TW202304954A - 用於肌肉萎縮症之基因療法的aavrh74載體 - Google Patents
用於肌肉萎縮症之基因療法的aavrh74載體 Download PDFInfo
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Abstract
本發明提供經修飾之AAV殼體蛋白、粒子、核酸載體及其組成物,以及其使用方法。
Description
相關申請案
本申請案根據35 U.S.C. § 119(e)主張2021年4月23日申請之美國臨時專利申請案第63/179,097號及2022年4月5日申請之美國臨時專利申請案第63/327,410號之益處,該等申請案各自之全部內容以引用之方式併入本文中。
經由EFS-WEB以文字檔案形式提交之序列表的參考
本申請案含有序列表,該序列表已以ASCII格式經由EFS-Web提交且以全文引用的方式併入本文中。2022年4月21日創建之該ASCII複本命名為U120270077WO00-SEQ-COB且大小為119,114個位元組。
基因療法有可能治療罹患遺傳疾病或處於罹患遺傳疾病之風險下的個體。用於攜帶遺傳載荷(payload)之改良型AAV載體將有益於基因療法之發展,例如用於影響肌肉組織及/或功能之某些疾病。肌肉疾病,諸如肌肉萎縮症,可由許多條件引起,該等條件包括例如先天性或後天性體細胞突變、損傷及暴露於有害化合物。在一些情況下,肌肉疾病會導致危及生命的併發症或導致嚴重的症狀及/或死亡。儘管已表明許多因素與調控肌肉疾病,包括肌肉萎縮症有關,但有效治療仍然有限。
本發明至少部分地基於以下認識:重組AAVrh74粒子之一或多種殼體蛋白中之某些胺基酸取代,及/或對藉由AAVrh74殼體包殼之AAV核酸載體的修飾相對於野生型AAVrh74粒子或藉由AAVrh74殼體包殼之未經修飾之AAV核酸載體產生改善之特性(例如轉導特定類型之細胞)。殼體蛋白之修飾(例如胺基酸取代)及核酸載體之修飾(例如D序列之取代或缺失,及轉錄調節因子結合元件之插入)可賦予AAVrh74粒子各種有益特性,諸如與特定細胞類型之增強結合、與細胞及/或其生物學機制之增強相互作用、細胞之增強轉導、細胞內轉殖基因之增強表現以及其他特性。多種修飾之組合(例如各種殼體蛋白修飾及/或核酸載體修飾之組合)可對併入其之AAVrh74粒子之各種特性具有協同效應。根據一些態樣,AAV核酸載體之修飾包含載體之左或右反向末端重複序列(inverted terminal repeat;ITR)之修飾。在一些具體實例中,AAV核酸載體之修飾包含取代AAV載體之左或右側ITR中之D序列。舉例而言,在一些具體實例中,AAV核酸載體之修飾包含用另一序列(例如,S序列或糖皮質激素受體結合元件(glucocorticoid receptor-binding element;GRE))取代AAV核酸載體中之序列(例如,ITR中之D序列)。用另一序列(例如S序列或GRE)取代AAV核酸載體中之序列(例如ITR中之D序列)可增加包含AAV核酸載體之AAV粒子的轉導效率及/或轉殖基因表現量。根據一些態樣,在一些具體實例中,除了經修飾之AAV核酸載體之外,本文所揭示之重組AAVrh74粒子包含具有一或多個胺基酸取代之殼體蛋白。經修飾之AAV核酸載體於包含一或多個胺基酸取代之AAVrh74殼體中的包殼可使得包含經修飾之AAV核酸載體及包含一或多個胺基酸取代之殼體的AAV粒子相對於包含未經修飾之AAV核酸載體及/或不包含胺基酸取代之殼體的相應AAV粒子產生改善之特性。在一些具體實例中,改善之特性為改善轉導效率,亦即,改善AAV粒子向目標細胞遞送遺傳載荷之效率。
根據本發明之一些態樣,提供殼體蛋白。在一些具體實例中,殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,其中殼體蛋白為AAVrh74血清型殼體蛋白。在一些具體實例中,取代為Y447F、T494V、K547R、N665R及/或Y733F。
根據一些態樣,提供AAVrh74粒子。在一些具體實例中,AAVrh74粒子包含本文所揭示之殼體蛋白。在一些具體實例中,AAVrh74粒子進一步包含核酸載體,其中核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中第一D序列或第二D序列係經S序列取代。在一些具體實例中,S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
在一些具體實例中,AAVrh74粒子包含核酸載體,其中核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中第一D序列及/或第二D序列係經糖皮質激素受體結合元件(GRE)取代。在一些具體實例中,GRE包含核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
根據本發明之一些態樣,提供包含AAV殼體蛋白或AAV粒子之組成物。在一些具體實例中,本文所揭示之組成物包含本文所揭示之AAVrh74殼體蛋白。在一些具體實例中,本文所揭示之組成物包含本文所揭示之AAVrh74粒子。
根據一些態樣,本文提供接觸細胞之方法。在一些具體實例中,一種方法包含使細胞與包含AAVrh74粒子之組成物接觸,其中AAVrh74粒子包含殼體蛋白及核酸載體,
(i)其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及/或
(ii)其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中該第一D序列或該第二D序列係經S序列取代,視需要其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
在一些具體實例中,一種方法包含使細胞與包含AAVrh74粒子之組成物接觸,其中AAVrh74粒子包含殼體蛋白及核酸載體,
(i)其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及/或
(ii)其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中該第一D序列及/或該第二D序列係經糖皮質激素受體結合元件(GRE)取代,視需要其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
在一些具體實例中,該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F。
在一些具體實例中,該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列或該第二D序列係經S序列取代,視需要其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
在一些具體實例中,該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列及/或該第二D序列係經該GRE取代,視需要其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
在一些具體實例中,該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,且該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列或該第二D序列係經該S序列取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,且視需要其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
在一些具體實例中,該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,且該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列及/或該第二D序列係經該GRE取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,且視需要其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
在一些具體實例中,該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之以下位置處包含胺基酸取代:
(a)Y447及Y733,視需要其中該等取代為Y447F及Y733F;
(b)Y447、Y733及N665,視需要其中該等取代為Y447F、Y733F及N665R;
(c)Y447、Y733及T494,視需要其中該等取代為Y447F、Y733F及T494V;
(d)Y447、Y733及K547,視需要其中該等取代為Y447F、Y733F及K547R;或
(e)Y447、Y733、N665、T494及K547,視需要其中該等取代為Y447F、Y733F、N665R、T494V及K547R。
在一些具體實例中,該第一ITR及該第二ITR各自為AAV2血清型ITR或AAV3血清型ITR。
在一些具體實例中,該第一D序列係經該S序列取代,或該第一D序列係經該GRE取代。在一些具體實例中,該第二D序列係經該S序列取代,或該第二D序列係經該GRE取代。在一些具體實例中,該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成,或該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
在一些具體實例中,該AAVrh74粒子之轉導效率比野生型AAVrh74粒子高至少兩倍。在一些具體實例中,該AAVrh74粒子之包裝效率相對於野生型AAVrh74粒子降低。
在一些具體實例中,該組成物進一步包含醫藥學上可接受之載劑。
在一些具體實例中,該細胞為哺乳動物細胞。在一些具體實例中,該細胞為肌細胞。在一些具體實例中,該細胞為骨胳肌細胞。在一些具體實例中,該細胞為腓腸肌細胞或脛骨前肌細胞。
在一些具體實例中,該核酸載體包含調控元件。在一些具體實例中,該調控元件包含啟動子、強化子、緘默子、絕緣子、反應元件、起始位點、終止信號或核糖體結合位點。在一些具體實例中,該啟動子為持續型啟動子。在一些具體實例中,該啟動子為可誘導型啟動子。在一些具體實例中,該啟動子為組織專一性啟動子、細胞類型專一性啟動子或合成啟動子。
在一些具體實例中,該核酸載體包含目標基因之核苷酸序列。在一些具體實例中,該目標基因編碼治療蛋白或診斷蛋白。
在一些具體實例中,該接觸為活體內的。
在一些具體實例中,該方法進一步包含向個體投予包含該AAVrh74粒子之該組成物。
在一些具體實例中,該細胞係在該個體中。
在一些具體實例中,該個體為人類。在一些具體實例中,該個體處於肌肉疾病風險下或患有肌肉疾病,視需要其中該肌肉疾病為肌肉萎縮性脊髓側索硬化症、恰克-馬利-杜斯氏病(Charcot-Marie-Tooth disease)、多發性硬化症、肌肉萎縮症、重症肌無力、肌病、肌炎、周邊神經病變或脊髓性肌肉萎縮症。在一些具體實例中,該肌肉疾病為杜氏肌肉萎縮症(Duchenne muscular dystrophy),視需要其中該個體具有肌肉萎縮蛋白(dystrophin)基因之突變。在一些具體實例中,該肌肉疾病為肢帶型肌肉萎縮症。在一些具體實例中,該肌肉疾病為X性聯肌微管性肌病,視需要其中該個體具有MTM1基因之突變。
在一些具體實例中,該組成物係藉由皮下注射、藉由肌肉內注射、藉由靜脈內注射、藉由腹膜內注射或經口投予至該個體。
在一些具體實例中,該接觸為試管內(in vitro)或活體外(ex vivo)的。
本發明至少部分地基於適用於遞送各種負荷(cargo)至特定細胞從而促進轉殖基因在其中表現之腺相關病毒(AAV)殼體蛋白、粒子、基因體、核酸載體及質體的研發。本發明至少部分地係關於以下發現:將AAVrh74殼體蛋白中之胺基酸取代及/或AAV核酸載體中之核苷酸序列修飾(例如取代或缺失)併入導致改善之轉導效率及/或轉殖基因表現。本文所揭示之AAV殼體蛋白、粒子、基因體、核酸載體及質體可用於多種應用中,包括(但不限於)組成物及方法(例如治療方法)。本文所揭示之治療方法包括適用於治療有需要之個體之疾病(例如肌肉病症,諸如肌肉萎縮症)的治療方法。
本文提供組成物,其包括AAV殼體蛋白、AAV粒子、包含於AAV粒子內之核酸,該等核酸包含一或多個ITR中之一或多個修飾;及使用該等組成物轉導目標細胞之方法(例如用於治療個體之疾病或病況)。
殼體蛋白
本文提供一種AAV殼體蛋白,其具有一或多個由胺基酸取代表徵之突變。在一些具體實例中,本文所揭示之AAV殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665或Y733的一或多個位置處包含胺基酸取代。在一些具體實例中,胺基酸取代係選自Y447F、T494V、K547R、N665R及/或Y733F。在一些具體實例中,本文所揭示之AAV殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447及Y733;Y447、Y733及N665;Y447、Y733及T494;Y447、Y733及K547;或Y447、Y733、N665、T494及K547的位置處包含胺基酸取代。在一些具體實例中,本文所揭示之AAV殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F及Y733F;Y447F、Y733F及N665R;Y447F、Y733F及T494V;Y447F、Y733F及K547R;或Y447F、Y733F、N665R、T494V及K547R的位置處包含胺基酸取代。
在一些具體實例中,如本文所揭示之AAV殼體蛋白為VP1蛋白、VP2蛋白或VP3蛋白。VP1、VP2及VP3殼體蛋白各自由AAV基因體之同一區段編碼,且基於替代性mRNA剪接而在其N端方面不同。
AAVrh74 殼體蛋白之胺基酸序列之實例: 編碼 AAVrh74 殼體蛋白之核苷酸序列之實例:
不同殼體蛋白VP1、VP2及VP3根據全長VP1蛋白之編號定義。在一些具體實例中,對於AAVrh74殼體蛋白,VP1殼體蛋白由SEQ ID NO: 1之胺基酸1-738定義;VP2殼體蛋白由SEQ ID NO: 1之胺基酸138-738定義;且VP3殼體蛋白由SEQ ID NO: 1之胺基酸204-738定義。根據VP1序列提供AAV殼體蛋白之編號。舉例而言,Y447係指VP1蛋白中之SEQ ID NO: 1之位置447處之酪胺酸或VP2或VP3蛋白中之對應的酪胺酸。類似地,T494、K547、N665及Y733分別係指VP1蛋白中之SEQ ID NO: 1之位置494處之蘇胺酸、位置547處之離胺酸、位置665處之天冬醯胺及位置733處之酪胺酸,或VP2或VP3蛋白中之對應的胺基酸。
本文所揭示之AAV殼體蛋白可具有任何血清型,或可為嵌合殼體蛋白(亦即,包含來自具有兩種或更多種血清型之殼體蛋白之區段)。在一些具體實例中,本文所揭示之殼體蛋白為AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAVrh10或AAVrh74殼體蛋白。在一些具體實例中,如本文所提供之AAV殼體蛋白具有血清型rh74。具有其他AAV血清型之殼體蛋白之胺基酸序列為已知的且可使用此項技術中已知之技術與SEQ ID NO: 1(AAVrh74殼體蛋白)比對。下文提供具有各種血清型之AAV殼體蛋白之胺基酸序列的實例:
野生型 AAV1 殼體蛋白之實例 野生型 AAV2 殼體蛋白之實例 野生型 AAV3 殼體蛋白之實例 野生型 AAV4 殼體蛋白之實例 野生型 AAV5 殼體蛋白之實例 野生型 AAV6 殼體蛋白之實例 野生型 AAV7 殼體蛋白之實例 野生型 AAV8 殼體蛋白之實例 野生型 AAV9 殼體蛋白之實例 野生型 AAV10 殼體蛋白之實例 野生型 AAV11 殼體蛋白之實例 野生型 AAV12 殼體蛋白之實例 野生型 AAVrh10 殼體蛋白之實例
本文亦提供編碼殼體蛋白之核酸。核酸可包含編碼此處所揭示之殼體蛋白(例如包含一或多個胺基酸取代之殼體蛋白)的序列。編碼本文所揭示之殼體蛋白的序列可由所屬技術領域中具有通常知識者藉由已知方法測定。編碼殼體蛋白之核酸可包含啟動子或其他可操作地連接至編碼序列的調節序列。編碼殼體蛋白之核酸可呈質體、mRNA或能夠由宿主細胞之酶或機構使用以產生殼體蛋白的另一核酸形式。如本文所提供之編碼殼體蛋白之核酸可用於製造AAV粒子,該等AAV粒子可用於將基因遞送至細胞。製造AAV粒子之方法為此項技術中已知的。舉例而言,參見
Scientific Reports第9卷, 文章編號:13601 (2019);
Methods Mol Biol.2012; 798: 267-284;及www.thermofisher.com/us/en/home/clinical/cell-gene-therapy/gene-therapy/aav-production-workflow.html。編碼殼體蛋白之核酸的例示序列提供於下文中。
編碼AAV1殼體蛋白之核苷酸序列之實例:
編碼AAV2殼體蛋白之核苷酸序列之實例:
編碼AAV3殼體蛋白之核苷酸序列之實例:
編碼AAV4殼體蛋白之核苷酸序列之實例:
編碼AAV5殼體蛋白之核苷酸序列之實例:
編碼AAV6殼體蛋白之核苷酸序列之實例:
編碼AAV7殼體蛋白之核苷酸序列之實例:
編碼AAV8殼體蛋白之核苷酸序列之實例:
編碼AAV9殼體蛋白之核苷酸序列之實例:
編碼AAV10殼體蛋白之核苷酸序列之實例:
核酸載體
根據一些態樣,本文提供核酸載體,其可藉由野生型AAV殼體或如本文所提供之AAV殼體中之任一者(例如,包含一或多個胺基酸取代之殼體蛋白)包殼。在一些具體實例中,如本文所提供之核酸載體包含第一反向末端重複序列(ITR)及第二ITR。在一些具體實例中,第一ITR經修飾。在一些具體實例中,第二ITR經修飾。在一些具體實例中,ITR之修飾包含整個D序列之取代或D序列之一部分之取代。在一些具體實例中,ITR之修飾包含整個D序列(例如左側ITR或右側ITR之D序列)之缺失或D序列之部分(例如相對於核酸載體之末端,ITR之遠端10個核苷酸)之缺失。舉例而言,ITR之修飾可在一些具體實例中包含D序列之1-20個核苷酸之缺失或取代。在一些具體實例中,相對於核酸載體之末端,D序列之遠端1、2、3、4、5、6、7、8、9、10、11、12、13、14或15個核苷酸缺失或經取代。在一些具體實例中,相對於核酸載體之末端,D序列之遠端10個核苷酸缺失或經取代。在一些具體實例中,D序列中間的1、2、3、4、5、6、7、8、9、10、11、12、13、14或15個核苷酸缺失或經取代(例如自D序列之3'或5'端的1、2、3、4、5、6、7、8、9或10個核苷酸開始的1、2、3、4、5、6、7、8、9、10、11、12、13、14或15個連續核苷酸)。在一些具體實例中,相對於核酸載體之末端,D序列之近端1、2、3、4、5、6、7、8、9、10、11、12、13、14或15個核苷酸缺失或經取代。在一些具體實例中,相對於核酸載體之末端,D序列之近端10個核苷酸缺失或經取代。在一些具體實例中,D序列包含SEQ ID NO: 16中提供之序列。在一些具體實例中,D序列由SEQ ID NO: 16中提供之序列定義。在其中ITR之一部分或整個D序列(例如本文所述之核酸載體之左側ITR或右側ITR的D序列)經取代之具體實例中,經取代之序列可為本文所述之任何替代序列,諸如S序列或GRE。
核酸載體可包含一或多個編碼目標基因(例如目標蛋白質或多肽)之異源核酸序列及一或多個包含側接一或多個異源核酸序列之反向末端重複(ITR)序列(例如野生型ITR序列或經修飾ITR序列)的序列。在一些具體實例中,核酸載體在AAV殼體內包殼從而形成AAV粒子。在一些具體實例中,本文所揭示之核酸載體藉由野生型AAVrh74殼體或本文所揭示之另一AAV殼體(諸如包含一或多個胺基酸取代之AAV殼體)包殼。
在一些具體實例中,核酸載體包含原生AAV基因或原生AAV核苷酸序列。在一些具體實例中,可自核酸載體移除一或多種原生AAV基因或原生AAV核苷酸序列。在一些具體實例中,可自核酸載體移除一或多種原生AAV基因或原生AAV核苷酸序列且用目標基因置換。
核酸載體可具有任何AAV血清型,諸如AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAVrh10或AAVrh74,或血清型之組合。在一些具體實例中,AAV殼體內之核酸載體包殼形成假型AAV粒子,使得核酸載體具有不同於在其中經包殼之AAV殼體的血清型。舉例而言,具有血清型AAV2之核酸載體可在具有血清型AAVrh74之殼體內包殼。
在一些具體實例中,核酸載體為單股的且包含第一反向末端重複序列(ITR)及第二ITR。如本文所揭示,第一ITR係指核酸載體之5'端處的ITR,且第二ITR係指核酸載體之3'端處的ITR。呈天然或野生型形式之各ITR的長度為或為約145個核苷酸(例如約140個核苷酸、約145個核苷酸、約150個核苷酸、約155個核苷酸、約160個核苷酸或約165個核苷酸)且包含D序列。各ITR可獨立地具有任何AAV血清型(例如AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、AAV12、AAV13、AAVrh10或AAVrh74),或兩個ITR可具有相同血清型。ITR描述於例如Grimm等人.
