TW202246501A - SMN1和miR-23a在治療脊髓性肌萎縮中的協同作用 - Google Patents
SMN1和miR-23a在治療脊髓性肌萎縮中的協同作用 Download PDFInfo
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Abstract
本申請涉及生物技術、病毒學、遺傳學和分子生物學領域。更具體地,本發明涉及用於產生基因療法病毒產物的分離的核酸、基於其的表達盒和載體,以及用於在目標細胞中表達SMN1基因的基於AAV9的重組病毒、包括所述重組病毒的藥物組合物和以上重組病毒和以上組合物的各種用途,所述分離的核酸包含編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的核酸和編碼微RNA miR-23a的核酸。
Description
本申請涉及生物技術、病毒學、遺傳學和分子生物學領域。更具體地,本發明涉及用於產生基因療法病毒產物的分離的核酸,所述分離的核酸包含編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白(運動神經元存活蛋白)的核酸和編碼微RNA miR-23a的核酸,涉及基於其的表達盒和載體,以及涉及用於在目標細胞中表達SMN1基因的基於AAV9 (腺相關病毒血清型9)的重組病毒,涉及包括所述重組病毒的藥物組合物和涉及以上重組病毒和以上組合物的各種用途。
脊髓性肌萎縮(SMA)涉及神經肌肉疾病組,並且其特徵是主要為常染色體隱性遺傳模式。目前,術語SMA典型地指的是由於位於5號染色體的長臂上的SMN1 (運動神經元存活1)基因中的突變和(或)缺失而發展的疾病的最常見形式(Lefebvre等人, Cell (1995) 80:155-165)。該疾病伴隨有脊髓的腹側(前)角中的運動神經元變性,其導致負責大肌肉運動技能(gross motor skills)(例如爬行、行走、頸部控制)的近端肌肉張力减退以及還導致吞嚥障礙和呼吸障礙(Sumner C.J., NeuroRx (2006) 3:235-245)。因此,SMA患者呈現出增加的呼吸窘迫和再添並發疾病的傾向。
基因療法是治療脊髓性肌萎縮有前景的方法。
腺相關病毒(AAV)載體在CNS基因療法中被認為是有效的,因為它們具有適合的毒性和免疫原性概況,它們可以在神經細胞轉導中使用,並且它們能夠介導CNS中的長期表達。
腺相關病毒(AAV)是小的(20 nm)獨立複製缺陷的無包膜病毒。已經在人和靈長目中描述了許多不同的AAV血清型。腺相關病毒基因組由(+或-)約為4,700個核苷酸長的單鏈DNA (ssDNA)構成。在基因組DNA分子的末端,容納有末端反向重複(ITR)。基因組包含兩個開放閱讀框(ORF) Rep和Cap,其包含編碼各種蛋白產物的幾個備選的閱讀框。rep產物對AAV複製至關重要,而三種衣殼蛋白(VP1、VP2和VP3)與其他備選的產物一起由Cap基因編碼。VP1、VP2和VP3以1:1:10的比存在,以形成二十面體衣殼(Xie Q等人. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA, 2002; 99:10405-10410)。在重組AAV (rAAV)載體產生期間,將兩側是ITR的表達盒包裝到AAV衣殼中。AAV複製所需要的基因不包括在盒中。重組AAV被認為是用於體內基因轉移的最安全和最廣泛使用的病毒載體之一。載體可以感染多種組織類型的細胞以提供強且持續的轉基因表達。它們也是非致病性的,並且具有低免疫原性概況(High KA等人, "rAAV human trial experience" Methods Mol Biol. 2011; 807:429-57)。
國際專利申請WO2017106354 (A1)、WO2010129021 (A1)、WO2015060722 (A1)、WO2017066579 (A1)、WO2015158749 (A2)公開了包含SMN1基因的AAV的各種變體及其用途。
本發明的作者開發了用於產生基因療法病毒產物的分離的核酸(所述分離的核酸包含編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的核酸和編碼微RNA miR-23a的核酸)、基於其的表達盒和載體,以及用於在目標細胞中表達SMN1基因的基於AAV9的重組病毒、包括所述重組病毒的藥物組合物,和以上重組病毒和以上組合物的各種用途。本發明的作者驚奇地發現miR-23a在體外增強SMN1的功能作用,並揭示了SMN1和miR-23a在SMA的動物模型中治療該疾病的協同作用。
