权利要求2所述的方法,其中所述亲本衣壳为AAV2 VP1,其中所述插入部位在AAV2 VP1的氨基酸580与581、氨基酸581与582、氨基酸582与583、氨基酸583与584、氨基酸584与585、氨基酸585与586、氨基酸586与587、氨基酸587与588、氨基酸588与589、氨基酸589与590、氨基酸590与591、氨基酸591与592、氨基酸592与593、氨基酸593与594或氨基酸594与595之间。
5.根据权利要求2所述的方法,其中所述肽具有下式:Y1Y2X1X2X3X4X5X6X7Y3Y4其中:
Y1-Y4中的每一个(如果存在)独立地选自Ala、Leu、Gly、Ser和Thr;
X1(如果存在)选自Leu、Asn和Lys;
X2选自Gly、Glu、Ala和Asp;
X3选自Glu、Thr、Gly和Pro;
X4选自Thr、Ile、Gln和Lys;
X5选自Thr和Ala;
X6选自Arg、Asn和Thr;
X7(如果存在)选自Pro和Asn。
6.根据权利要求5所述的方法,其中所述肽包含氨基酸序列LGETTRP(SEQ ID NO:11)。
7.根据权利要求1所述的方法,其中所述锥状光感受器为中央窝视锥。
8.根据权利要求1所述的方法,其中所述个体为灵长类动物。
9.一种用于在个体中在锥状光感受器中表达基因产物的方法,所述方法包含:
将有效量的包含编码所述基因产物的多核苷酸的重组腺相关病毒(rAAV)变体递送到所述眼睛的玻璃体中。
10.根据权利要求9所述的方法,其中所述rAAV变体包含变体AAV衣壳蛋白,其在所述亲本AAV衣壳蛋白的GH环中包含氨基酸肽插入。
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AU2016226289A1 (en) | 2017-09-21 |
JP7095994B2 (ja) | 2022-07-05 |
SG11201707063TA (en) | 2017-09-28 |
WO2016141078A1 (en) | 2016-09-09 |
IL254148A0 (en) | 2017-10-31 |
MY187898A (en) | 2021-10-27 |
CA2978068A1 (en) | 2016-09-09 |
JP2018508519A (ja) | 2018-03-29 |
EA201791939A1 (ru) | 2018-01-31 |
EP3265178A4 (en) | 2018-09-05 |
MX2017011041A (es) | 2018-03-02 |
AU2021209206A1 (en) | 2021-08-19 |
KR20170137730A (ko) | 2017-12-13 |
JP2020122008A (ja) | 2020-08-13 |
US20180066022A1 (en) | 2018-03-08 |
HK1249067A1 (zh) | 2018-10-26 |
US20210388030A1 (en) | 2021-12-16 |
EP3265178A1 (en) | 2018-01-10 |
US11021519B2 (en) | 2021-06-01 |
AU2016226289B2 (en) | 2021-04-29 |
IL254148B (en) | 2022-09-01 |
BR112017018846A2 (pt) | 2018-07-31 |
CN107405507A (zh) | 2017-11-28 |
JP2022107042A (ja) | 2022-07-20 |
CN107405507B (zh) | 2022-05-03 |
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