J. Virol.80(1):426-439 (2006)中。例示性左側ITR序列提供於下文中。右側ITR具有一個核苷酸序列,該核苷酸序列為對應左側ITR之反向互補序列(例如AAV2右側ITR具有一個核苷酸序列,該核苷酸序列為AAV2左側ITR之反向互補序列)。
野生型 AAV1 左側 ITR 之實例: 野生型 AAV2 左側 ITR 之實例: 野生型 AAV3 左側 ITR 之實例: 野生型 AAV4 左側 ITR 之實例: 野生型 AAV5 左側 ITR 之實例: 野生型 AAV6 左側 ITR 之實例:
在一些具體實例中,核酸載體包含ITR之D序列之修飾(例如缺失或取代)。在一些具體實例中,核酸載體包含左側ITR之D序列之修飾(例如缺失或取代)。在一些具體實例中,核酸載體包含右側ITR之D序列之修飾(例如缺失或取代)。在一些具體實例中,核酸載體包含左側ITR及右側ITR兩者之D序列的修飾(例如缺失或取代)。在一些具體實例中,核酸載體包含左側ITR或右側ITR之修飾(例如缺失或取代),但不包含兩者(亦即核酸載體包含僅一個ITR之修飾)。
ITR序列包含在形成回文雙股T形髮夾結構之AAV基因體之5'或3'端處的末端序列,及保持單股(亦即,不為T形髮夾結構之一部分)的另一序列,稱為D序列。ITR之D序列典型地為位於ITR之遠端(相對於核酸載體之末端)末端(亦即左側ITR之3'端或右側ITR之5'端)處之大約20個(例如約15、16、17、18、19、20、21、22、23、24或25個)核苷酸,且對應於SEQ ID NO: 12之野生型AAV2左側ITR之CTCCATCACTAGGGGTTCCT之序列(SEQ ID NO: 16)。在一些具體實例中,ITR之D序列包含核酸序列CTCCATCACTAGGGGTTCCT(SEQ ID NO: 16)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
在一些具體實例中,本文所揭示之核酸載體之ITR(例如第一ITR或第二ITR)之D序列係經完全或部分移除。在一些具體實例中,本文所揭示之核酸載體之兩個ITR之D序列係經完全或部分移除。在一些具體實例中,ITR(例如第一ITR或第二ITR)之D序列係經非AAV序列(亦即不來自AAV核酸之核苷酸序列)完全或部分置換。在一些具體實例中,ITR(例如第一ITR或第二ITR)之D序列係經S序列完全或部分置換。在一些具體實例中,S序列包含核酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。在一些具體實例中,S序列與序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)具有至少70%一致性(例如至少75%一致性、至少80%一致性、至少85%一致性、至少90%一致性、至少91%一致性、至少92%一致性、至少93%一致性、至少94%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性或至少99%一致性)。在一些具體實例中,S序列與序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)具有小於95%一致性(例如小於90%一致性、小於85%一致性、小於80%一致性、小於75%一致性或小於70%一致性)。在一些具體實例中,S序列與序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)具有約70%至約95%一致性(例如約95%一致性、約90%一致性、約85%一致性、約80%一致性、約75%一致性或約70%一致性)。在一些具體實例中,S序列相對於序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)具有少於6個錯配(例如少於5個、少於4個、少於3個、少於2個、1個或無錯配)。在一些具體實例中,S序列相對於序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)具有1、2、3、4、5或6個錯配。在一些具體實例中,S序列之長度為或約為15、16、17、18、19、20、21、22、23、24或25個核苷酸。
在一些具體實例中,ITR(例如第一ITR或第二ITR)之D序列係經糖皮質激素受體結合元件(GRE)完全或部分地取代。在一些具體實例中,將GRE插入至核酸載體中(亦即而非取代ITR之一部分)。舉例而言,GRE可插入ITR之D序列內部、ITR之D序列上游或ITR之D序列下游。
糖皮質激素受體結合元件亦稱為糖皮質激素反應性元件或糖皮質激素反應元件。GRE為糖皮質激素受體結合之核苷酸序列,其在其原生基因座中在基因之轉錄起始位點上游一般為約100至2,000個鹼基對。本發明部分地基於以下發現:AAV2 D序列之一部分與GRE之共通半位點共用部分同源性,且在AAV2感染或轉導之後活化糖皮質激素受體信號傳導路徑。在一些具體實例中,用GRE取代AAV ITR之一部分或全部D序列增加由核酸載體編碼之轉殖基因的表現,該核酸載體在AAV粒子內包殼。
在一些具體實例中,GRE包含以下、基本上由以下組成或由以下組成:核酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸),其中各N獨立地為T、C、G或A。在一些具體實例中,GRE與序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有至少70%一致性(例如至少75%一致性、至少80%一致性、至少85%一致性、至少90%一致性、至少91%一致性、至少92%一致性、至少93%一致性、至少94%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性或至少99%一致性),其中各N獨立地為T、C、G或A。在一些具體實例中,GRE與序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有小於95%一致性(例如小於90%一致性、小於85%一致性、小於80%一致性、小於75%一致性或小於70%一致性),其中各N獨立地為T、C、G或A。在一些具體實例中,GRE與序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有約70%至約95%一致性(例如約95%一致性、約90%一致性、約85%一致性、約80%一致性、約75%一致性或約70%一致性),其中各N獨立地為T、C、G或A。在一些具體實例中,GRE相對於序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列具有少於6個錯配(例如少於5個、少於4個、少於3個、少於2個、1個或無錯配),其中各N獨立地為T、C、G或A。在一些具體實例中,GRE相對於序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列具有1、2、3、4、5或6個錯配,其中各N獨立地為T、C、G或A。在一些具體實例中,GRE之長度為或約為8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核苷酸。在一些具體實例中,GRE長度為15個核苷酸。在一些具體實例中,GRE包含核酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
在一些具體實例中,GRE包含核酸序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)、基本上由該核苷酸序列或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)組成或由該核苷酸序列或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)組成,其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE與序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有至少70%一致性(例如至少75%一致性、至少80%一致性、至少85%一致性、至少90%一致性、至少91%一致性、至少92%一致性、至少93%一致性、至少94%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性或至少99%一致性),其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE與序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有小於95%一致性(例如小於90%一致性、小於85%一致性、小於80%一致性、小於75%一致性或小於70%一致性),其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE與序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有約70%至約95%一致性(例如約95%一致性、約90%一致性、約85%一致性、約80%一致性、約75%一致性或約70%一致性),其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE相對於序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列具有小於6個錯配(例如小於5個、小於4個、小於3個、小於2個、1個或無錯配),其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE相對於序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列具有1、2、3、4、5或6個錯配,其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE之長度為或約為8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核苷酸。在一些具體實例中,GRE長度為15個核苷酸。在一些具體實例中,GRE包含核酸序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A,且其中Y為T或C。
在一些具體實例中,GRE包含核酸序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)、基本上由該核苷酸序列或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)組成或由該核苷酸序列或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)組成。在一些具體實例中,GRE與序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有至少70%一致性(例如至少75%一致性、至少80%一致性、至少85%一致性、至少90%一致性、至少91%一致性、至少92%一致性、至少93%一致性、至少94%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性或至少99%一致性)。在一些具體實例中,GRE與序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有小於95%一致性(例如小於90%一致性、小於85%一致性、小於80%一致性、小於75%一致性或小於70%一致性)。在一些具體實例中,GRE與序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列之至少8個連續核苷酸(例如8、9、10、11、12、13、14或15個連續核苷酸)具有約70%至約95%一致性(例如約95%一致性、約90%一致性、約85%一致性、約80%一致性、約75%一致性或約70%一致性)。在一些具體實例中,GRE相對於序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列具有少於6個錯配(例如少於5個、少於4個、少於3個、少於2個、1個或無錯配)。在一些具體實例中,GRE相對於序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列具有1、2、3、4、5或6個錯配。在一些具體實例中,GRE之長度為或約為8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核苷酸。在一些具體實例中,GRE長度為15個核苷酸。在一些具體實例中,GRE包含核酸序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成。
根據本發明適用之GRE序列之另一實例為5'-GGCACAGTGTGGTCT-3'(SEQ ID NO: 21)。可使用其他GRE序列,包括例如此項技術中已知之GRE序列。
在一些具體實例中,取代D序列包含用不同核苷酸序列(例如S序列或其部分,或GRE或其部分)取代D序列之至少5個核苷酸(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個核苷酸)。在一些具體實例中,取代D序列包含取代D序列之10個核苷酸。在一些具體實例中,取代D序列包含取代D序列之最接近3'端之10個核苷酸。在一些具體實例中,取代D序列包含取代D序列之最接近5'端之10個核苷酸。在一些具體實例中,取代D序列包含取代D序列之內部部分(亦即不包含末端核苷酸),諸如取代D序列之內部部分之10個核苷酸。
在一些具體實例中,D序列之缺失包含缺失D序列之至少5個核苷酸(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個核苷酸)。在一些具體實例中,D序列之缺失包含缺失D序列之10個核苷酸。在一些具體實例中,D序列之缺失包含缺失D序列之最接近3'端之10個核苷酸。在一些具體實例中,D序列之缺失包含缺失D序列之最接近5'端之10個核苷酸。在一些具體實例中,D序列之缺失包含缺失D序列之內部部分(亦即不包含末端核苷酸),諸如缺失D序列之內部部分之10個核苷酸。
在一些具體實例中,如本文所揭示之核酸載體包含一或多種調節元件。調節元件係指核酸載體之核苷酸序列或結構組分,其涉及調節核酸載體之組分(例如包含於其中之目標基因)之表現。調節元件包括(但不限於)啟動子、強化子、緘默子、絕緣子、反應元件、起始位點、終止信號及核糖體結合位點。
啟動子包括持續型啟動子、可誘導型啟動子、組織專一性啟動子、細胞類型專一性啟動子及合成啟動子。舉例而言,本文所揭示之核酸載體可包括病毒啟動子或來自哺乳動物基因之通常在促進轉錄方面具有活性的啟動子。持續型病毒啟動子之非限制性實例包括單純疱疹病毒(Herpes Simplex virus;HSV)、胸苷激酶(thymidine kinase;TK)、勞氏肉瘤病毒(Rous Sarcoma Virus;RSV)、猿猴病毒40(Simian Virus 40;SV40)、小鼠乳房腫瘤病毒(Mouse Mammary Tumor Virus;MMTV)、Ad E1A及巨細胞病毒(cytomegalovirus;CMV)啟動子。持續型哺乳動物啟動子之非限制性實例包括各種管家基因啟動子,如
β-肌動蛋白啟動子所例示。
可誘導型啟動子或其他可誘導型調節元件亦可用於達成所需目標基因(例如目標蛋白質或多肽)的表現量。適合的可誘導型啟動子之非限制性實例包括來自諸如細胞色素P450基因、熱休克蛋白基因、金屬硫蛋白基因及激素可誘導型基因之基因的彼等啟動子,諸如雌激素基因啟動子。可誘導型啟動子之另一實例為對四環素起反應之tetVP16啟動子。
本文中亦涵蓋組織專一性啟動子或其他組織專一性調節元件。可使用之此類啟動子之非限制性實例包括肌肉專一性啟動子。
合成啟動子亦涵蓋於本文中。合成啟動子可包含例如已知啟動子、調節元件、轉錄因子結合位點、強化子元件、抑制因子元件及其類似物之區域。
在一些具體實例中,本文所提供之核酸包含編碼產物(例如蛋白質或多肽產物)之核苷酸序列。在一些具體實例中,核苷酸序列包含目標基因之核苷酸序列。在一些具體實例中,目標基因編碼治療或診斷蛋白或多肽。在一些具體實例中,治療或診斷蛋白或多肽為抗體、肽體、生長因子、凝血因子、激素、膜蛋白、細胞介素、趨化介素、作用於細胞表面受體或離子通道之活化或抑制性肽、靶向細胞內過程之細胞滲透性肽、溶栓劑、酶、骨形態生成蛋白、核酸酶、用於基因編輯之蛋白質、Fc融合蛋白、抗凝血劑或可使用實驗室測試偵測之蛋白質或多肽。在一些具體實例中,視需要除用於基因編輯之蛋白質之外,本文中提供之核酸包含編碼引導RNA或其他用於基因編輯之核酸的核苷酸序列。
在一些具體實例中,由本文揭示之核酸編碼之產物為可偵測分子。可偵測分子為(例如使用裸眼、在顯微鏡下或使用諸如攝影機之光偵測裝置)可觀測到之分子。在一些具體實例中,可偵測分子為螢光分子、生物發光分子或提供顏色之分子(例如β-半乳糖苷酶、β-內醯胺酶、β-葡糖醛酸酶或球形烯醇(spheroidenone))。在一些具體實例中,可偵測分子為螢光、生物發光或酶促蛋白或其功能性肽或多肽。
在一些具體實例中,螢光蛋白為藍色螢光蛋白、青色螢光蛋白、綠色螢光蛋白、黃色螢光蛋白、橙色螢光蛋白、紅色螢光蛋白或其功能性肽或多肽。藍色螢光蛋白可為石青(azurite)、EBFP、EBFP2、mTagBFP或Y66H。青色螢光蛋白可為ECFP、AmCyan1、Cerulean、CyPet、mECFP、Midori-ishi Cyan、mTFP1或TagCFP。綠色螢光蛋白可為AcGFP、Azami Green、EGFP、Emarald、GFP或GFP之突變形式(例如,GFP-S65T、mWasabi、Stemmer、Superfolder GFP、TagGFP、TurboGFP或ZsGreen)。黃色螢光蛋白可為EYFP、mBanana、mCitrine、PhiYFp、TagYFP、Topaz、Venus、YPet或ZsYellow1。橙色螢光蛋白可為DsRed、RFP、DsRed2、DsRed-Express、Ds-Red-單體、Tomato、tdTomato、Kusabira Orange、mKO2、mOrange、mOrange2、mTangerine、TagRFP或TagRFP-T。紅色螢光蛋白可為AQ142、AsRed2、dKeima-Tandem、HcRed1、tHcRed、Jred、mApple、mCherry、mPlum、mRasberry、mRFP1、mRuby或mStrawberry。
在一些具體實例中,可偵測分子為生物發光蛋白質或其功能肽或多肽。生物發光蛋白質之非限制性實例為螢火蟲螢光素酶、叩頭蟲(click-beetle)螢光素酶、海腎(Renilla)螢光素酶及來自纖細葉蟬(Oplophorus gracilirostris)之螢光素酶。
在一些具體實例中,可偵測分子可為可使用此項技術中已知之方法偵測的任何多肽或蛋白質。偵測之非限制性方法為螢光成像、發光成像、亮視野成像,且包括藉由免疫螢光或免疫組織化學染色促進之成像。
AAV粒子、核酸載體及殼體蛋白之額外特徵描述於美國專利公開案第2017/0356009號中,其內容以全文引用之方式併入本文中。
AAV 粒子
根據一些態樣,本文提供AAV粒子。AAV粒子為60個個別殼體蛋白次單位以形成能夠保護4.7 kb單股DNA基因體之非包膜T-1二十面體晶格的超分子組裝體。成熟AAV粒子之直徑為約20 nm,且其殼體由三個結構殼體蛋白VP1、VP2及VP3形成,該等殼體蛋白分別具有87、73及62 kDa之分子質量,呈約1:1:18之比率。60個殼體蛋白以反平行β股類桶狀(barreloid)排列佈置,產生規定的向性及高耐降解性。
在一些具體實例中,AAV粒子包含空殼體(例如無負荷之殼體)。在一些具體實例中,AAV粒子包含使核酸(例如,包含目標基因的核酸載體,諸如本文所揭示之核酸載體)包殼之殼體。在一些具體實例中,AAV殼體內之核酸包殼以產生包含本文所揭示之核酸載體的AAV粒子。在一些具體實例中,本文所揭示之AAV粒子包含殼體蛋白,其包含一或多個突變,例如一或多個胺基酸取代。
本文中經考慮,本文所揭示之任何殼體蛋白突變(例如,胺基酸取代)可與本文所揭示之任何核酸載體修飾(例如,序列缺失或取代)組合。舉例而言,本文所述之AAV粒子可具有AAVrh74殼體蛋白(例如野生型AAVrh74殼體蛋白或包含一或多個胺基酸取代之AAVrh74殼體蛋白)及包含修飾(例如D序列之缺失或取代,及/或非AAV序列(諸如GRE)之插入)之AAV核酸載體(例如AAV2核酸載體)。
在一些具體實例中,本文所揭示之AAV粒子包含殼體蛋白,該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及Y733之一或多個位置處包含胺基酸取代。在一些具體實例中,本文所揭示之AAV粒子包含殼體蛋白,該殼體蛋白包含對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V、K547R、N665R及Y733F的一或多個胺基酸取代。
在一些具體實例中,本文所揭示之AAV粒子包含殼體蛋白,該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及Y733之一或多個位置處包含胺基酸取代;且進一步包含核酸載體,該核酸載體包含ITR之D序列之修飾(例如缺失或取代)(例如右側ITR、左側ITR或右側ITR及左側ITR兩者之D序列之修飾)。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及Y733之一或多個位置處包含胺基酸取代;及核酸載體,該核酸載體包含用S序列取代ITR之D序列。在一些具體實例中,胺基酸取代對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V、K547R、N665R及Y733F。在一些具體實例中,S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經S序列取代。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白包含對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F及Y733F的胺基酸取代;及核酸載體,該核酸載體包含經S序列取代ITR之D序列。在一些具體實例中,S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經S序列取代。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白包含對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V及Y733F的胺基酸取代;及核酸載體,該核酸載體包含經S序列取代ITR之D序列。在一些具體實例中,S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經S序列取代。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及Y733的一或多個位置處包含胺基酸取代;及核酸載體,該核酸載體包含核酸載體之ITR之所有或部分D序列的缺失。在一些具體實例中,胺基酸取代對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F及Y733F。在一些具體實例中,胺基酸取代對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V及Y733F。在一些具體實例中,胺基酸取代對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V、K547R、N665R及Y733F。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及Y733之一或多個位置處包含胺基酸取代;及核酸載體,該核酸載體包含經GRE取代ITR之D序列。在一些具體實例中,胺基酸取代對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V、K547R、N665R及Y733F。在一些具體實例中,GRE包含核酸序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE包含核酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。在一些具體實例中,GRE包含核酸序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經GRE取代。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白包含對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F及Y733F的胺基酸取代;及核酸載體,該核酸載體包含經GRE取代ITR之D序列。在一些具體實例中,GRE包含核酸序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE包含核酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。在一些具體實例中,GRE包含核酸序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經GRE取代。
在一些具體實例中,AAV粒子包含殼體蛋白,該殼體蛋白包含對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447F、T494V及Y733F的胺基酸取代;及核酸載體,該核酸載體包含經GRE取代ITR之D序列。在一些具體實例中,GRE包含核酸序列GGTACANNNTGTYCT(SEQ ID NO: 19)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A,且其中Y為T或C。在一些具體實例中,GRE包含核酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。在一些具體實例中,GRE包含核酸序列AGAACAGGATGTTCT(SEQ ID NO: 20)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成。在一些具體實例中,ITR之部分或全部D序列(例如左側ITR之D序列)經GRE取代。
在一些具體實例中,本文揭示之AAV粒子為複製型的。複製型AAV粒子能夠在宿主細胞(例如個體內之宿主細胞或培養物中之宿主細胞)內複製。在一些具體實例中,本文所揭示之AAV粒子為非複製的。非複製AAV粒子不能夠在宿主細胞(例如,個體內之宿主細胞或培養物中之宿主細胞)內複製,但可感染宿主且將遺傳組分併入宿主之基因體中以用於表現。在一些具體實例中,本文所揭示之AAV粒子能夠感染宿主細胞。在一些具體實例中,本文所揭示之AAV粒子能夠促進遺傳組分穩定整合至宿主細胞之基因體中。在一些具體實例中,本文所揭示之AAV粒子不能夠促進遺傳組分整合至宿主細胞之基因體中。
在一些具體實例中,本文所揭示之AAV粒子包含核酸載體。在一些具體實例中,核酸載體包含兩個反向末端重複序列(ITR),該等反向末端重複序列鄰接於編碼目標基因之序列的末端。在一些具體實例中,核酸載體包含於AAV之ssDNA基因體內。在一些具體實例中,本文所揭示之AAV粒子包含一個單股DNA。在一些具體實例中,本文所揭示之AAV粒子包含兩個互補DNA股,形成自互補AAV(scAAV)。
在一些具體實例中,可包含於AAV粒子(例如WT粒子或包含殼體之粒子,該殼體包含如本文所揭示之任何一或多個突變)中的核酸載體包含ITR,該ITR包含ITR之部分或所有D序列之修飾(例如缺失或取代)。在一些具體實例中,ITR之D序列之一部分或全部經S序列或其一部分取代。在一些具體實例中,ITR之D序列之一部分或全部經GRE或其一部分取代。在一些具體實例中,ITR之D序列之一部分或全部缺失。此類修飾(例如缺失及取代)之進一步描述提供於本文別處。
本文中所揭示之AAV粒子可具有任何AAV血清型(例如AAV血清型1、2、3、4、5、6、7、8、9、10、11、12或13),包括任何衍生物(包括非天然存在之血清型變體)或假型。衍生物及假型之非限制性實例包括AAV2-AAV3雜合體、AAVrh.10、AAVhu.14、AAV3a/3b、AAVrh32.33、AAV-HSC15、AAV-HSC17、AAVhu.37、AAVrh.8、CHt-P6、AAV2.5、AAV6.2、AAV2i8、AAV-HSC15/17、AAVM41、AAV9.45、AAV2.5T、AAV-HAE1/2、AAV純系32/83、AAVShH10、AAV2.15、AAV2.4、AAVM41及AAVr3.45。此類AAV血清型及衍生物/假型,及產生該等衍生物/假型之方法為此項技術中已知的(參見例如
Mol. Ther.2012年4月;20(4):699-708. 數位物件識別碼:10.1038/mt.2011.287. Epub 2012年1月24日. The AAV vector toolkit: poised at the clinical crossroads. Asokan A, Schaffer DV, Samulski RJ.)。在一些具體實例中,AAV粒子為假型AAV粒子,其包含核酸載體,該核酸載體包含來自一個血清型(例如AAV2或AAV3)之ITR;及殼體,該殼體包含來源於另一血清型(亦即分別除AAV2或AAV3以外之血清型)之殼體蛋白。用於產生及使用假型rAAV載體之方法在此項技術中已知(參見例如Duan等人,
J. Virol., 75:7662-7671 (2001);Halbert等人,
J. Virol., 74:1524-1532 (2000);Zolotukhin等人,
Methods, 28:158-167 (2002);及Auricchio等人,
Hum. Molec. Genet., 10:3075-3081 (2001))。
在一些具體實例中,本文揭示之AAV粒子為重組AAV(rAAV)粒子,例如包含重組核酸或轉殖基因。
本文所述之修飾之任何組合(例如殼體蛋白修飾、D序列之缺失或取代及/或非AAV序列插入AAV基因體中)可產生累加或協同效應,其中所得組合之有益特性分別等於或大於個別修飾之作用之總和。舉例而言,相對於對應野生型AAV粒子,包含經修飾殼體蛋白及經修飾基因體的AAV粒子可在轉導效率、轉殖基因表現及/或包裝效率方面具有改善,該等改善等於個別殼體蛋白修飾及基因體修飾賦予之改善的總和,或大於由個別修飾賦予之改善的總和。
轉導效率
根據一些態樣,本文所揭示之AAV粒子的轉導效率相對於對應野生型AAV粒子經修飾。AAV粒子之轉導效率可例如藉由在使細胞與AAV粒子接觸之後比較目標基因在細胞中之表現,或藉由在使細胞群體與AAV粒子接觸之後量測每個細胞之病毒基因體複本之數目來確定。在一些具體實例中,如本文所揭示之AAV粒子(例如包含經修飾殼體蛋白(例如包含一或多個胺基酸取代)之AAV粒子)、經修飾核酸載體(例如藉由D序列之缺失及/或取代修飾)或經修飾殼體蛋白(例如包含一或多個胺基酸取代)及經修飾核酸載體(例如藉由D序列之缺失及/或取代修飾)兩者)的轉導效率高於對應野生型AAV粒子之轉導效率。在一些具體實例中,如本文所揭示之AAV粒子的轉導效率比對應野生型AAV粒子之轉導效率高至少5%(例如高至少10%、高至少15%、高至少20%、高至少25%、高至少30%、高至少35%、高至少40%、高至少50%、高至少60%、高至少70%、高至少80%、高至少90%、高至少100%、高至少150%、高至少200%、高至少250%或更高)。在一些具體實例中,如本文所揭示之AAV粒子之轉導效率比對應野生型AAV粒子之轉導效率高至少1.5倍(例如高至少2倍、高至少2.5倍、高至少3倍、高至少3.5倍、高至少4倍、高至少4.5倍、高至少5倍、高至少5.5倍、高至少6倍、高至少6.5倍、高至少7倍、高至少7.5倍、高至少8倍、高至少8.5倍、高至少9倍、高至少9.5倍、高至少10倍、高至少10.5倍、高至少11倍、高至少11.5倍、高至少12倍、高至少12.5倍、高至少13倍、高至少13.5倍、高至少14倍、高至少14.5倍、高至少15倍、高至少15.5倍、高至少16倍、高至少16.5倍、高至少17倍、高至少17.5倍、高至少18倍、高至少18.5倍、高至少19倍、高至少19.5倍、高至少20倍或更高)。在一些具體實例中,如本文所揭示之AAV粒子的轉導效率相對於對應野生型AAV粒子未經修飾。
轉殖基因表現
根據一些態樣,由包含本文揭示之修飾(例如序列,諸如D序列之缺失或取代)之核酸載體編碼的轉殖基因之表現相對於由不包含該修飾之核酸載體編碼的轉殖基因之表現改變。在一些具體實例中,轉殖基因表現之此類改變基於每個核酸載體複本數(例如,當相對於細胞中核酸載體之總量標準化時,轉殖基因在細胞中之表現改變)。舉例而言,在一些具體實例中,如本文中所揭示之經修飾之AAV粒子相對於不包含相同修飾但將可比數目之病毒基因體遞送至細胞的對應AAV粒子產生較大轉殖基因表現。相對轉殖基因表現量可例如藉由以下方式測定:在使細胞與包含編碼轉殖基因之經修飾核酸載體的AAV粒子接觸之後,藉由此項技術中已知之方法量測轉殖基因在細胞中之表現,且比較在與包含核酸載體(不包含修飾)的AAV粒子接觸之另一細胞中之等效量測值。
在一些具體實例中,來自如本文所揭示之經修飾核酸載體(例如,藉由D序列之缺失及/或取代修飾)的轉殖基因表現高於來自不包含修飾之對應核酸載體的轉殖基因表現。在一些具體實例中,來自如本文所揭示之經修飾核酸載體的轉殖基因表現比來自不包含修飾之對應核酸載體的轉殖基因表現高至少5%(例如高至少10%、高至少15%、高至少20%、高至少25%、高至少30%、高至少35%、高至少40%、高至少50%、高至少60%、高至少70%、高至少80%、高至少90%、高至少100%、高至少150%、高至少200%、高至少250%或更高)。
在一些具體實例中,來自如本文所揭示之經修飾核酸載體的轉殖基因表現比來自不包含修飾之對應核酸載體的轉殖基因表現高至少1.5倍(例如高至少2倍、高至少2.5倍、高至少3倍、高至少3.5倍、高至少4倍、高至少4.5倍、高至少5倍、高至少5.5倍、高至少6倍、高至少6.5倍、高至少7倍、高至少7.5倍、高至少8倍、高至少8.5倍、高至少9倍、高至少9.5倍、高至少10倍、高至少10.5倍、高至少11倍、高至少11.5倍、高至少12倍、高至少12.5倍、高至少13倍、高至少13.5倍、高至少14倍、高至少14.5倍、高至少15倍、高至少15.5倍、高至少16倍、高至少16.5倍、高至少17倍、高至少17.5倍、高至少18倍、高至少18.5倍、高至少19倍、高至少19.5倍、高至少20倍或更高)。
在一些具體實例中,來自如本文中所揭示之經修飾核酸載體的轉殖基因表現相對於來自不包含修飾之對應核酸載體的轉殖基因表現不變化。
包裝效率
根據一些態樣,本文所揭示之AAV粒子的包裝效率相對於對應野生型AAV粒子經修飾。AAV粒子之包裝效率係指特定AAV殼體能夠使特定病毒基因體包殼之能力。包裝效率可藉由所屬技術領域中具有通常知識者,諸如藉由定量殼體與病毒基因體之比率來量測。(參見例如Grimm等人.
Gene Ther.6:1322-1330 (1999))。
在一些具體實例中,如本文所揭示之AAV粒子(例如包含經修飾殼體蛋白、經修飾核酸載體或經修飾殼體蛋白及經修飾核酸載體兩者之AAV粒子)的包裝效率高於對應野生型AAV粒子的包裝效率。在一些具體實例中,如本文所揭示之AAV粒子的包裝效率比對應野生型AAV粒子之包裝效率高至少5%(例如高至少10%、高至少15%、高至少20%、高至少25%、高至少30%、高至少35%、高至少40%、高至少50%、高至少60%、高至少70%、高至少80%、高至少90%、高至少100%、高至少150%、高至少200%、高至少250%或更高)。在一些具體實例中,如本文所揭示之AAV粒子的包裝效率比對應野生型AAV粒子之包裝效率高至少1.5倍(例如高至少2倍、高至少2.5倍、高至少3倍、高至少3.5倍、高至少4倍、高至少4.5倍、高至少5倍、高至少5.5倍、高至少6倍、高至少6.5倍、高至少7倍、高至少7.5倍、高至少8倍、高至少8.5倍、高至少9倍、高至少9.5倍、高至少10倍、高至少10.5倍、高至少11倍、高至少11.5倍、高至少12倍、高至少12.5倍、高至少13倍、高至少13.5倍、高至少14倍、高至少14.5倍、高至少15倍、高至少15.5倍、高至少16倍、高至少16.5倍、高至少17倍、高至少17.5倍、高至少18倍、高至少18.5倍、高至少19倍、高至少19.5倍、高至少20倍或更高)。
在一些具體實例中,如本文所揭示之AAV粒子(例如包含經修飾殼體蛋白、經修飾核酸載體或經修飾殼體蛋白及經修飾核酸載體兩者之AAV粒子)的包裝效率低於對應野生型AAV粒子之包裝效率。在一些具體實例中,如本文所揭示之AAV粒子的包裝效率相對於對應野生型AAV粒子之包裝效率減少至少5%(例如至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%或更多)。
在一些具體實例中,本文所揭示之AAV粒子的包裝效率相對於對應野生型AAV粒子未經修飾。
在一些具體實例中,相對於對應未經修飾或野生型AAV粒子(例如相同血清型之AAV粒子),如本文所揭示之AAV粒子之轉導效率及包裝效率經修飾(亦即增加或降低)。在一些具體實例中,如本文所揭示之AAV粒子的免疫原性相對於對應未經修飾或野生型AAV粒子(例如相同血清型之AAV粒子)經修飾。
醫藥組成物
本文所揭示之AAV粒子、殼體蛋白或核酸中之任一者可以包含於包含醫藥學上可接受之載劑的醫藥組成物內或可以包含於醫藥學上可接受之載劑內。術語「載劑(carrier)」係指包含AAV粒子、殼體蛋白或核酸或向個體投予之稀釋劑、佐劑、賦形劑或媒劑。此類醫藥載劑可為無菌液體,諸如水及油,包括石油之彼等,諸如礦物油、植物油(諸如花生油、大豆油及芝麻油)、動物油或合成來源之油。亦可採用鹽水溶液及右旋糖水溶液及甘油溶液作為液體載劑。醫藥學上可接受之載劑的非限制性實例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、澱粉、阿拉伯膠、磷酸鈣、海藻酸鹽、西黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、生理食鹽水、糖漿、甲基纖維素、乙基纖維素、羥丙基甲基纖維素、聚丙烯酸、潤滑劑(諸如滑石、硬脂酸鎂及礦物油)、潤濕劑、乳化劑、懸浮劑、防腐劑(諸如甲基-、乙基-及丙基-羥基-苯甲酸鹽)及pH調節劑(諸如無機及有機酸及鹼)以及其溶液或組成物。載劑之其他實例包括磷酸鹽緩衝鹽水、HEPES-緩衝鹽水及注射用水,其中任一者可視需要與二水合氯化鈣、無水磷酸二鈉、六水合氯化鎂、氯化鉀、磷酸二氫鉀、氯化鈉或蔗糖中之一或多者組合。可使用之載劑之其他實例包括生理食鹽水(例如滅菌的無熱原質生理食鹽水)、生理食鹽水緩衝液(例如,檸檬酸鹽緩衝液、磷酸鹽緩衝液、乙酸鹽緩衝液及碳酸氫鹽緩衝液)、胺基酸、尿素、醇、抗壞血酸、磷脂、蛋白質(例如,血清白蛋白)、EDTA、氯化鈉、脂質體、甘露糖醇、山梨糖醇及甘油。USP級載劑及賦形劑尤其適用於將AAV粒子遞送至人類個體。
通常,此類組成物可含有至少約0.1%之治療劑(例如AAV粒子)或更高,但活性成分之百分比當然可變化且可適宜地在總調配物之重量或體積之約1%或2%與約70%或80%或更高之間。自然地,可以使得將以任何給定單位劑量之化合物獲得適合劑量的此類方式製備各治療適用組成物中之治療劑(例如AAV粒子)的量。製備此類醫藥調配物之熟習此項技術者應考慮諸如溶解度、生物可用性、生物半衰期、投予途徑、產物存放期以及其他藥理學考慮因素之因素,且因此,可設計各種劑量及治療方案。
使細胞接觸之方法
根據一些態樣,本文提供使細胞與AAV粒子接觸之方法。使細胞接觸之方法可包含例如使培養物中之細胞與包含AAV粒子之組成物接觸。在一些具體實例中,使細胞接觸包含將包含AAV粒子之組成物添加至細胞培養物(例如組織培養盤或培養皿上之細胞培養物)之上清液中或將包含AAV粒子之組成物與細胞培養物(例如懸浮細胞培養物)混合。在一些具體實例中,使細胞接觸包含將包含AAV粒子之組成物與另一溶液(諸如細胞培養基)混合,且將細胞與該混合物一起培育。
在一些具體實例中,使細胞與AAV粒子接觸包含向細胞所位於之個體或裝置投予包含AAV粒子之組成物。在一些具體實例中,使細胞接觸包含將包含AAV粒子之組成物注射至細胞所位於之個體中。在一些具體實例中,使細胞接觸包含向細胞、或向細胞所存在之個體之組織中或在與其基本上相鄰處直接投予包含AAV粒子之組成物。
在一些具體實例中,「投予(administering/administration)」意謂以藥理學上適用之方式向個體提供物質。在一些具體實例中,rAAV粒子係向個體經腸投予的。在一些具體實例中,必需金屬元素之經腸投予為經口。在一些具體實例中,rAAV粒子係向個體非經腸投予的。在一些具體實例中,如下向個體投予rAAV粒子:皮下、眼內、玻璃體內、視網膜下、靜脈內(經靜脈內;IV)、腦室內、肌肉內、鞘內(鞘內;IT)、腦池內、腹膜內、經由吸入、局部或藉由直接注射至一或多個細胞、組織或器官。在一些具體實例中,藉由注射至肝動脈或門靜脈中來向個體投予rAAV粒子。
在一些具體實例中,向個體投予AAV粒子組成物以治療疾病或病況。為「治療」如本文所用之疾病,意謂降低個體所經歷之疾病或病症之至少一種病徵或症狀的頻率或嚴重程度。上文或本文在別處所描述之組成物典型地以有效量向個體投予,該有效量為能夠產生所需結果之量。所需結果將取決於所投予之活性劑。舉例而言,rAAV粒子之有效量可為能夠將表現構築體轉移至宿主器官、組織或細胞的粒子之量。治療可接受量可為能夠治療疾病例如肌肉萎縮症之量。如醫學及獸醫學技術中所熟知,用於任一個體之劑量取決於許多因素,包括個體之體型、體表面積、年齡、待投予之特定組成物、組成物中之活性成分、投予時間及途徑、總體健康狀況及並行地投予之其他藥物。
在一些具體實例中,本文所揭示之細胞為分離或來源於個體之細胞。在一些具體實例中,細胞為哺乳動物細胞(例如分離或來源於哺乳動物之細胞)。在一些具體實例中,細胞為人類細胞。在一些具體實例中,細胞分離或來源於個體之特定組織,諸如肌肉組織。在一些具體實例中,細胞為肌細胞。在一些具體實例中,細胞為骨胳肌細胞或平滑肌細胞。在一些具體實例中,細胞為試管內細胞。在一些具體實例中,細胞為活體外細胞。在一些具體實例中,細胞為活體內細胞。在一些具體實例中,細胞在個體內(例如在個體之組織或器官內)。在一些具體實例中,細胞為初級細胞。在一些具體實例中,細胞來自細胞系(例如永生化細胞系)。在一些具體實例中,細胞為癌細胞或永生化細胞。
在一些具體實例中,「投予」意謂以藥理學上適用之方式向個體提供物質。
在某些情況下,期望以本文所揭示之適合的經調配醫藥組成物形式遞送本文所揭示之AAV粒子,抑或經皮下、眼內、玻璃體內、視網膜下、非經腸、經靜脈內(IV)、腦室內、肌肉內、鞘內(IT)、腦池內、經口、腹膜內、藉由經口或經鼻吸入,或藉由直接注射來直接注射至一或多種細胞、組織或器官。在一些具體實例中,投予為適用於全身遞送,諸如藉由靜脈內注射之途徑。在一些具體實例中,投予為適用於局部遞送,諸如藉由肌肉內注射之途徑。在一些具體實例中,「投予」意謂以藥理學上適用之方式向個體提供物質。
在一些具體實例中,向個體投予之AAV粒子的濃度可在10
6至10
14個粒子/毫升或10
3至10
15個粒子/毫升之量級範圍內,或其間任一範圍之任何值,諸如(例如)約10
6、10
7、10
8、10
9、10
10、10
11、10
12、10
13或10
14個粒子/毫升。在一些具體實例中,投予濃度高於10
13個粒子/毫升之AAV粒子。在一些具體實例中,向個體投予之AAV粒子的濃度可在10
6至10
14個載體基因體(vgs)/毫升或10
3至10
15vgs/毫升之量級範圍內,或其間任一範圍之任何值(例如10
6、10
7、10
8、10
9、10
10、10
11、10
12、10
13或10
14vgs/毫升)。在一些具體實例中,投予濃度高於10
13vgs/毫升之AAV粒子。AAV粒子可以單次劑量投予,或可以達成所治療之特定疾病或病症之療法所需的形式分成兩次或更多次投予。在一些具體實例中,向個體遞送0.0001 ml至10 ml。在一些具體實例中,向個體投予之AAV粒子的數目可在每公斤個體體重10
6-10
14vgs的量級範圍內,或其間之任何值(例如10
6、10
7、10
8、10
9、10
10、10
11、10
12、10
13或10
14vgs/kg)。在一些具體實例中,向個體投予之AAV粒子的劑量可在10
12-10
14vgs/kg量級範圍內。在一些具體實例中,遞送至個體(例如經由如本文所述之一或多種投予途徑)之AAVrh74組成物之體積為0.0001 ml至10 ml。
在一些具體實例中,向個體投予本文所揭示之組成物(例如包含AAV粒子)一次。在一些具體實例中,向個體投予組成物多次(例如兩次、三次、四次、五次、六次或更多次)。視需要,以常規間隔(例如每天、每隔一天、每週兩次、每週一次、每月兩次、每月一次、每六個月、每年一次或更低頻率或更頻繁)對個體進行重複投予,以治療(例如改善或緩解)個體之疾病、病症或病況之一或多種症狀。
個體
本發明之態樣係關於適用於諸如人類或非人類靈長類動物個體之個體、個體原位之宿主細胞或來源於個體之宿主細胞(例如活體外或試管內)的方法。非人類靈長類動物個體之非限制性實例包括短尾猿(例如食蟹獼猴或恆河猴)、狨猴、絹毛猴、蜘蛛猴、梟猴、黑長尾猴、松鼠猴、狒狒、大猩猩、黑猩猩及紅毛猩猩。在一些具體實例中,個體為人類個體。其他例示性個體包括家養動物,諸如狗及貓;家畜,諸如馬、牛、豬、綿羊、山羊及雞;及諸如小鼠、大鼠、天竺鼠及倉鼠之其他動物。
在一些具體實例中,個體患有或疑似患有可用基因療法治療之疾病或病症。在一些具體實例中,個體患有或疑似患有肌肉疾病或病症。肌肉疾病或病症通常特徵在於基因體中之一或多個突變,其導致與肌肉發育、健康、維持及/或功能相關之一或多個蛋白質之異常結構或功能。例示性肌肉疾病及病症包括肌肉萎縮性脊髓側索硬化症、恰克-馬利-杜斯氏病、多發性硬化症、肌肉萎縮症(例如杜興氏肌肉萎縮症、面肩胛肱型肌肉萎縮症、貝氏肌肉萎縮症(Becker muscular dystrophy)或肢帶型肌肉萎縮症(LGMD),諸如LGMD 1型或LGMD 2型)、重症肌無力、肌病(例如X性聯肌微管性肌病)、肌炎、周邊神經病變或脊髓性肌肉萎縮症。肌肉疾病及病症可例如經由實驗室測試及/或藉由臨床醫師評估來表徵及鑑別。在一些具體實例中,個體患有或疑似患有涉及肌細胞之疾病(例如,由一或多種肌細胞或與其相關之基因中之缺陷(諸如基因突變)引起之疾病)。在一些具體實例中,自個體分離或衍生之核酸(例如來自個體之基因體DNA、mRNA或cDNA)經由定序(例如桑格(Sanger)或次世代定序法)鑑別以包含突變(例如在與肌肉發育、健康、維持或功能相關之基因中)。
在一些具體實例中,與肌肉發育、健康、維持或功能相關之基因為肌肉萎縮蛋白/DMD、SCN4A、DMPK、ACTA、TPM3、TPM2、TNNT1、CFL2、KBTBD13、KLHL30、KKLHL3、KLHL41、LMOD3、MYPN、MTM1、伴肌動蛋白、DNM2、TTN、RYR1、MYH7、TK2、GAA(α-葡糖苷酶)、ClC1、LMNA、CAV3、DNAJB6、TRIM32、肌間線蛋白、LAMA2、COL6A1、COL6A2、COL6A3或DUX4。在一些具體實例中,基因為肌肉萎縮蛋白(DMD)或MTM1。在一些具體實例中,基因為已顯示突變引起肢帶型肌肉萎縮症(例如LGMD1或LGMD2)的基因,諸如MYOT、LMNA、CAV3、DNAJB6、DES、TNP03、HNRNPDL、CAPN3、DYSF、SGCG、SGCA、SGCB、SGCD、TCAP、TRIM32、FKRP、TTN、POMT1、ANO5、FKTN、POMT2、POMGnT1、DAG1、PLEC1、DES、TRAPPC11、GMPPB、ISPD、GAA、LIMS2、BVES或TOR1A1P1。在一些具體實例中,個體包含與肌肉發育、健康、維持或功能相關之一或多個基因之突變形式。在一些具體實例中,本文所揭示之方法提供具有與肌肉發育、健康、維持或功能相關之基因之功能形式的個體之細胞(例如,肌細胞)。
實施例
包括以下實施例以說明本發明之例示性具體實例且不視為限制性的。所屬技術領域中具有通常知識者應瞭解,此等實施例中所揭示之技術代表本發明人發現在本發明之實踐中運行良好之技術,且因此可視為構成其實踐之較佳模式。然而,根據本發明,所屬技術領域中具有通常知識者應瞭解,在不背離本發明之精神及範疇的情況下可對所揭示之特定具體實例作出許多改變且仍獲得相似或類似結果。
實施例 1. 開發在初級人類骨胳肌細胞中具有增加的轉導效率之經殼體修飾之下一代 AAVrh74 載體 :在 肌肉萎縮症之基因療法中的意義
愈來愈清楚地,對AAV之宿主免疫反應與所投予之AAV載體劑量直接相關。舉例而言,在X性聯肌微管性肌病之基因療法試驗中,儘管已顯示至多1×10
14vgs/kg之AAV8載體之劑量為安全的,但3×10
14vgs/kg之劑量已與3名患者中之嚴重併發症相關,該併發症經證明對於其中兩個患者為致命的(
Hum. Gene Ther., 31: 787, 2020)。儘管2×10
14vgs/kg之AAVrh74載體之劑量已顯示在患有杜興氏肌肉萎縮症之患者中充分耐受(
JAMA Neurol., 77: 1122-1131, 2020),但在顯著較低載體劑量下達成臨床功效將為合乎需要的。據先前報告,特定表面暴露之酪胺酸(Y)殘基至苯丙胺酸(F)之定點突變誘發產生在減少之劑量下顯著更有效(
Proc. Natl. Acad. Sci. USA, 105: 7827-7832, 2008;
Mol. Ther., 18: 2048-2056, 2010)且免疫原性較低(
Blood, 8: 121: 2224-2233, 2013)之下一代(「NextGen」)AAV2載體。因為大部分(若非全部)表面暴露之Y殘基在AAVrh74中保守,所以產生對應Y733F單突變型(「single-mutant;SM」)及Y733+447F雙重突變型(double-mutant;DM)AAVrh74載體。表現EGFP報導基因之此等載體的轉導效率分別比希拉細胞中之習知野生型(「WT」)AAVrh74載體的轉導效率高至多約12倍及約16倍(圖1A)。Y-F突變型載體在轉導C2C12細胞系之永生化小鼠成肌細胞方面亦顯著更高效(圖1B)。據先前報告,包括表面暴露之蘇胺酸(T)至纈胺酸(V)殘基之定點突變誘發進一步加強AAV2載體之轉導效率(PLoS One, 8: e59142, 2013),因此另外產生Y733+Y447F+T494V三重突變型(「triple-mutant;TM」)ssAAVrh74載體,其轉導效率在初級人類骨胳肌細胞中比第一代ssAAVrh74載體高至多約5倍(圖2)。此外,產生單突變型T494V、K547R及N665R、三重突變型Y447+733F+N665R及Y447+733F+K547R及五重突變型Y447+733F+N665R+T494V+K547R ssAAVrh74載體,且測試其轉導效率。相對於野生型ssAAVrh74載體,三重突變體中之每一者展示增加的希拉細胞轉導效率,正如五重突變體一樣,且此等多重突變體中之每一者之轉導效率類似於Y733+447F+T494V三重突變體(圖3A及圖3B)。當前正進行研究以評估突變型ssAAVrh74載體在活體內鼠類模型中之骨胳肌中之功效。綜合而言,此等研究表明使用NextGen AAVrh74載體可在不需要免疫抑制之情況下在減少的劑量下引起人類肌肉萎縮症之潛在安全且有效的基因療法。
實施例 2. 開發在初級人類骨胳肌細胞中具有改善的轉殖基因表現的經基因體修飾之第 x 代單股 AAVrh74 載體
天然存在之AAV含有單股DNA基因體,且由於ssDNA為轉錄失活的且不存在能夠轉錄ssDNA之RNA聚合酶,因此表現病毒基因較差。類似地,自重組ssAAV載體之轉殖基因表現量亦受到負面影響。據先前報告,載體基因體之3'端處之AAV反向末端重複序列(ITR)中之D序列在限制自ssAAV載體之轉殖基因表現方面起重要作用(
Proc. Natl. Acad. Sci. USA, 94: 10879-10884, 1997)。在AAV-ITR中之D序列中鑑別出已知抑制轉錄之NF-κB負調節因子(negative regulatory factor;NRF)的結合位點。在左側ITR(LC1)或右側ITR(LC2)中用S序列取代D序列產生第X代(「GenX」)ssAAV載體,其介導之轉殖基因表現改善至多8倍(
J. Virol., 89: 952-961, 2015)。在本研究中,評估此等經修飾之ssAAV基因體在AAVrh74殼體中之包殼是否亦將引起增加之轉殖基因表現。用表現hrGFP報導基因之WT、LC1及LC2載體以1,000、3,000及10,000 vgs/細胞之感染倍率轉導希拉細胞,且在轉導後72小時定量hrGFP螢光。展示於圖4A中之此等結果證明,相對於無D序列取代之ssAAVrh74載體包殼基因體,由LC1及LC2載體介導之轉殖基因表現分別增加約5倍及約2.5倍(p<0.01)。所觀測到之轉殖基因表現的增加並非歸因於LC1及LC2載體之進入量的增加,如藉由qPCR分析對自利用此等載體中之每一者的轉導細胞分離之低分子量DNA樣品進行定量的大致類似數目的載體基因體所證明(圖4B)。亦在初級人類骨胳肌細胞中評估自此等載體之轉殖基因表現程度,此等載體中之每一者以1,000、3,000及10,000 vgs/細胞的感染倍率轉導。螢光影像之定量指示,與來自習知ssAAVrh74載體之轉殖基因表現相比,ssLC1-AAVrh74載體在轉殖基因表現方面平均增加約13倍,且ssLC2-AAVrh74載體平均增加約5倍(圖4C)。基於先前公開之NextGen AAV2及AAV3血清型載體之研究(
Hum. Gene Ther. Meth., 27: 143-149, 2016),預期將LC1及LC2 GenX AAV基因體包殼於NextGen AAVrh74殼體中對於在活體內鼠類模型中達成顯著較高水平之轉殖基因表現將為可行的。為了測試此類載體之功效,產生包含以S序列取代左側ITR之D序列的Y733+Y447F+T494V三重突變型(「TM」)ssAAVrh74載體且將其與無基因體修飾之TM ssAAVrh74載體及WT ssAAVrh74載體進行比較。圖5及圖6A至圖6B中之結果展示,TM/D序列組合之突變型ssAAVrh74載體(「Opt
X」)相對於WT ssAAVrh74載體在希拉細胞中展示出高約4倍之轉殖基因表現,且相比於TM ssAAVrh74(無D序列取代)展示出高約2倍之轉殖基因表現,如藉由對由該等載體表現之hrGFP進行螢光顯微鏡成像(圖5)及流式細胞測量術(圖6A至圖6B)所量測。此等觀測結果對GenX AAVrh74載體在進一步減少劑量下之肌肉萎縮症之基因療法方面之潛在用途具有顯著意義。
實施例 3. 開發在全身投予後在試管內初級人類骨胳肌細胞中及在活體內小鼠肌肉中具有增加轉導效率之最佳化 ( Opt
X ) AAVrh74 載體
在一項使用AAV9載體之I期/II期臨床試驗中,報告了嚴重不良事件,諸如補體活化及血小板減少症,從而導致腎損傷及心肺功能不全。在另一亦使用AAV9載體之試驗中,亦報告了若干嚴重不良事件,諸如涉及非典型性溶血性尿毒症症候群及血小板減少症之急性腎損傷,且近年來,亦報告了患者死亡。Sarepta Therapeutics報告了使用AAVrh74載體之I期/II期試驗之結果,其中嘔吐作為唯一不良事件,指示AAVrh74載體更安全,甚至在所用2×10
14vgs/kg之高劑量下亦如此。
如前述實施例中所描述,經殼體修飾之下一代(「NextGen」)AAVrh74載體及經基因體修飾之第X代(「GenX」)AAVrh74載體比其野生型(WT)對應物顯著更高效(亦參見
Mol. Ther., 29: 159-160, 2021;
Mol. Ther., 29: 184-185, 2021)。在本發明實施例中,將兩種修飾合併以產生最佳化(「Opt
X」)AAVrh74載體。在試管內初級人類骨胳肌細胞中評估Opt
XAAVrh74載體之轉導效率。結果證實,此等細胞之轉導效率比野生型AAVrh74載體之轉導效率高至多約5倍。亦在全身投予後在活體內小鼠肌肉中評估WT及Opt
XAAVrh74載體之功效。圖7A至圖7D展現,Opt
XAAVrh74載體之轉導效率在腓腸肌(GA;圖7A)及脛骨前肌(TA;圖7B)肌肉中高約5倍。有趣地,GA、TA、橫膈及心臟肌肉中WT或Opt
XAAVrh74載體之總基因體複本數彼此未顯著不同(圖7C),表明觀測到的Opt
XAAVrh74載體之轉導效率的增加可能由此等載體之改善的胞內遷移及核轉運引起。
綜合而言,此等研究表明使用Opt
XAAVrh74載體可在減少之劑量下產生對人類肌肉萎縮症安全且有效的基因療法。
實施例 4. 開發在小鼠骨胳肌細胞系及初級人類骨胳肌細胞中具有經改善轉殖基因表現之基因體修飾之第 Y 代 ( GenY ) AAVrh74 載體
由於ssDNA為轉錄失活的,來自重組ssAAV載體之轉殖基因表現量通常相對較低。取代AAV載體之左反向末端重複序列(ITR)中之D序列以形成「第X代」(「GenX」)AAV載體產生介導至多8倍改善之轉殖基因表現的AAV載體(
J. Virol., 89: 952-961, 2015)。自GenX AAVrh74載體之轉殖基因表現程度亦比自野生型(WT)AAVrh74載體之轉殖基因表現程度高約5倍(
Mol. Ther., 29: 184-185, 2021)。AAV2 D序列中之遠端10個核苷酸與糖皮質激素受體結合元件(GRE)之共通半位點共用部分同源性,且在AAV2感染或AAV2載體轉導之後活化糖皮質激素受體信號傳導路徑(
Mol. Ther., 24: S6, 2016)。在當前實施例中,評估用真GRE取代D序列中遠端(相對於核酸載體末端)的10個核苷酸以增加自AAVrh74載體之轉殖基因表現的能力,該等載體稱為「第Y代」(「GenY」)載體,示意性地示於圖8A中。在C2C12小鼠骨胳肌細胞中評估自WT及GenY AAVrh74載體之轉殖基因表現。相比於WT AAVrh74載體,GenY AAVrh74載體在轉殖基因表現方面平均增加約2-3倍(圖8B)。在用泰福斯汀(一種細胞表皮生長因子受體蛋白酪胺酸激酶之專一性抑制劑)預處理後,轉殖基因表現進一步增加約4-5倍(圖8B)。亦在初級人類骨胳肌細胞中評估WT、GenX及GenY載體。相比於WT AAVrh74載體,自GenX及GenY AAVrh74載體之轉殖基因表現分別高約4倍及約6倍(圖8C)。藉由qPCR對自經WT、GenX或GenY AAVrh74載體轉導之初級人類骨胳肌細胞分離的低分子量DNA樣品進行之分析在經各載體轉導之細胞中展示類似的載體基因體複本數(圖8D),指示所觀測到的轉殖基因表現增加並非由GenX或GenY載體的進入量增加而引起。
此等研究表明經殼體修飾之NextGen + GenY(Opt
Y)AAVrh74載體之組合使用可進一步減少對使用高載體劑量之需求,其在Opt
YAAVrh74載體潛在用於對人類之肌肉萎縮症安全且有效的基因療法方面具有顯著意義。
實施例 5. Opt
X 及 Opt
YAAVrh74
載體之活體內功效
在此實施例中,測試包含Y733+Y447F+T494V三重突變型(TM)殼體及GenX(左側ITR中以S序列取代D序列)或GenY(左側ITR中以GRE序列置換D序列之部分)修飾之基因體的AAVrh74載體的功效。TM + GenX載體稱為「Opt
X」且TM + GenY載體稱為「Opt
Y」。
為測試Opt
X載體,向C57BL/6小鼠靜脈內投予PBS、一定劑量之野生型AAVrh74粒子(「WT」)或一定劑量之Opt
XAAVrh74粒子(「Opt
X」)。WT及Opt
X粒子之劑量等效於1×10
12個病毒基因體。在投予該等粒子後八週,收集各種組織且萃取RNA。對自該等載體表現之hrGFP mRNA進行反轉錄-定量PCR(RT-qPCR)。圖9A展示肝臟(斜條紋條形圖)、橫膈(實心條形圖)及心臟(空心條形圖)中每μg總RNA之hrGFP mRNA的量。結果證明,當在測試組織中合計數值時,相對於WT AAVrh74,Opt
XAAVrh74載體在小鼠組織中達成高約2倍的hrGFP表現。圖9B展示,當相對於內源性β-肌動蛋白基因表現計算時,自橫膈及心臟而非肝臟中之Opt
XAAVrh74載體之轉殖基因表現顯著高於自WT AAVrh74載體之轉殖基因表現。
圖10A及圖10B展示來自經投予PBS、WT AAVrh74粒子或Opt
XAAVrh74粒子之小鼠的樣品中β-肌動蛋白mRNA之表現。結果表明各種樣品之間β-肌動蛋白表現無差異,展示在來自經Opt
X粒子處理之小鼠之樣品中量測之增加的hrGFP表現係歸因於該等粒子之改善特性。
為測試Opt
Y載體,向C57BL/6小鼠靜脈內投予PBS,一定劑量之具有TM殼體蛋白之AAVrh74粒子(「TM」)或一定劑量之Opt
YAAVrh74粒子(「Opt
Y」)。AAVrh74粒子之劑量等效於1×10
12個病毒基因體。在投予該等粒子後八週,收集各種組織。製備組織切片且萃取RNA。對組織切片之螢光顯微鏡檢查表明,相對於僅TM粒子,在投予Opt
Y粒子之後肝臟、腓腸肌(「GA」)及脛骨前肌(「TA」)中之hrGFP螢光增加(圖11A;圖11B中定量之螢光)。
圖12中顯示之結果表明,在用僅TM AAVrh74粒子(「TM」)處理之小鼠對比用Opt
Y粒子(「Opt
Y」)處理之小鼠中,肝臟(斜條紋條形圖)、心臟(空心條形圖)、橫膈(實心條形圖)、腓腸肌(「GA肌肉」;方形圖案化條形圖)及脛骨前肌(「TA肌肉」;水平條紋條形圖)中載體基因體之複本數沒有顯著差異。相比之下,自AAVrh74載體之hrGFP mRNA表現在某些組織中不同。如圖13中所示,相對於僅TM粒子處理之小鼠,在Opt
Y粒子處理之小鼠中,hrGFP表現在肝臟中減少,在橫膈中增加,在腓腸肌中增加,且在脛骨前肌中略微增加。
此實施例中呈現之結果表明,Opt
X及Opt
YAAVrh74載體能夠在向小鼠靜脈內投予之後實現改善的活體內轉殖基因表現概況。
等效物及範疇
儘管本文中已描述及說明若干個發明具體實例,但所屬技術領域中具有通常知識者將容易設想多種其他方法及/或結構來執行功能及/或獲得本文所述之結果及/或一或多種優點,且此類變化及/或修飾中之每一者視為屬於本文所述之本發明具體實例之範疇內。更一般而言,所屬技術領域中具有通常知識者將容易瞭解,本文所述之所有參數、尺寸、材料及組態均意欲為例示性的且實際參數、尺寸、材料及/或組態將視利用本發明教示內容之一或多種特定應用而定。所屬技術領域中具有通常知識者將認識到,或僅使用常規實驗便能夠確定本文所述之特定發明具體實例的許多等效物。因此,應理解,前述具體實例僅藉助於實例呈現且在隨附申請專利範圍及其等效物之範疇內,本發明具體實例可以不同於特定描述及主張之其他方式來實踐。本發明之發明具體實例係有關本文中所描述之各個別特徵、系統、物品、材料、套組及/或方法。另外,若兩種或更多種此類特徵、系統、物品、材料、套組及/或方法彼此間無不一致,則此類特徵、系統、物品、材料、套組及/或方法之任何組合包括於本發明之發明範疇內。
如本文所定義及使用之全部定義應理解為控制在辭典定義、以引用之方式併入的文獻中的定義及/或所定義術語之普通含義內。
本文所揭示之全部參考文獻、專利及專利申請案關於各自所引述之主題以引用之方式併入,在一些情況下可涵蓋整個文獻。
除非明確相反指示,否則如本文在說明書及申請專利範圍中使用之不定冠詞「一(a)」及「一(an)」應理解為意謂「至少一個」。
如本說明書及申請專利範圍中所用,片語「及/或(and/or)」應理解為意謂如此結合之要素中的「任一者或兩者」,亦即在一些情況下結合地存在且在其他情況下未結合地存在的要素。使用「及/或」列出之多個要素應以相同方式解釋,亦即,如此結合之要素之「一或多個(one or more)」。可視需要存在除了藉由「及/或(and/or)」子句所確切地鑑別之要素外之其他要素,無論與確切地鑑別之彼等要素相關抑或不相關。因此,作為非限制性實例,在結合諸如「包含(comprising)」之開放式語言使用時之「A及/或B」之提及可在一個具體實例中僅指A(視需要包括除B之外之要素);在另一具體實例中可僅指B(視需要包括除A之外之要素);在又另一具體實例中可指A及B(視需要包括其他要素);等。
如在本說明書及申請專利範圍中所用,「或(or)」應理解為具有與上文所定義之「及/或」相同的含義。舉例而言,當分隔清單中之項目時,「或」或「及/或」應被解釋為包括性的,亦即,包括一些或一列要素中之至少一個而且包括多於一個,及(視需要)其他未列出的項目。只有指示截然相反的術語,諸如「中之僅一者(only one of)」或「中之恰好一者(exactly one of)」或當用於申請專利範圍中時「由……組成(consisting of)」將指包括一些或一列要素中之恰好一個要素。一般而言,當置於諸如「任一(either)」、「中之一者(one of)」、「中之僅一者」或「中之恰好一者」的排他性術語之前時,如本文所用之術語「或」應僅被解釋為表明排他性替代方案(亦即「一者或另一者但非二者」)。當用於申請專利範圍中時,「主要由……組成」應具有如其在專利法律領域中所使用之普通含義。
如本說明書及申請專利範圍中所用,關於一或多個要素之清單的片語「至少一個」應被理解為意謂由要素之清單中要素之任何一或多個中選出的至少一個要素,但未必包括要素之清單內具體列出的每一及每個要素中之至少一者,且未必排除要素之清單中之要素的任何組合。此定義亦允許可視需要存在除片語「至少一個」所指的要素之清單內具體鑑別的要素以外的要素,而無論與具體鑑別的彼等要素相關抑或不相關。由此,作為非限制性實例,「A及B中之至少一者(at least one of A and B)」(或等效地「A或B中之至少一者(at least one of A or B)」,或,等效地「A及/或B中之至少一者(at least one of A and/or B)」)可在一個具體實例中指至少一個(視需要包括超過一個)A而不存在B(且視需要包括除B以外的要素);在另一具體實例中,指至少一個(視需要包括超過一個)B而不存在A(且視需要包括除A以外的要素);在又另一具體實例中,指至少一個(視需要包括超過一個)A及至少一個(視需要包括超過一個)B(且視需要包括其他要素);等。
亦應理解,除非截然相反地指示,否則在本文所主張之包括超過一個步驟或操作之任何方法中,該方法之步驟或操作之順序無需侷限於敍述該方法之步驟或操作之順序。
在申請專利範圍中以及在上述說明書中,所有過渡片語,諸如「包含(comprising)」、「包括(including)」、「帶有(carrying)」、「具有(having)」、「含有(containing)」、「涉及(involving)」、「容納(holding)」、「由……構成(composed of)」及類似片語,應理解為開放的,亦即,意謂包括但不限於。僅過渡片語「由……組成」及「基本上由……組成」應分別為封閉或半封閉過渡片語,如美國專利局手冊專利審查程序(United States Patent Office Manual of Patent Examining Procedures)第2111.03節中所闡述。應瞭解,在替代性具體實例中,亦將此文件中使用開放式過渡片語(例如「包含」)描述之具體實例考慮為「由該開放式過渡片語所描述之特徵組成」及「基本上由該開放式過渡片語所描述之特徵組成」。舉例而言,若本發明描述「包含A及B之組成物(a composition comprising A and B)」,則本發明亦涵蓋替代具體實例「由A及B組成之組成物(a composition consisting of A and B)」及「基本上由A及B組成之組成物(a composition consisting essentially of A and B)」。
無
[
圖 1A]
至[
圖 1B]展示人類希拉(HeLa)(
圖 1A)及小鼠C2C12(
圖 1B)細胞中野生型(WT)及Y-F突變型ssAAVrh74載體之轉導效率。將細胞在37℃下用各載體在指定載體基因體複本數(vgs)/細胞下轉導2小時,且在螢光顯微鏡下在轉導後72小時觀測轉殖基因表現。使用ImageJ軟體定量資料。左圖展示轉導後細胞中之EGFP螢光。圖1A之右圖中之資料展示在針對WT、Y733F及Y447+733F ssAAVrh74載體中之每一者以1,000 vgs/細胞(左,較亮條形圖)或3,000 vgs/細胞(右,較暗條形圖)轉導之後的轉殖基因表現之定量(像素
2/視野)。圖1B之右圖中之資料展示在針對WT、Y733F及Y447+733F ssAAVrh74載體中之每一者用3,000 vgs/細胞(左,較亮條形圖)或9,000 vgs/細胞(右,較暗條形圖)轉導之後的轉殖基因表現(像素
2/視野)。
[
圖 2]展示原生人類骨胳肌細胞中野生型(「WT」)及Y733+447F+T494V三重突變型(「triple mutant;TM」)ssAAVrh74載體之轉導效率。將細胞用各載體在指定感染倍率(vgs/細胞)下轉導,且轉殖基因表現量如上文圖1A-1B中所述定量。左圖展示轉導之後骨胳肌細胞中之EGFP螢光。右圖展示分別針對WT及TM AAVrh74載體以1,000 vgs/細胞(左,較亮條形圖)或3,000 vgs/細胞(右,較暗條形圖)轉導之後的轉殖基因表現之定量(像素
2/視野)。
[
圖 3A]
至[
圖 3B]展示希拉細胞中ssAAV-rh74突變體之轉導效率。
圖 3A展示在用3,000 vgs/細胞之野生型(WT)或殼體突變型ssAAVrh74載體轉導後72小時的GFP螢光。
圖 3B展示GFP螢光轉導資料之定量(轉殖基因表現,量測為像素
2/視野)。
[
圖 4A]
至[
圖 4C]展示野生型(「WT」)ssAAVrh74載體或其中左側ITR之D序列(「LC1」)或右側ITR之D序列(「LC2」)經取代之ssAAVrh74載體之轉導效率。
圖 4A展示希拉細胞中由WT、LC1或LC2 ssAAVrh74載體介導之轉殖基因表現。左圖展示在以1,000 vgs/細胞、3,000 vgs/細胞或10,000 vgs/細胞轉導各各別ssAAVrh74載體之後希拉細胞中之hrGFP螢光。右圖展示在分別以1,000 vgs/細胞(每組條形圖之左側條形圖)、3,000 vgs/細胞(中間條形圖)或10,000 vgs/細胞(右側條形圖)轉導WT、LC1或LC2 AAVrh74載體之後之轉殖基因表現之定量(像素
2/視野)。
圖 4B展示用WT、LC1或LC2 ssAAVrh74載體轉導之希拉細胞中之載體基因體複本數(每μg DNA×10
8之複本數)。每組三個條形圖展示以1,000 vgs/細胞(左側條形圖)、3,000 vgs/細胞(中間條形圖)或10,000 vgs/細胞(右側條形圖)轉導後之複本數。
圖 4C展示原生人類骨胳肌細胞中由WT、LC1或LC2 ssAAVrh74載體介導之轉殖基因表現。左圖展示在以1,000 vgs/細胞、3,000 vgs/細胞或10,000 vgs/細胞轉導各各別ssAAVrh74載體之後初級人類骨胳肌細胞中之hrGFP螢光。右圖展示在分別針對WT、LC1或LC2 AAVrh74載體以1,000 vgs/細胞(每組條形圖之左側條形圖)、3,000 vgs/細胞(中間條形圖)或10,000 vgs/細胞(右側條形圖)轉導之後之轉殖基因表現之定量(像素
2/視野)。對於圖3A與圖3B兩者,將細胞在37℃下用指定感染倍率(vgs/細胞)之各載體轉導2小時,且在螢光顯微鏡下在轉導後72小時觀測轉殖基因表現。使用ImageJ軟體定量資料。
[
圖 5]展示使用野生型(「WT」)ssAAVrh74載體、Y447+733F+T494V三重突變型(「TM」)ssAAVrh74載體及左側ITR之D序列具有額外取代的Y447+733F+T494V三重突變型ssAAVrh74載體(「Opt
X」)的希拉細胞轉導效率。將希拉細胞以1,000 vgs/細胞轉導且在轉導後72小時測定轉導效率。
[
圖 6A]
至[
圖 6B]展示希拉細胞中WT、TM及Opt
XssAAV-rh74載體之轉導效率,其藉由流式細胞測量術定量GFP螢光(
圖 6A)及流式細胞測量術定量平均GFP螢光(
圖 6B)量測。WT、TM及Opt
X如上圖5中所定義。將希拉細胞以1,000 vgs/細胞轉導且在轉導後72小時測定轉導效率。
[
圖 7A]
至[
圖 7D]展示在C57Bl6小鼠中靜脈內投予1×10
12vgs/小鼠後,活體內WT及Opt
XssAAVrh74載體之功效。
圖 7A展示在靜脈內投予該等載體後定量之腓腸肌(gastrocnemius;GA)肌肉中之轉殖基因表現,且
圖 7B展示在靜脈內投予該等載體後定量之脛骨前肌(tibialis anterior;TA)肌肉的轉殖基因表現。
圖 7C展示在投予該等載體後8週收集之各種組織中定量的載體基因體複本數。
圖 7D展示在投予該等載體後肝臟、GA及TA中量測的相對轉殖基因表現。對螢光顯微影像使用NIH ImageJ軟體分析來定量轉殖基因表現資料。
[
圖 8A]
至[
圖 8D]展示試管內WT、GenX及GenY載體之功效。
圖 8A展示WT(在遠離核酸載體末端之ITR末端處具有D序列)、GenX(一個D序列經取代)及GenY(一個D序列之一部分經GRE取代)基因體之示意性結構。
圖 8B展示小鼠C2C12細胞中之GenX及GenY AAVrh74載體在不存在或存在泰福斯汀(tyrphostin)(「Tyr.」)下之轉導效率。
圖 8C展示初級人類骨胳肌細胞中WT、GenX及GenY AAVrh74載體之轉導效率。將細胞在37℃下經各載體以每細胞指定載體基因體複本數轉導2小時,且轉殖基因表現在轉導後72小時在螢光顯微鏡下觀測到。對螢光顯微影像使用NIH ImageJ軟體分析來定量轉殖基因表現。
圖 8D展示用WT、GenX及GenY AAVrh74載體轉導之初級人類骨胳肌細胞中定量的載體基因體複本數。
[
圖 9A]
至[
圖 9B]展示Opt
XAAVrh74載體之功效。
圖 9A展示自投予PBS、含有hrGFP轉殖基因之野生型AAVrh74粒子(「WT」)或含有hrGFP轉殖基因之Opt
XAAVrh74粒子(「Opt
X」)之小鼠之肝臟、橫膈及心臟組織萃取之每μg總RNA的hrGFP mRNA複本數之反轉錄定量PCR(reverse transcription-quantitative PCR;RT-qPCR)量測結果。
圖 9B展示來自投予含有hrGFP轉殖基因之WT或Opt
XAAVrh74粒子之小鼠之肝臟、橫膈及心臟組織樣品中hrGFP之相對表現量。
[
圖 10A]
至[
圖 10B]展示投予PBS、含有hrGFP轉殖基因之WT或Opt
XAAVrh74粒子之小鼠之肝臟、橫膈及心臟組織中之基因表現的對照量測結果。
圖 10A展示藉由RT-qPCR量測之β-肌動蛋白之表現。
圖 10B展示來自β-肌動蛋白RT-qPCR量測之循環閾值(cycle threshold;CT)值。
[
圖 11A]
至[
圖 11B]展示Opt
YAAVrh74載體之功效。
圖 11A展示來自投予含有hrGFP轉殖基因之Y447+733F+T494V三重突變型AAVrh74粒子(「TM」)或含有hrGFP轉殖基因之Opt
YAAVrh74粒子(「Opt
Y」)之小鼠之肝臟、腓腸肌(「GA」)及脛骨前肌(「TA」)組織切片的螢光顯微鏡影像。
圖 11B展示來自螢光顯微鏡影像之hrGFP轉殖基因表現之定量。
[
圖 12]展示對投予含有hrGFP轉殖基因之Y447+733F+T494V三重突變型AAVrh74粒子(「TM」)或含有hrGFP轉殖基因之Opt
YAAVrh74粒子(「Opt
Y」)之小鼠之肝臟、心臟、橫膈、腓腸肌(「GA肌肉」)及脛骨前肌(「TA肌肉」)組織中載體基因體複本數的定量。
[
圖 13]展示對投予含有hrGFP轉殖基因之Y447+733F+T494V三重突變型AAVrh74粒子(「TM」)或含有hrGFP轉殖基因之Opt
YAAVrh74粒子(「Opt
Y」)之小鼠之肝臟、心臟、橫膈、腓腸肌(「GA肌肉」)及脛骨前肌(「TA肌肉」)組織中每載體基因體複本數之hrGFP mRNA表現的定量。
<![CDATA[<110> 佛羅里達大學研究基金會公司(University of Florida Research Foundation, Incorporated)]]> <![CDATA[<120> 用於肌肉萎縮症之基因療法的AAVRH74載體]]> <![CDATA[<130> U1202.70077WO00]]> <![CDATA[<140> TW 111115475]]> <![CDATA[<141> 2022-04-22]]> <![CDATA[<150> US 63/327,410]]> <![CDATA[<151> 2022-04-05]]> <![CDATA[<150> US 63/179,097]]> <![CDATA[<151> 2021-04-23]]> <![CDATA[<160> 36 ]]> <![CDATA[<170> PatentIn版本3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 738]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<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 Asn Gly Arg Gly Leu Val Leu Pro 35 40 45 Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro 50 55 60 Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp 65 70 75 80 Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala 85 90 95 Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly 100 105 110 Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro 115 120 125 Leu Gly Leu Val Glu Ser Pro Val Lys Thr Ala Pro Gly Lys Lys Arg 130 135 140 Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile 145 150 155 160 Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln 165 170 175 Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro 180 185 190 Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly 195 200 205 Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser 210 215 220 Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val 225 230 235 240 Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His 245 250 255 Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp 260 265 270 Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn 275 280 285 Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn 290 295 300 Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn 305 310 315 320 Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala 325 330 335 Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln 340 345 350 Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe 355 360 365 Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn 370 375 380 Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr 385 390 395 400 Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr 405 410 415 Asn Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser 420 425 430 Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu 435 440 445 Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu 450 455 460 Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp 465 470 475 480 Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser 485 490 495 Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His 500 505 510 Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr 515 520 525 His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met 530 535 540 Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val 545 550 555 560 Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr 565 570 575 Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala 580 585 590 Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val 595 600 605 Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile 610 615 620 Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe 625 630 635 640 Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val 645 650 655 Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ala Lys Leu Ala Ser Phe 660 665 670 Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu 675 680 685 Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr 690 695 700 Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Glu 705 710 715 720 Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg 725 730 735 Asn Leu <![CDATA[<210> 2]]> <![CDATA[<211> 736]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV1]]> <![CDATA[<400> 2]]> 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 <![CDATA[<210> 3]]> <![CDATA[<211> 735]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV2]]> <![CDATA[<400> 3]]> 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 <![CDATA[<210> 4]]> <![CDATA[<211> 736]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV3]]> <![CDATA[<400> 4]]> 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 <![CDATA[<210> 5]]> <![CDATA[<211> 734]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV4]]> <![CDATA[<400> 5]]> 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 <![CDATA[<210> 6]]> <![CDATA[<211> 724]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV5]]> <![CDATA[<400> 6]]> 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 <![CDATA[<210> 7]]> <![CDATA[<211> 736]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV6]]> <![CDATA[<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 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 <![CDATA[<210> 8]]> <![CDATA[<211> 737]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV7]]> <![CDATA[<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 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 <![CDATA[<210> 9]]> <![CDATA[<211> 738]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV8]]> <![CDATA[<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 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 <![CDATA[<210> 10]]> <![CDATA[<211> 736]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV9]]> <![CDATA[<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 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 <![CDATA[<210> 11]]> <![CDATA[<211> 738]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV10]]> <![CDATA[<400> 11]]> Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser 1 5 10 15 Glu Gly Ile Arg Glu Trp Trp Asp Leu Lys Pro Gly Ala Pro Lys Pro 20 25 30 Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro 35 40 45 Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro 50 55 60 Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp 65 70 75 80 Gln Gln Leu Lys Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala 85 90 95 Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly 100 105 110 Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro 115 120 125 Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg 130 135 140 Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile 145 150 155 160 Gly Lys Lys Gly Gln Gln Pro Ala Lys Lys Arg Leu Asn Phe Gly Gln 165 170 175 Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Ile Gly Glu Pro 180 185 190 Pro Ala Gly Pro Ser Gly Leu Gly Ser Gly Thr Met Ala Ala Gly Gly 195 200 205 Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser 210 215 220 Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val 225 230 235 240 Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His 245 250 255 Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ser Thr Asn Asp 260 265 270 Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn 275 280 285 Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn 290 295 300 Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn Phe Lys Leu Phe Asn 305 310 315 320 Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala 325 330 335 Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln 340 345 350 Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe 355 360 365 Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn 370 375 380 Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr 385 390 395 400 Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Phe Ser Tyr 405 410 415 Gln Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser 420 425 430 Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu 435 440 445 Ser Arg Thr Gln Ser Thr Gly Gly Thr Ala Gly Thr Gln Gln Leu Leu 450 455 460 Phe Ser Gln Ala Gly Pro Asn Asn Met Ser Ala Gln Ala Lys Asn Trp 465 470 475 480 Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Leu Ser 485 490 495 Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Gly Ala Thr Lys Tyr His 500 505 510 Leu Asn Gly Arg Asp Ser Leu Val Asn Pro Gly Val Ala Met Ala Thr 515 520 525 His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Ser Gly Val Leu Met 530 535 540 Phe Gly Lys Gln Gly Ala Gly Lys Asp Asn Val Asp Tyr Ser Ser Val 545 550 555 560 Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr 565 570 575 Glu Gln Tyr Gly Val Val Ala Asp Asn Leu Gln Gln Gln Asn Ala Ala 580 585 590 Pro Ile Val Gly Ala Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val 595 600 605 Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile 610 615 620 Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe 625 630 635 640 Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val 645 650 655 Pro Ala Asp Pro Pro Thr Thr Phe Ser Gln Ala Lys Leu Ala Ser Phe 660 665 670 Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu 675 680 685 Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr 690 695 700 Ser Asn Tyr Tyr Lys Ser Thr Asn Val Asp Phe Ala Val Asn Thr Asp 705 710 715 720 Gly Thr Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg 725 730 735 Asn Leu <![CDATA[<210> 12]]> <![CDATA[<211> 145]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV2]]> <![CDATA[<400> 12]]> ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60 cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120 gccaactcca tcactagggg ttcct 145 <![CDATA[<210> 13]]> <![CDATA[<211> 146]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV3]]> <![CDATA[<400> 13]]> ttggccactc cctctatgcg cactcgctcg ctcggtgggg cctggcgacc aaaggtcgcc 60 agacggacgt gctttgcacg tccggcccca ccgagcgagc gagtgcgcat agagggagtg 120 gccaactcca tcactagagg tatggc 146 <![CDATA[<210> 14]]> <![CDATA[<211> 167]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV5]]> <![CDATA[<400> 14]]> ctctcccccc tgtcgcgttc gctcgctcgc tggctcgttt gggggggtgg cagctcaaag 60 agctgccaga cgacggccct ctggccgtcg cccccccaaa cgagccagcg agcgagcgaa 120 cgcgacaggg gggagagtgc cacactctca agcaaggggg ttttgta 167 <![CDATA[<210> 15]]> <![CDATA[<211> 142]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV6]]> <![CDATA[<400> 15]]> ttgcccactc cctctatgcg cgctcgctcg ctcggtgggg cctgcggacc aaaggtccgc 60 agacggcaga gctctgctct gccggcccca ccgagcgagc gagcgcgcat agagggagtg 120 ggcaactcca tcactagggg ta 142 <![CDATA[<210> 16]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 16]]> ctccatcact aggggttcct 20 <![CDATA[<210> 17]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 17]]> tattagatct gatggccgct 20 <![CDATA[<210> 18]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (7)..(9)]]> <![CDATA[<223> n為a、c、g或t]]> <![CDATA[<400> 18]]> agaacannnt gttct 15 <![CDATA[<210> 19]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<220>]]> <![CDATA[<22]]>1> misc_feature]]> <br/><![CDATA[<222> (7)..(9)]]> <br/><![CDATA[<223> n為a、c、g或t]]> <br/> <br/><![CDATA[<400> 19]]> <br/><![CDATA[ggtacannnt gtyct 15 <![CDATA[<210> 20]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 20]]> agaacaggat gttct 15 <![CDATA[<210> 21]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 21]]> ggcacagtgt ggtct 15 <![CDATA[<210> 22]]> <![CDATA[<211> 2217]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 22]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg acctgaaacc tggagccccg aaacccaaag ccaaccagca aaagcaggac 120 aacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggacgca gcggccctcg agcacgacaa ggcctacgac 240 cagcagctcc aagcgggtga caatccgtac ctgcggtata atcacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgcgc agtcttccag 360 gccaaaaagc gggttctcga acctctgggc ctggttgaat cgccggttaa gacggctcct 420 ggaaagaaga gaccggtaga gccatcaccc cagcgctctc cagactcctc tacgggcatc 480 ggcaagaaag gccagcagcc cgcaaaaaag agactcaatt ttgggcagac tggcgactca 540 gagtcagtcc ccgaccctca accaatcgga gaaccaccag caggcccctc tggtctggga 600 tctggtacaa tggctgcagg cggtggcgct ccaatggcag acaataacga aggcgccgac 660 ggagtgggta gttcctcagg aaattggcat tgcgattcca catggctggg cgacagagtc 720 atcaccacca gcacccgcac ctgggccctg cccacctaca acaaccacct ctacaagcaa 780 atctccaacg ggacctcggg aggaagcacc aacgacaaca cctacttcgg ctacagcacc 840 ccctgggggt attttgactt caacagattc cactgccact tttcaccacg tgactggcag 900 cgactcatca acaacaactg gggattccgg cccaagaggc tcaacttcaa gctcttcaac 960 atccaagtca aggaggtcac gcagaatgaa ggcaccaaga ccatcgccaa taaccttacc 1020 agcacgattc aggtctttac ggactcggaa taccagctcc cgtacgtgct cggctcggcg 1080 caccagggct gcctgcctcc gttcccggcg gacgtcttca tgattcctca gtacgggtac 1140 ctgactctga acaatggcag tcaggctgtg ggccggtcgt ccttctactg cctggagtac 1200 tttccttctc aaatgctgag aacgggcaac aactttgaat tcagctacaa cttcgaggac 1260 gtgcccttcc acagcagcta cgcgcacagc cagagcctgg accggctgat gaaccctctc 1320 atcgaccagt acttgtacta cctgtcccgg actcaaagca cgggcggtac tgcaggaact 1380 cagcagttgc tattttctca ggccgggcct aacaacatgt cggctcaggc caagaactgg 1440 ctacccggtc cctgctaccg gcagcaacgc gtctccacga cactgtcgca gaacaacaac 1500 agcaactttg cctggacggg tgccaccaag tatcatctga atggcagaga ctctctggtg 1560 aatcctggcg ttgccatggc tacccacaag gacgacgaag agcgattttt tccatccagc 1620 ggagtcttaa tgtttgggaa acagggagct ggaaaagaca acgtggacta tagcagcgtg 1680 atgctaacca gcgaggaaga aataaagacc accaacccag tggccacaga acagtacggc 1740 gtggtggccg ataacctgca acagcaaaac gccgctccta ttgtaggggc cgtcaatagt 1800 caaggagcct tacctggcat ggtgtggcag aaccgggacg tgtacctgca gggtcccatc 1860 tgggccaaga ttcctcatac ggacggcaac tttcatccct cgccgctgat gggaggcttt 1920 ggactgaagc atccgcctcc tcagatcctg attaaaaaca cacctgttcc cgccgatcct 1980 ccgaccacct tcaatcaggc caagctggct tctttcatca cgcagtacag taccggtcag 2040 gtcagcgtgg agatcgagtg ggagctgcag aaggagaaca gcaaacgctg gaacccagag 2100 attcagtaca cttccaacta ctacaaatct acaaatgtgg actttgctgt caatactgag 2160 ggtacttatt ccgagcctcg ccccattggc acccgttacc tcacccgtaa tctgtaa 2217 <![CDATA[<210> 23]]> <![CDATA[<211> 733]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV11]]> <![CDATA[<400> 23]]> 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 Leu Glu Ser Pro Gln Glu Pro Asp Ser Ser Ser Gly Ile Gly Lys 145 150 155 160 Lys Gly Lys Gln Pro Ala Arg Lys Arg Leu Asn Phe Glu Glu Asp Thr 165 170 175 Gly Ala Gly Asp Gly Pro Pro Glu Gly Ser Asp Thr Ser Ala Met Ser 180 185 190 Ser Asp Ile Glu Met Arg Ala Ala Pro Gly Gly Asn Ala Val Asp Ala 195 200 205 Gly Gln Gly Ser Asp Gly Val Gly Asn Ala Ser Gly Asp Trp His Cys 210 215 220 Asp Ser Thr Trp Ser Glu Gly Lys Val Thr Thr Thr Ser Thr Arg Thr 225 230 235 240 Trp Val Leu Pro Thr Tyr Asn Asn His Leu Tyr Leu Arg Leu Gly Thr 245 250 255 Thr Ser Ser 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 Leu 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 Ile Val Thr Gly Glu Asn Gln Asn Gln Thr Asp Arg Asn Ala 370 375 380 Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn 385 390 395 400 Asn Phe Glu Met Ala Tyr Asn Phe Glu Lys Val Pro Phe His Ser Met 405 410 415 Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Leu Asp 420 425 430 Gln Tyr Leu Trp His Leu Gln Ser Thr Thr Ser Gly Glu Thr Leu Asn 435 440 445 Gln Gly Asn Ala Ala Thr Thr Phe Gly Lys Ile Arg Ser Gly Asp Phe 450 455 460 Ala Phe Tyr Arg Lys Asn Trp Leu Pro Gly Pro Cys Val Lys Gln Gln 465 470 475 480 Arg Phe Ser Lys Thr Ala Ser Gln Asn Tyr Lys Ile Pro Ala Ser Gly 485 490 495 Gly Asn Ala Leu Leu Lys Tyr Asp Thr His Tyr Thr Leu Asn Asn Arg 500 505 510 Trp Ser Asn Ile Ala Pro Gly Pro Pro Met Ala Thr Ala Gly Pro Ser 515 520 525 Asp Gly Asp Phe Ser Asn Ala Gln Leu Ile Phe Pro Gly Pro Ser Val 530 535 540 Thr Gly Asn Thr Thr Thr Ser Ala Asn Asn Leu Leu Phe Thr Ser Glu 545 550 555 560 Glu Glu Ile Ala Ala Thr Asn Pro Arg Asp Thr Asp Met Phe Gly Gln 565 570 575 Ile Ala Asp Asn Asn Gln Asn Ala Thr Thr Ala Pro Ile Thr Gly Asn 580 585 590 Val Thr Ala Met Gly Val Leu Pro Gly Met Val Trp Gln Asn Arg Asp 595 600 605 Ile Tyr Tyr Gln Gly Pro Ile Trp Ala Lys Ile Pro His Ala Asp Gly 610 615 620 His Phe His Pro Ser Pro Leu Ile Gly Gly Phe Gly Leu Lys His Pro 625 630 635 640 Pro Pro Gln Ile Phe Ile Lys Asn Thr Pro Val Pro Ala Asn Pro Ala 645 650 655 Thr Thr Phe Thr Ala Ala Arg Val Asp Ser Phe Ile Thr Gln Tyr Ser 660 665 670 Thr Gly Gln Val Ala Val Gln Ile Glu Trp Glu Ile Glu Lys Glu Arg 675 680 685 Ser Lys Arg Trp Asn Pro Glu Val Gln Phe Thr Ser Asn Tyr Gly Asn 690 695 700 Gln Ser Ser Met Leu Trp Ala Pro Asp Thr Thr Gly Lys Tyr Thr Glu 705 710 715 720 Pro Arg Val Ile Gly Ser Arg Tyr Leu Thr Asn His Leu 725 730 <![CDATA[<210> 24]]> <![CDATA[<211> 742]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV12]]> <![CDATA[<400> 24]]> 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 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 Glu Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp 65 70 75 80 Lys Gln Leu Glu Gln Gly Asp Asn Pro Tyr Leu Lys Tyr Asn His Ala 85 90 95 Asp Ala Glu Phe Gln Gln Arg Leu Ala Thr 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 Gly Val Lys Thr Ala Pro Gly Lys Lys Arg 130 135 140 Pro Leu Glu Lys Thr Pro Asn Arg Pro Thr Asn Pro Asp Ser Gly Lys 145 150 155 160 Ala Pro Ala Lys Lys Lys Gln Lys Asp Gly Glu Pro Ala Asp Ser Ala 165 170 175 Arg Arg Thr Leu Asp Phe Glu Asp Ser Gly Ala Gly Asp Gly Pro Pro 180 185 190 Glu Gly Ser Ser Ser Gly Glu Met Ser His Asp Ala Glu Met Arg Ala 195 200 205 Ala Pro Gly Gly Asn Ala Val Glu Ala Gly Gln Gly Ala Asp Gly Val 210 215 220 Gly Asn Ala Ser Gly Asp Trp His Cys Asp Ser Thr Trp Ser Glu Gly 225 230 235 240 Arg Val Thr Thr Thr Ser Thr Arg Thr Trp Val Leu Pro Thr Tyr Asn 245 250 255 Asn His Leu Tyr Leu Arg Ile Gly Thr Thr Ala Asn Ser Asn Thr Tyr 260 265 270 Asn Gly Phe 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 Leu Arg Pro Lys Ser Met Arg Val Lys Ile Phe Asn Ile Gln Val 305 310 315 320 Lys Glu Val Thr Thr Ser Asn Gly Glu Thr Thr Val Ala Asn Asn Leu 325 330 335 Thr Ser Thr Val Gln Ile Phe Ala Asp Ser Thr Tyr Glu Leu Pro Tyr 340 345 350 Val Met Asp Ala Gly Gln Glu Gly Ser Phe Pro Pro Phe Pro Asn Asp 355 360 365 Val Phe Met Val Pro Gln Tyr Gly Tyr Cys Gly Val Val Thr Gly Lys 370 375 380 Asn Gln Asn Gln Thr Asp Arg Asn Ala Phe Tyr Cys Leu Glu Tyr Phe 385 390 395 400 Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Glu Val Ser Tyr Gln 405 410 415 Phe Glu Lys Val Pro Phe His Ser Met Tyr Ala His Ser Gln Ser Leu 420 425 430 Asp Arg Met Met Asn Pro Leu Leu Asp Gln Tyr Leu Trp His Leu Gln 435 440 445 Ser Thr Thr Thr Gly Asn Ser Leu Asn Gln Gly Thr Ala Thr Thr Thr 450 455 460 Tyr Gly Lys Ile Thr Thr Gly Asp Phe Ala Tyr Tyr Arg Lys Asn Trp 465 470 475 480 Leu Pro Gly Ala Cys Ile Lys Gln Gln Lys Phe Ser Lys Asn Ala Asn 485 490 495 Gln Asn Tyr Lys Ile Pro Ala Ser Gly Gly Asp Ala Leu Leu Lys Tyr 500 505 510 Asp Thr His Thr Thr Leu Asn Gly Arg Trp Ser Asn Met Ala Pro Gly 515 520 525 Pro Pro Met Ala Thr Ala Gly Ala Gly Asp Ser Asp Phe Ser Asn Ser 530 535 540 Gln Leu Ile Phe Ala Gly Pro Asn Pro Ser Gly Asn Thr Thr Thr Ser 545 550 555 560 Ser Asn Asn Leu Leu Phe Thr Ser Glu Glu Glu Ile Ala Thr Thr Asn 565 570 575 Pro Arg Asp Thr Asp Met Phe Gly Gln Ile Ala Asp Asn Asn Gln Asn 580 585 590 Ala Thr Thr Ala Pro His Ile Ala Asn Leu Asp Ala Met Gly Ile Val 595 600 605 Pro Gly Met Val Trp Gln Asn Arg Asp Ile Tyr Tyr Gln Gly Pro Ile 610 615 620 Trp Ala Lys Val Pro His Thr Asp Gly His Phe His Pro Ser Pro Leu 625 630 635 640 Met Gly Gly Phe Gly Leu Lys His Pro Pro Pro Gln Ile Phe Ile Lys 645 650 655 Asn Thr Pro Val Pro Ala Asn Pro Asn Thr Thr Phe Ser Ala Ala Arg 660 665 670 Ile Asn Ser Phe Leu Thr Gln Tyr Ser Thr Gly Gln Val Ala Val Gln 675 680 685 Ile Asp Trp Glu Ile Gln Lys Glu His Ser Lys Arg Trp Asn Pro Glu 690 695 700 Val Gln Phe Thr Ser Asn Tyr Gly Thr Gln Asn Ser Met Leu Trp Ala 705 710 715 720 Pro Asp Asn Ala Gly Asn Tyr His Glu Leu Arg Ala Ile Gly Ser Arg 725 730 735 Phe Leu Thr His His Leu 740 <![CDATA[<210> 25]]> <![CDATA[<211> 2211]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 25]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg acttgaaacc tggagccccg aagcccaaag ccaaccagca aaagcaggac 120 gacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggacgca gcggccctcg agcacgacaa ggcctacgac 240 cagcagctca aagcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360 gccaagaagc gggttctcga acctctcggt ctggttgagg aaggcgctaa gacggctcct 420 ggaaagaaac gtccggtaga gcagtcgcca caagagccag actcctcctc gggcatcggc 480 aagacaggcc agcagcccgc taaaaagaga ctcaattttg gtcagactgg cgactcagag 540 tcagtccccg atccacaacc tctcggagaa cctccagcaa cccccgctgc tgtgggacct 600 actacaatgg cttcaggcgg tggcgcacca atggcagaca ataacgaagg cgccgacgga 660 gtgggtaatg cctcaggaaa ttggcattgc gattccacat ggctgggcga cagagtcatc 720 accaccagca cccgcacctg ggccttgccc acctacaata accacctcta caagcaaatc 780 tccagtgctt caacgggggc cagcaacgac aaccactact tcggctacag caccccctgg 840 gggtattttg atttcaacag attccactgc cacttttcac cacgtgactg gcagcgactc 900 atcaacaaca attggggatt ccggcccaag agactcaact tcaaactctt caacatccaa 960 gtcaaggagg tcacgacgaa tgatggcgtc acaaccatcg ctaataacct taccagcacg 1020 gttcaagtct tctcggactc ggagtaccag cttccgtacg tcctcggctc tgcgcaccag 1080 ggctgcctcc ctccgttccc ggcggacgtg ttcatgattc cgcaatacgg ctacctgacg 1140 ctcaacaatg gcagccaagc cgtgggacgt tcatcctttt actgcctgga atatttccct 1200 tctcagatgc tgagaacggg caacaacttt accttcagct acacctttga ggaagtgcct 1260 ttccacagca gctacgcgca cagccagagc ctggaccggc tgatgaatcc tctcatcgac 1320 caatacctgt attacctgaa cagaactcaa aatcagtccg gaagtgccca aaacaaggac 1380 ttgctgttta gccgtgggtc tccagctggc atgtctgttc agcccaaaaa ctggctacct 1440 ggaccctgtt atcggcagca gcgcgtttct aaaacaaaaa cagacaacaa caacagcaat 1500 tttacctgga ctggtgcttc aaaatataac ctcaatgggc gtgaatccat catcaaccct 1560 ggcactgcta tggcctcaca caaagacgac gaagacaagt tctttcccat gagcggtgtc 1620 atgatttttg gaaaagagag cgccggagct tcaaacactg cattggacaa tgtcatgatt 1680 acagacgaag aggaaattaa agccactaac cctgtggcca ccgaaagatt tgggaccgtg 1740 gcagtcaatt tccagagcag cagcacagac cctgcgaccg gagatgtgca tgctatggga 1800 gcattacctg gcatggtgtg gcaagataga gacgtgtacc tgcagggtcc catttgggcc 1860 aaaattcctc acacagatgg acactttcac ccgtctcctc ttatgggcgg ctttggactc 1920 aagaacccgc ctcctcagat cctcatcaaa aacacgcctg ttcctgcgaa tcctccggcg 1980 gagttttcag ctacaaagtt tgcttcattc atcacccaat actccacagg acaagtgagt 2040 gtggaaattg aatgggagct gcagaaagaa aacagcaagc gctggaatcc cgaagtgcag 2100 tacacatcca attatgcaaa atctgccaac gttgatttta ctgtggacaa caatggactt 2160 tatactgagc ctcgccccat tggcacccgt taccttaccc gtcccctgta a 2211 <![CDATA[<210> 26]]> <![CDATA[<211> 2208]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 26]]> atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga aggaataaga 60 cagtggtgga agctcaaacc tggcccacca ccaccaaagc ccgcagagcg gcataaggac 120 gacagcaggg gtcttgtgct tcctgggtac aagtacctcg gacccttcaa cggactcgac 180 aagggagagc cggtcaacga ggcagacgcc gcggccctcg agcacgacaa agcctacgac 240 cggcagctcg acagcggaga caacccgtac ctcaagtaca accacgccga cgcggagttt 300 caggagcgcc ttaaagaaga tacgtctttt gggggcaacc tcggacgagc agtcttccag 360 gcgaaaaaga gggttcttga acctctgggc ctggttgagg aacctgttaa gacggctccg 420 ggaaaaaaga ggccggtaga gcactctcct gtggagccag actcctcctc gggaaccgga 480 aaggcgggcc agcagcctgc aagaaaaaga ttgaattttg gtcagactgg agacgcagac 540 tcagtacctg acccccagcc tctcggacag ccaccagcag ccccctctgg tctgggaact 600 aatacgatgg ctacaggcag tggcgcacca atggcagaca ataacgaggg cgccgacgga 660 gtgggtaatt cctccggaaa ttggcattgc gattccacat ggatgggcga cagagtcatc 720 accaccagca cccgaacctg ggccctgccc acctacaaca accacctcta caaacaaatt 780 tccagccaat caggagcctc gaacgacaat cactactttg gctacagcac cccttggggg 840 tattttgact tcaacagatt ccactgccac ttttcaccac gtgactggca aagactcatc 900 aacaacaact ggggattccg acccaagaga ctcaacttca agctctttaa cattcaagtc 960 aaagaggtca cgcagaatga cggtacgacg acgattgcca ataaccttac cagcacggtt 1020 caggtgttta ctgactcgga gtaccagctc ccgtacgtcc tcggctcggc gcatcaagga 1080 tgcctcccgc cgttcccagc agacgtcttc atggtgccac agtatggata cctcaccctg 1140 aacaacggga gtcaggcagt aggacgctct tcattttact gcctggagta ctttccttct 1200 cagatgctgc gtaccggaaa caactttacc ttcagctaca cttttgagga cgttcctttc 1260 cacagcagct acgctcacag ccagagtctg gaccgtctca tgaatcctct catcgaccag 1320 tacctgtatt acttgagcag aacaaacact ccaagtggaa ccaccacgca gtcaaggctt 1380 cagttttctc aggccggagc gagtgacatt cgggaccagt ctaggaactg gcttcctgga 1440 ccctgttacc gccagcagcg agtatcaaag acatctgcgg ataacaacaa cagtgaatac 1500 tcgtggactg gagctaccaa gtaccacctc aatggcagag actctctggt gaatccgggc 1560 ccggccatgg caagccacaa ggacgatgaa gaaaagtttt ttcctcagag cggggttctc 1620 atctttggga agcaaggctc agagaaaaca aatgtggaca ttgaaaaggt catgattaca 1680 gacgaagagg aaatcaggac aaccaatccc gtggctacgg agcagtatgg ttctgtatct 1740 accaacctcc agagaggcaa cagacaagca gctaccgcag atgtcaacac acaaggcgtt 1800 cttccaggca tggtctggca ggacagagat gtgtaccttc aggggcccat ctgggcaaag 1860 attccacaca cggacggaca ttttcacccc tctcccctca tgggtggatt cggacttaaa 1920 caccctcctc cacagattct catcaagaac accccggtac ctgcgaatcc ttcgaccacc 1980 ttcagtgcgg caaagtttgc ttccttcatc acacagtact ccacgggaca ggtcagcgtg 2040 gagatcgagt gggagctgca gaaggaaaac agcaaacgct ggaatcccga aattcagtac 2100 acttccaact acaacaagtc tgttaatgtg gactttactg tggacactaa tggcgtgtat 2160 tcagagcctc gccccattgg caccagatac ctgactcgta atctgtaa 2208 <![CDATA[<210> 27]]> <![CDATA[<211> 2211]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 27]]> atggctgctg acggttatct tccagattgg ctcgaggaca acctttctga aggcattcgt 60 gagtggtggg ctctgaaacc tggagtccct caacccaaag cgaaccaaca acaccaggac 120 aaccgtcggg gtcttgtgct tccgggttac aaatacctcg gacccggtaa cggactcgac 180 aaaggagagc cggtcaacga ggcggacgcg gcagccctcg aacacgacaa agcttacgac 240 cagcagctca aggccggtga caacccgtac ctcaagtaca accacgccga cgccgagttt 300 caggagcgtc ttcaagaaga tacgtctttt gggggcaacc ttggcagagc agtcttccag 360 gccaaaaaga ggatccttga gcctcttggt ctggttgagg aagcagctaa aacggctcct 420 ggaaagaagg gggctgtaga tcagtctcct caggaaccgg actcatcatc tggtgttggc 480 aaatcgggca aacagcctgc cagaaaaaga ctaaatttcg gtcagactgg agactcagag 540 tcagtcccag accctcaacc tctcggagaa ccaccagcag cccccacaag tttgggatct 600 aatacaatgg cttcaggcgg tggcgcacca atggcagaca ataacgaggg tgccgatgga 660 gtgggtaatt cctcaggaaa ttggcattgc gattcccaat ggctgggcga cagagtcatc 720 accaccagca ccagaacctg ggccctgccc acttacaaca accatctcta caagcaaatc 780 tccagccaat caggagcttc aaacgacaac cactactttg gctacagcac cccttggggg 840 tattttgact ttaacagatt ccactgccac ttctcaccac gtgactggca gcgactcatt 900 aacaacaact ggggattccg gcccaagaaa ctcagcttca agctcttcaa catccaagtt 960 agaggggtca cgcagaacga tggcacgacg actattgcca ataaccttac cagcacggtt 1020 caagtgttta cggactcgga gtatcagctc ccgtacgtgc tcgggtcggc gcaccaaggc 1080 tgtctcccgc cgtttccagc ggacgtcttc atggtccctc agtatggata cctcaccctg 1140 aacaacggaa gtcaagcggt gggacgctca tccttttact gcctggagta cttcccttcg 1200 cagatgctaa ggactggaaa taacttccaa ttcagctata ccttcgagga tgtacctttt 1260 cacagcagct acgctcacag ccagagtttg gatcgcttga tgaatcctct tattgatcag 1320 tatctgtact acctgaacag aacgcaagga acaacctctg gaacaaccaa ccaatcacgg 1380 ctgcttttta gccaggctgg gcctcagtct atgtctttgc aggccagaaa ttggctacct 1440 gggccctgct accggcaaca gagactttca aagactgcta acgacaacaa caacagtaac 1500 tttccttgga cagcggccag caaatatcat ctcaatggcc gcgactcgct ggtgaatcca 1560 ggaccagcta tggccagtca caaggacgat gaagaaaaat ttttccctat gcacggcaat 1620 ctaatatttg gcaaagaagg gacaacggca agtaacgcag aattagataa tgtaatgatt 1680 acggatgaag aagagattcg taccaccaat cctgtggcaa cagagcagta tggaactgtg 1740 gcaaataact tgcagagctc aaatacagct cccacgactg gaactgtcaa tcatcagggg 1800 gccttacctg gcatggtgtg gcaagatcgt gacgtgtacc ttcaaggacc tatctgggca 1860 aagattcctc acacggatgg acactttcat ccttctcctc tgatgggagg ctttggactg 1920 aaacatccgc ctcctcaaat catgatcaaa aatactccgg taccggcaaa tcctccgacg 1980 actttcagcc cggccaagtt tgcttcattt atcactcagt actccactgg acaggtcagc 2040 gtggaaattg agtgggagct acagaaagaa aacagcaaac gttggaatcc agagattcag 2100 tacacttcca actacaacaa gtctgttaat gtggacttta ctgtagacac taatggtgtt 2160 tatagtgaac ctcgccctat tggaacccgg tatctcacac gaaacttgtg a 2211 <![CDATA[<210> 28]]> <![CDATA[<211> 2285]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223>]]> 合成的 <![CDATA[<400> 28]]> atgactgacg gttaccttcc agattggcta gaggacaacc tctctgaagg cgttcgagag 60 tggtgggcgc tgcaacctgg agcccctaaa cccaaggcaa atcaacaaca tcaggacaac 120 gctcggggtc ttgtgcttcc gggttacaaa tacctcggac ccggcaacgg actcgacaag 180 ggggaacccg tcaacgcagc ggacgcggca gccctcgagc acgacaaggc ctacgaccag 240 cagctcaagg ccggtgacaa cccctacctc aagtacaacc acgccgacgc ggagttccag 300 cagcggcttc agggcgacac atcgtttggg ggcaacctcg gcagagcagt cttccaggcc 360 aaaaagaggg ttcttgaacc tcttggtctg gttgagcaag cgggtgagac ggctcctgga 420 aagaagagac cgttgattga atccccccag cagcccgact cctccacggg tatcggcaaa 480 aaaggcaagc agccggctaa aaagaagctc gttttcgaag acgaaactgg agcaggcgac 540 ggaccccctg agggatcaac ttccggagcc atgtctgatg acagtgagat gcgtgcagca 600 gctggcggag ctgcagtcga gggcggacaa ggtgccgatg gagtgggtaa tgcctcgggt 660 gattggcatt gcgattccac ctggtctgag ggccacgtca cgaccaccag caccagaacc 720 tgggtcttgc ccacctacaa caaccacctc tacaagcgac tcggagagag cctgcagtcc 780 aacacctaca acggattctc caccccctgg ggatactttg acttcaaccg cttccactgc 840 cacttctcac cacgtgactg gcagcgactc atcaacaaca actggggcat gcgacccaaa 900 gccatgcggg tcaaaatctt caacatccag gtcaaggagg tcacgacgtc gaacggcgag 960 acaacggtgg ctaataacct taccagcacg gttcagatct ttgcggactc gtcgtacgaa 1020 ctgccgtacg tgatggatgc gggtcaagag ggcagcctgc ctccttttcc caacgacgtc 1080 tttatggtgc cccagtacgg ctactgtgga ctggtgaccg gcaacacttc gcagcaacag 1140 actgacagaa atgccttcta ctgcctggag tactttcctt cgcagatgct gcggactggc 1200 aacaactttg aaattacgta cagttttgag aaggtgcctt tccactcgat gtacgcgcac 1260 agccagagcc tggaccggct gatgaaccct ctcatcgacc agtacctgtg gggactgcaa 1320 tcgaccacca ccggaaccac cctgaatgcc gggactgcca ccaccaactt taccaagctg 1380 cggcctacca acttttccaa ctttaaaaag aactggctgc ccgggccttc aatcaagcag 1440 cagggcttct caaagactgc caatcaaaac tacaagatcc ctgccaccgg gtcagacagt 1500 ctcatcaaat acgagacgca cagcactctg gacggaagat ggagtgccct gacccccgga 1560 cctccaatgg ccacggctgg acctgcggac agcaagttca gcaacagcca gctcatcttt 1620 gcggggccta aacagaacgg caacacggcc accgtacccg ggactctgat cttcacctct 1680 gaggaggagc tggcagccac caacgccacc gatacggaca tgtggggcaa cctacctggc 1740 ggtgaccaga gcaacagcaa cctgccgacc gtggacagac tgacagcctt gggagccgtg 1800 cctggaatgg tctggcaaaa cagagacatt tactaccagg gtcccatttg ggccaagatt 1860 cctcataccg atggacactt tcacccctca ccgctgattg gtgggtttgg gctgaaacac 1920 ccgcctcctc aaatttttat caagaacacc ccggtacctg cgaatcctgc aacgaccttc 1980 agctctactc cggtaaactc cttcattact cagtacagca ctggccaggt gtcggtgcag 2040 attgactggg agatccagaa ggagcggtcc aaacgctgga accccgaggt ccagtttacc 2100 tccaactacg gacagcaaaa ctctctgttg tgggctcccg atgcggctgg gaaatacact 2160 gagcctaggg ctatcggtac ccgctacctc acccaccacc tgtaataacc tgttaatcaa 2220 taaaccggtt tattcgtttc agttgaactt tggtctccgt gtccttctta tcttatctcg 2280 tttcc 2285 <![CDATA[<210> 29]]> <![CDATA[<211> 2175]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 29]]> atgtcttttg ttgatcaccc tccagattgg ttggaagaag ttggtgaagg tcttcgcgag 60 tttttgggcc ttgaagcggg cccaccgaaa ccaaaaccca atcagcagca tcaagatcaa 120 gcccgtggtc ttgtgctgcc tggttataac tatctcggac ccggaaacgg tctcgatcga 180 ggagagcctg tcaacagggc agacgaggtc gcgcgagagc acgacatctc gtacaacgag 240 cagcttgagg cgggagacaa cccctacctc aagtacaacc acgcggacgc cgagtttcag 300 gagaagctcg ccgacgacac atccttcggg ggaaacctcg gaaaggcagt ctttcaggcc 360 aagaaaaggg ttctcgaacc ttttggcctg gttgaagagg gtgctaagac ggcccctacc 420 ggaaagcgga tagacgacca ctttccaaaa agaaagaagg ctcggaccga agaggactcc 480 aagccttcca cctcgtcaga cgccgaagct ggacccagcg gatcccagca gctgcaaatc 540 ccagcccaac cagcctcaag tttgggagct gatacaatgt ctgcgggagg tggcggccca 600 ttgggcgaca ataaccaagg tgccgatgga gtgggcaatg cctcgggaga ttggcattgc 660 gattccacgt ggatggggga cagagtcgtc accaagtcca cccgaacctg ggtgctgccc 720 agctacaaca accaccagta ccgagagatc aaaagcggct ccgtcgacgg aagcaacgcc 780 aacgcctact ttggatacag caccccctgg gggtactttg actttaaccg cttccacagc 840 cactggagcc cccgagactg gcaaagactc atcaacaact actggggctt cagaccccgg 900 tccctcagag tcaaaatctt caacattcaa gtcaaagagg tcacggtgca ggactccacc 960 accaccatcg ccaacaacct cacctccacc gtccaagtgt ttacggacga cgactaccag 1020 ctgccctacg tcgtcggcaa cgggaccgag ggatgcctgc cggccttccc tccgcaggtc 1080 tttacgctgc cgcagtacgg ttacgcgacg ctgaaccgcg acaacacaga aaatcccacc 1140 gagaggagca gcttcttctg cctagagtac tttcccagca agatgctgag aacgggcaac 1200 aactttgagt ttacctacaa ctttgaggag gtgcccttcc actccagctt cgctcccagt 1260 cagaacctgt tcaagctggc caacccgctg gtggaccagt acttgtaccg cttcgtgagc 1320 acaaataaca ctggcggagt ccagttcaac aagaacctgg ccgggagata cgccaacacc 1380 tacaaaaact ggttcccggg gcccatgggc cgaacccagg gctggaacct gggctccggg 1440 gtcaaccgcg ccagtgtcag cgccttcgcc acgaccaata ggatggagct cgagggcgcg 1500 agttaccagg tgcccccgca gccgaacggc atgaccaaca acctccaggg cagcaacacc 1560 tatgccctgg agaacactat gatcttcaac agccagccgg cgaacccggg caccaccgcc 1620 acgtacctcg agggcaacat gctcatcacc agcgagagcg agacgcagcc ggtgaaccgc 1680 gtggcgtaca acgtcggcgg gcagatggcc accaacaacc agagctccac cactgccccc 1740 gcgaccggca cgtacaacct ccaggaaatc gtgcccggca gcgtgtggat ggagagggac 1800 gtgtacctcc aaggacccat ctgggccaag atcccagaga cgggggcgca ctttcacccc 1860 tctccggcca tgggcggatt cggactcaaa cacccaccgc ccatgatgct catcaagaac 1920 acgcctgtgc ccggaaatat caccagcttc tcggacgtgc ccgtcagcag cttcatcacc 1980 cagtacagca ccgggcaggt caccgtggag atggagtggg agctcaagaa ggaaaactcc 2040 aagaggtgga acccagagat ccagtacaca aacaactaca acgaccccca gtttgtggac 2100 tttgccccgg acagcaccgg ggaatacaga accaccagac ctatcggaac ccgatacctt 2160 acccgacccc tttaa 2175 <![CDATA[<210> 30]]> <![CDATA[<211> 2212]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 30]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg acttgaaacc tggagccccg aaacccaaag ccaaccagca aaagcaggac 120 gacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggatgca gcggccctcg agcacgacaa ggcctacgac 240 cagcagctca aagcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360 gccaagaaga gggttctcga accttttggt ctggttgagg aaggtgctaa gacggctcct 420 ggaaagaaac gtccggtaga gcagtcgcca caagagccag actcctcctc gggcattggc 480 aagacaggcc agcagcccgc taaaaagaga ctcaattttg gtcagactgg cgactcagag 540 tcagtccccg acccacaacc tctcggagaa cctccagcaa cccccgctgc tgtgggacct 600 actacaatgg cttcaggcgg tggcgcacca atggcagaca ataacgaagg cgccgacgga 660 gtgggtaatg cctcaggaaa ttggcattgc gattccacat ggctgggcga cagagtcatc 720 accaccagca cccgaacatg ggccttgccc acctataaca accacctcta caagcaaatc 780 tccagtgctt caacgggggc cagcaacgac aaccactact tcggctacag caccccctgg 840 gggtattttg atttcaacag attccactgc catttctcac cacgtgactg gcagcgactc 900 atcaacaaca attggggatt ccggcccaag agactcaact tcaagctctt caacatccaa 960 gtcaaggagg tcacgacgaa tgatggcgtc acgaccatcg ctaataacct taccagcacg 1020 gttcaagtct tctcggactc ggagtaccag ttgccgtacg tcctcggctc tgcgcaccag 1080 ggctgcctcc ctccgttccc ggcggacgtg ttcatgattc cgcagtacgg ctacctaacg 1140 ctcaacaatg gcagccaggc agtgggacgg tcatcctttt actgcctgga atatttccca 1200 tcgcagatgc tgagaacggg caataacttt accttcagct acaccttcga ggacgtgcct 1260 ttccacagca gctacgcgca cagccagagc ctggaccggc tgatgaatcc tctcatcgac 1320 cagtacctgt attacctgaa cagaactcag aatcagtccg gaagtgccca aaacaaggac 1380 ttgctgttta gccgggggtc tccagctggc atgtctgttc agcccaaaaa ctggctacct 1440 ggaccctgtt accggcagca gcgcgtttct aaaacaaaaa cagacaacaa caacagcaac 1500 tttacctgga ctggtgcttc aaaatataac cttaatgggc gtgaatctat aatcaaccct 1560 ggcactgcta tggcctcaca caaagacgac aaagacaagt tctttcccat gagcggtgtc 1620 atgatttttg gaaaggagag cgccggagct tcaaacactg cattggacaa tgtcatgatc 1680 acagacgaag aggaaatcaa agccactaac cccgtggcca ccgaaagatt tgggactgtg 1740 gcagtcaatc tccagagcag cagcacagac cctgcgaccg gagatgtgca tgttatggga 1800 gccttacctg gaatggtgtg gcaagacaga gacgtatacc tgcagggtcc tatttgggcc 1860 aaaattcctc acacggatgg acactttcac ccgtctcctc tcatgggcgg ctttggactt 1920 aagcacccgc ctcctcagat cctcatcaaa aacacgcctg ttcctgcgaa tcctccggca 1980 gagttttcgg ctacaaagtt tgcttcattc atcacccagt attccacagg acaagtgagc 2040 gtggagattg aatgggagct gcagaaagaa aacagcaaac gctggaatcc cgaagtgcag 2100 tatacatcta actatgcaaa atctgccaac gttgatttca ctgtggacaa caatggactt 2160 tatactgagc ctcgccccat tggcacccgt tacctcaccc gtcccctgta at 2212 <![CDATA[<210> 31]]> <![CDATA[<211> 2214]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 31]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg acctgaaacc tggagccccg aaacccaaag ccaaccagca aaagcaggac 120 aacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggacgca gcggccctcg agcacgacaa ggcctacgac 240 cagcagctca aagcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtcattt gggggcaacc tcgggcgagc agtcttccag 360 gccaagaagc gggttctcga acctctcggt ctggttgagg aaggcgctaa gacggctcct 420 gcaaagaaga gaccggtaga gccgtcacct cagcgttccc ccgactcctc cacgggcatc 480 ggcaagaaag gccagcagcc cgccagaaag agactcaatt tcggtcagac tggcgactca 540 gagtcagtcc ccgaccctca acctctcgga gaacctccag cagcgccctc tagtgtggga 600 tctggtacag tggctgcagg cggtggcgca ccaatggcag acaataacga aggtgccgac 660 ggagtgggta atgcctcagg aaattggcat tgcgattcca catggctggg cgacagagtc 720 attaccacca gcacccgaac ctgggccctg cccacctaca acaaccacct ctacaagcaa 780 atctccagtg aaactgcagg tagtaccaac gacaacacct acttcggcta cagcaccccc 840 tgggggtatt ttgactttaa cagattccac tgccacttct caccacgtga ctggcagcga 900 ctcatcaaca acaactgggg attccggccc aagaagctgc ggttcaagct cttcaacatc 960 caggtcaagg aggtcacgac gaatgacggc gttacgacca tcgctaataa ccttaccagc 1020 acgattcagg tattctcgga ctcggaatac cagctgccgt acgtcctcgg ctctgcgcac 1080 cagggctgcc tgcctccgtt cccggcggac gtcttcatga ttcctcagta cggctacctg 1140 actctcaaca atggcagtca gtctgtggga cgttcctcct tctactgcct ggagtacttc 1200 ccctctcaga tgctgagaac gggcaacaac tttgagttca gctacagctt cgaggacgtg 1260 cctttccaca gcagctacgc acacagccag agcctggacc ggctgatgaa tcccctcatc 1320 gaccagtact tgtactacct ggccagaaca cagagtaacc caggaggcac agctggcaat 1380 cgggaactgc agttttacca gggcgggcct tcaactatgg ccgaacaagc caagaattgg 1440 ttacctggac cttgcttccg gcaacaaaga gtctccaaaa cgctggatca aaacaacaac 1500 agcaactttg cttggactgg tgccaccaaa tatcacctga acggcagaaa ctcgttggtt 1560 aatcccggcg tcgccatggc aactcacaag gacgacgagg accgcttttt cccatccagc 1620 ggagtcctga tttttggaaa aactggagca actaacaaaa ctacattgga aaatgtgtta 1680 atgacaaatg aagaagaaat tcgtcctact aatcctgtag ccacggaaga atacgggata 1740 gtcagcagca acttacaagc ggctaatact gcagcccaga cacaagttgt caacaaccag 1800 ggagccttac ctggcatggt ctggcagaac cgggacgtgt acctgcaggg tcccatctgg 1860 gccaagattc ctcacacgga tggcaacttt cacccgtctc ctttgatggg cggctttgga 1920 cttaaacatc cgcctcctca gatcctgatc aagaacactc ccgttcccgc taatcctccg 1980 gaggtgttta ctcctgccaa gtttgcttcg ttcatcacac agtacagcac cggacaagtc 2040 agcgtggaaa tcgagtggga gctgcagaag gaaaacagca agcgctggaa cccggagatt 2100 cagtacacct ccaactttga aaagcagact ggtgtggact ttgccgttga cagccagggt 2160 gtttactctg agcctcgccc tattggcact cgttacctca cccgtaatct gtaa 2214 <![CDATA[<210> 32]]> <![CDATA[<211> 2217]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 32]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg cgctgaaacc tggagccccg aagcccaaag ccaaccagca aaagcaggac 120 gacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggacgca gcggccctgg agcacgacaa ggcctacgac 240 cagcagctgc aggcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360 gccaagaagc gggttctcga acctctcggt ctggttgagg aaggcgctaa gacggctcct 420 ggaaagaaga gaccggtaga gccatcaccc cagcgttctc cagactcctc tacgggcatc 480 ggcaagaaag gccaacagcc cgccagaaaa agactcaatt ttggtcagac tggcgactca 540 gagtcagttc cagaccctca acctctcgga gaacctccag cagcgccctc tggtgtggga 600 cctaatacaa tggctgcagg cggtggcgca ccaatggcag acaataacga aggcgccgac 660 ggagtgggta gttcctcggg aaattggcat tgcgattcca catggctggg cgacagagtc 720 atcaccacca gcacccgaac ctgggccctg cccacctaca acaaccacct ctacaagcaa 780 atctccaacg ggacatcggg aggagccacc aacgacaaca cctacttcgg ctacagcacc 840 ccctgggggt attttgactt taacagattc cactgccact tttcaccacg tgactggcag 900 cgactcatca acaacaactg gggattccgg cccaagagac tcagcttcaa gctcttcaac 960 atccaggtca aggaggtcac gcagaatgaa ggcaccaaga ccatcgccaa taacctcacc 1020 agcaccatcc aggtgtttac ggactcggag taccagctgc cgtacgttct cggctctgcc 1080 caccagggct gcctgcctcc gttcccggcg gacgtgttca tgattcccca gtacggctac 1140 ctaacactca acaacggtag tcaggccgtg ggacgctcct ccttctactg cctggaatac 1200 tttccttcgc agatgctgag aaccggcaac aacttccagt ttacttacac cttcgaggac 1260 gtgcctttcc acagcagcta cgcccacagc cagagcttgg accggctgat gaatcctctg 1320 attgaccagt acctgtacta cttgtctcgg actcaaacaa caggaggcac ggcaaatacg 1380 cagactctgg gcttcagcca aggtgggcct aatacaatgg ccaatcaggc aaagaactgg 1440 ctgccaggac cctgttaccg ccaacaacgc gtctcaacga caaccgggca aaacaacaat 1500 agcaactttg cctggactgc tgggaccaaa taccatctga atggaagaaa ttcattggct 1560 aatcctggca tcgctatggc aacacacaaa gacgacgagg agcgtttttt tcccagtaac 1620 gggatcctga tttttggcaa acaaaatgct gccagagaca atgcggatta cagcgatgtc 1680 atgctcacca gcgaggaaga aatcaaaacc actaaccctg tggctacaga ggaatacggt 1740 atcgtggcag ataacttgca gcagcaaaac acggctcctc aaattggaac tgtcaacagc 1800 cagggggcct tacccggtat ggtctggcag aaccgggacg tgtacctgca gggtcccatc 1860 tgggccaaga ttcctcacac ggacggcaac ttccacccgt ctccgctgat gggcggcttt 1920 ggcctgaaac atcctccgcc tcagatcctg atcaagaaca cgcctgtacc tgcggatcct 1980 ccgaccacct tcaaccagtc aaagctgaac tctttcatca cgcaatacag caccggacag 2040 gtcagcgtgg aaattgaatg ggagctgcag aaggaaaaca gcaagcgctg gaaccccgag 2100 atccagtaca cctccaacta ctacaaatct acaagtgtgg actttgctgt taatacagaa 2160 ggcgtgtact ctgaaccccg ccccattggc acccgttacc tcacccgtaa tctgtaa 2217 <![CDATA[<210> 33]]> <![CDATA[<211> 2211]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 33]]> atggctgccg atggttatct tccagattgg ctcgaggaca accttagtga aggaattcgc 60 gagtggtggg ctttgaaacc tggagcccct caacccaagg caaatcaaca acatcaagac 120 aacgctcgag gtcttgtgct tccgggttac aaataccttg gacccggcaa cggactcgac 180 aagggggagc cggtcaacgc agcagacgcg gcggccctcg agcacgacaa ggcctacgac 240 cagcagctca aggccggaga caacccgtac ctcaagtaca accacgccga cgccgagttc 300 caggagcggc tcaaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360 gccaaaaaga ggcttcttga acctcttggt ctggttgagg aagcggctaa gacggctcct 420 ggaaagaaga ggcctgtaga gcagtctcct caggaaccgg actcctccgc gggtattggc 480 aaatcgggtg cacagcccgc taaaaagaga ctcaatttcg gtcagactgg cgacacagag 540 tcagtcccag accctcaacc aatcggagaa cctcccgcag ccccctcagg tgtgggatct 600 cttacaatgg cttcaggtgg tggcgcacca gtggcagaca ataacgaagg tgccgatgga 660 gtgggtagtt cctcgggaaa ttggcattgc gattcccaat ggctggggga cagagtcatc 720 accaccagca cccgaacctg ggccctgccc acctacaaca atcacctcta caagcaaatc 780 tccaacagca catctggagg atcttcaaat gacaacgcct acttcggcta cagcaccccc 840 tgggggtatt ttgacttcaa cagattccac tgccacttct caccacgtga ctggcagcga 900 ctcatcaaca acaactgggg attccggcct aagcgactca acttcaagct cttcaacatt 960 caggtcaaag aggttacgga caacaatgga gtcaagacca tcgccaataa ccttaccagc 1020 acggtccagg tcttcacgga ctcagactat cagctcccgt acgtgctcgg gtcggctcac 1080 gagggctgcc tcccgccgtt cccagcggac gttttcatga ttcctcagta cgggtatctg 1140 acgcttaatg atggaagcca ggccgtgggt cgttcgtcct tttactgcct ggaatatttc 1200 ccgtcgcaaa tgctaagaac gggtaacaac ttccagttca gctacgagtt tgagaacgta 1260 cctttccata gcagctacgc tcacagccaa agcctggacc gactaatgaa tccactcatc 1320 gaccaatact tgtactatct ctcaaagact attaacggtt ctggacagaa tcaacaaacg 1380 ctaaaattca gtgtggccgg acccagcaac atggctgtcc agggaagaaa ctacatacct 1440 ggacccagct accgacaaca acgtgtctca accactgtga ctcaaaacaa caacagcgaa 1500 tttgcttggc ctggagcttc ttcttgggct ctcaatggac gtaatagctt gatgaatcct 1560 ggacctgcta tggccagcca caaagaagga gaggaccgtt tctttccttt gtctggatct 1620 ttaatttttg gcaaacaagg aactggaaga gacaacgtgg atgcggacaa agtcatgata 1680 accaacgaag aagaaattaa aactactaac ccggtagcaa cggagtccta tggacaagtg 1740 gccacaaacc accagagtgc ccaagcacag gcgcagaccg gctgggttca aaaccaagga 1800 atacttccgg gtatggtttg gcaggacaga gatgtgtacc tgcaaggacc catttgggcc 1860 aaaattcctc acacggacgg caactttcac ccttctccgc tgatgggagg gtttggaatg 1920 aagcacccgc ctcctcagat cctcatcaaa aacacacctg tacctgcgga tcctccaacg 1980 gccttcaaca aggacaagct gaactctttc atcacccagt attctactgg ccaagtcagc 2040 gtggagatcg agtgggagct gcagaaggaa aacagcaagc gctggaaccc ggagatccag 2100 tacacttcca actattacaa gtctaataat gttgaatttg ctgttaatac tgaaggtgta 2160 tatagtgaac cccgccccat tggcaccaga tacctgactc gtaatctgta a 2211 <![CDATA[<210> 34]]> <![CDATA[<211> 2217]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 34]]> atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60 gagtggtggg acttgaaacc tggagccccg aaacccaaag ccaaccagca aaagcaggac 120 gacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180 aagggggagc ccgtcaacgc ggcggacgca gcggccctcg agcacgacaa ggcctacgac 240 cagcagctca aagcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300 caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360 gccaagaagc gggttctcga acctctcggt ctggttgagg aaggcgctaa gacggctcct 420 ggaaagaaga gaccggtaga gccatcaccc cagcgttctc cagactcctc tacgggcatc 480 ggcaagaaag gccagcagcc cgcgaaaaag agactcaact ttgggcagac tggcgactca 540 gagtcagtgc ccgaccctca accaatcgga gaaccccccg caggcccctc tggtctggga 600 tctggtacaa tggctgcagg cggtggcgct ccaatggcag acaataacga aggcgccgac 660 ggagtgggta gttcctcagg aaattggcat tgcgattcca catggctggg cgacagagtc 720 atcaccacca gcacccgaac ctgggccctc cccacctaca acaaccacct ctacaagcaa 780 atctccaacg ggacttcggg aggaagcacc aacgacaaca cctacttcgg ctacagcacc 840 ccctgggggt attttgactt taacagattc cactgccact tctcaccacg tgactggcag 900 cgactcatca acaacaactg gggattccgg cccaagagac tcaacttcaa gctcttcaac 960 atccaggtca aggaggtcac gcagaatgaa ggcaccaaga ccatcgccaa taaccttacc 1020 agcacgattc aggtctttac ggactcggaa taccagctcc cgtacgtcct cggctctgcg 1080 caccagggct gcctgcctcc gttcccggcg gacgtcttca tgattcctca gtacgggtac 1140 ctgactctga acaatggcag tcaggccgtg ggccgttcct ccttctactg cctggagtac 1200 tttccttctc aaatgctgag aacgggcaac aactttgagt tcagctacca gtttgaggac 1260 gtgccttttc acagcagcta cgcgcacagc caaagcctgg accggctgat gaaccccctc 1320 atcgaccagt acctgtacta cctgtctcgg actcagtcca cgggaggtac cgcaggaact 1380 cagcagttgc tattttctca ggccgggcct aataacatgt cggctcaggc caaaaactgg 1440 ctacccgggc cctgctaccg gcagcaacgc gtctccacga cactgtcgca aaataacaac 1500 agcaactttg cctggaccgg tgccaccaag tatcatctga atggcagaga ctctctggta 1560 aatcccggtg tcgctatggc aacccacaag gacgacgaag agcgattttt tccgtccagc 1620 ggagtcttaa tgtttgggaa acagggagct ggaaaagaca acgtggacta tagcagcgtt 1680 atgctaacca gtgaggaaga aattaaaacc accaacccag tggccacaga acagtacggc 1740 gtggtggccg ataacctgca acagcaaaac gccgctccta ttgtaggggc cgtcaacagt 1800 caaggagcct tacctggcat ggtctggcag aaccgggacg tgtacctgca gggtcctatc 1860 tgggccaaga ttcctcacac ggacggaaac tttcatccct cgccgctgat gggaggcttt 1920 ggactgaaac acccgcctcc tcagatcctg attaagaata cacctgttcc cgcggatcct 1980 ccaactacct tcagtcaagc taagctggcg tcgttcatca cgcagtacag caccggacag 2040 gtcagcgtgg aaattgaatg ggagctgcag aaagaaaaca gcaaacgctg gaacccagag 2100 attcaataca cttccaacta ctacaaatct acaaatgtgg actttgctgt taacacagat 2160 ggcacttatt ctgagcctcg ccccatcggc acccgttacc tcacccgtaa tctgtaa 2217 <![CDATA[<210> 35]]> <![CDATA[<211> 143]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV1]]> <![CDATA[<400> 35]]> ttgcccactc cctctctgcg cgctcgctcg ctcggtgggg cctgcggacc aaaggtccgc 60 agacggcaga ggtctcctct gccggcccca ccgagcgagc gagcgcgcag agagggagtg 120 ggcaactcca tcactagggg taa 143 <![CDATA[<210> 36]]> <![CDATA[<211> 146]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知]]> <![CDATA[<220>]]> <![CDATA[<223> AAV4]]> <![CDATA[<400> 36]]> ttggccactc cctctatgcg cgctcgctca ctcactcggc cctggagacc aaaggtctcc 60 agactgccgg cctctggccg gcagggccga gtgagtgagc gagcgcgcat agagggagtg 120 gccaactcca tcatctaggt ttgccc 146
Claims (42)
- 一種殼體蛋白,其在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,其中該殼體蛋白為AAVrh74血清型殼體蛋白, 視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F。
- 一種AAVrh74粒子,其包含如請求項1之殼體蛋白。
- 如請求項2之AAVrh74粒子,其進一步包含核酸載體,其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(inverted terminal repeat;ITR)及包含第二D序列之第二ITR,其中該第一D序列或該第二D序列係經S序列取代, 視需要其中該S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
- 如請求項2之AAVrh74粒子,其進一步包含核酸載體,其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中該第一D序列及/或該第二D序列係經糖皮質激素受體結合元件(glucocorticoid receptor-binding element;GRE)取代, 視需要其中該GRE包含核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
- 一種組成物,其包含如請求項1之殼體蛋白。
- 一種組成物,其包含如請求項2至4中任一項之AAVrh74粒子。
- 一種方法,其包含使細胞與包含AAVrh74粒子之組成物接觸,其中該AAVrh74粒子包含殼體蛋白及核酸載體, (i)其中該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及/或 (ii)其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中該第一D序列及/或該第二D序列係經S序列取代,視需要其中該S序列包含核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
- 一種方法,其包含使細胞與包含AAVrh74粒子之組成物接觸,其中該AAVrh74粒子包含殼體蛋白及核酸載體, (i)其中該殼體蛋白在對應於SEQ ID NO: 1之野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及/或 (ii)其中該核酸載體包含有包含第一D序列之第一反向末端重複序列(ITR)及包含第二D序列之第二ITR,其中該第一D序列及/或該第二D序列係經糖皮質激素受體結合元件(GRE)取代,視需要其中該GRE包含核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
- 如請求項7或8之方法,其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733的位置處包含胺基酸取代,視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F。
- 如請求項7之方法,其中該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列或該第二D序列係經該S序列取代,視需要其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
- 如請求項8之方法,其中該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列及/或該第二D序列係經該GRE取代,視需要其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
- 如請求項7之方法,其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,及 其中該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列或該第二D序列係經該S序列取代, 視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及 視需要其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成。
- 如請求項8之方法,其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之Y447、T494、K547、N665及/或Y733之位置處包含胺基酸取代,及 其中該核酸載體包含該第一ITR及該第二ITR,其中該第一D序列及/或該第二D序列係經該GRE取代, 視需要其中該取代為Y447F、T494V、K547R、N665R及/或Y733F,及 視需要其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
- 如請求項7至13中任一項之方法,其中該殼體蛋白在對應於SEQ ID NO: 1之該野生型AAVrh74殼體蛋白之以下位置處包含胺基酸取代: (a)Y447及Y733,視需要其中該等取代為Y447F及Y733F; (b)Y447、Y733及N665,視需要其中該等取代為Y447F、Y733F及N665R; (c)Y447、Y733及T494,視需要其中該等取代為Y447F、Y733F及T494V; (d)Y447、Y733及K547,視需要其中該等取代為Y447F、Y733F及K547R;或 (e)Y447、Y733、N665、T494及K547,視需要其中該等取代為Y447F、Y733F、N665R、T494V及K547R。
- 如請求項7至13中任一項之方法,其中該第一ITR及該第二ITR各自為AAV2血清型ITR或AAV3血清型ITR。
- 如請求項7至15中任一項之方法,其中該第一D序列係經該S序列取代,或其中該第一D序列係經該GRE取代。
- 如請求項7至15中任一項之方法,其中該第二D序列係經該S序列取代,或其中該第二D序列係經該GRE取代。
- 如請求項7至17中任一項之方法,其中該S序列包含該核苷酸序列TATTAGATCTGATGGCCGCT(SEQ ID NO: 17)、基本上由該核苷酸序列組成或由該核苷酸序列組成,或 其中該GRE包含該核苷酸序列AGAACANNNTGTTCT(SEQ ID NO: 18)或其反向或反向互補序列、基本上由該核苷酸序列或其反向或反向互補序列組成或由該核苷酸序列或其反向或反向互補序列組成,其中各N獨立地為T、C、G或A。
- 如請求項7至18中任一項之方法,其中該AAVrh74粒子之轉導效率比野生型AAVrh74粒子高至少兩倍。
- 如請求項7至19中任一項之方法,其中該AAVrh74粒子之包裝效率相對於野生型AAVrh74粒子降低。
- 如請求項7至20中任一項之方法,其中該組成物進一步包含醫藥學上可接受之載劑。
- 如請求項7至21中任一項之方法,其中該細胞為哺乳動物細胞。
- 如請求項7至22中任一項之方法,其中該細胞為肌細胞。
- 如請求項7至23中任一項之方法,其中該細胞為骨胳肌細胞。
- 如請求項7至23中任一項之方法,其中該細胞為腓腸肌細胞或脛骨前肌細胞。
- 如請求項7至25中任一項之方法,其中該核酸載體包含調節元件。
- 如請求項26之方法,其中該調節元件包含啟動子、強化子、緘默子、絕緣子、反應元件、起始位點、終止信號或核糖體結合位點。
- 如請求項27之方法,其中該啟動子為持續型啟動子。
- 如請求項27之方法,其中該啟動子為可誘導型啟動子。
- 如請求項27至29中任一項之方法,其中該啟動子為組織專一性啟動子、細胞類型專一性啟動子或合成啟動子。
- 如請求項7至30中任一項之方法,其中該核酸載體包含目標基因之核苷酸序列。
- 如請求項31之方法,其中該目標基因編碼治療蛋白或診斷蛋白。
- 如請求項7至32中任一項之方法,其中該接觸為活體內的。
- 如請求項33之方法,其進一步包含向個體投予該包含AAVrh74粒子之組成物。
- 如請求項34之方法,其中該細胞係在該個體中。
- 如請求項34或35之方法,其中該個體為人類。
- 如請求項34、35或36之方法,其中該個體處於肌肉疾病風險下或罹患肌肉疾病,視需要其中該肌肉疾病為肌肉萎縮性脊髓側索硬化症、恰克-馬利-杜斯氏病(Charcot-Marie-Tooth disease)、多發性硬化症、肌肉萎縮症、重症肌無力、肌病、肌炎、周邊神經病變或脊髓性肌肉萎縮症。
- 如請求項37之方法,其中該肌肉疾病為杜氏肌肉萎縮症(Duchenne muscular dystrophy),視需要其中該個體具有肌肉萎縮蛋白基因之突變。
- 如請求項37之方法,其中該肌肉疾病為肢帶型肌肉萎縮症。
- 如請求項37之方法,其中該肌肉疾病為X性聯肌微管性肌病,視需要其中該個體具有MTM1基因之突變。
- 如請求項34至37中任一項之方法,其中該組成物係藉由皮下注射、藉由肌肉內注射、藉由靜脈內注射、藉由腹膜內注射或經口投予至該個體。
- 如請求項7至32中任一項之方法,其中該接觸為試管內或活體外的。
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TW111115475A TW202304954A (zh) | 2021-04-23 | 2022-04-22 | 用於肌肉萎縮症之基因療法的aavrh74載體 |
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EP (1) | EP4326857A2 (zh) |
JP (1) | JP2024514962A (zh) |
KR (1) | KR20240000542A (zh) |
AU (1) | AU2022262407A1 (zh) |
BR (1) | BR112023021495A2 (zh) |
CA (1) | CA3217649A1 (zh) |
CO (1) | CO2023015911A2 (zh) |
IL (1) | IL307881A (zh) |
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BR112014025985A2 (pt) * | 2012-04-18 | 2017-07-11 | Childrens Hospital Philadelphia | composição e métodos para transferência de gene altamente eficaz com o uso de variantes de capsídeo de aav |
WO2016081927A2 (en) | 2014-11-21 | 2016-05-26 | University Of Florida Research Foundation, Inc. | Genome-modified recombinant adeno-associated virus vectors |
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2022
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- 2022-04-22 KR KR1020237039756A patent/KR20240000542A/ko unknown
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- 2022-04-22 IL IL307881A patent/IL307881A/en unknown
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WO2022226289A2 (en) | 2022-10-27 |
BR112023021495A2 (pt) | 2023-12-19 |
WO2022226289A3 (en) | 2023-03-02 |
EP4326857A2 (en) | 2024-02-28 |
CA3217649A1 (en) | 2022-10-27 |
KR20240000542A (ko) | 2024-01-02 |
US20220347317A1 (en) | 2022-11-03 |
JP2024514962A (ja) | 2024-04-03 |
AU2022262407A1 (en) | 2023-10-26 |
AU2022262407A9 (en) | 2023-11-09 |
IL307881A (en) | 2023-12-01 |
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