發明說明在一個方面,本發明涉及用於產生基因療法病毒產物的分離的核酸,所述分離的核酸包含編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白(運動神經元存活蛋白)的核酸和編碼微RNA miR-23a的核酸。
在一些實施方案中,編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的分離的核酸包括SEQ ID NO: 2的核苷酸序列。
在一些實施方案中,分離的核酸包括具有SEQ ID NO: 3的核苷酸序列的微RNA miR-23a。
在一些實施方案中,分離的核酸包括編碼微RNA miR-23a的核酸,該核酸包括SEQ ID NO: 4的核苷酸序列。
在一些實施方案中,分離的核酸在5'端至3'端方向包括以下元件:
編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的核酸,和
編碼微RNA miR-23a的核酸。
在一個方面,本發明涉及包含以上核酸的任一種的表達盒。
在一些實施方案中,表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,表達盒包括具有SEQ ID NO: 6的核酸。
在一個方面,本發明涉及包括以上核酸的任一種或以上盒的任一個的表達載體。
在一個方面,本發明涉及用於SMN1基因在目標細胞中的表達的基於AAV9 (腺相關病毒血清型9)的重組病毒,其包括衣殼和以上表達盒的任一個。
在一些實施方案中,基於AAV9的重組病毒包括AAV9蛋白VP1。
在一些實施方案中,基於AAV9的重組病毒包括具有SEQ ID NO: 7的胺基酸序列的AAV9蛋白VP1。
在一些實施方案中,基於AAV9的重組病毒包括具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的AAV9蛋白VP1。
在一些實施方案中,基於AAV9的重組病毒包括具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的AAV9蛋白VP1,和表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,基於AAV9的重組病毒包括具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的AAV9蛋白VP1,和表達盒包含具有SEQ ID NO: 6的核酸。
在一個方面,本發明涉及用於將SMN1基因遞送至目標細胞的藥物組合物,其包括與一種或多種藥學上可接受的賦形劑組合的以上基於AAV9的重組病毒的任一種。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於將SMN1基因遞送至目標細胞的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的存活的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於將SMN1蛋白提供給患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於在患有脊髓性肌萎縮的受試者中治療脊髓性肌萎縮的用途。
在一個方面,本發明涉及用於在患有運動神經元病症的受試者中調整運動功能的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到受試者的細胞中。
在一個方面,本發明涉及用於將SMN蛋白提供給患有脊髓性肌萎縮的受試者的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到有需要的受試者的細胞中。
在一個方面,本發明涉及用於將SMN1基因遞送至患有脊髓性肌萎縮的受試者的目標細胞的方法,所述方法包含將以上基於AAV9的重組病毒的任一種或以上組合物施用到受試者的細胞中。
在一個方面,本發明涉及用於在受試者中治療脊髓性肌萎縮的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到患有脊髓性肌萎縮的受試者中。
定義和一般方法除非本文另有定義,與本發明有關的所有技術和科學術語將具有與本領域技術人員通常所理解的相同的含義。
此外,除非上下文另有要求,否則單數術語應包括複數術語,並且複數術語應包括單數術語。典型地,本文所述的細胞培養、分子生物學、免疫學、微生物學、遺傳學、分析化學、有機合成化學、醫學和藥物化學以及蛋白和核酸的雜交和化學的現有分類和方法是技術人員所熟知並且在本領域廣泛使用的。如本領域常見的,或如本文所述的,酶反應和純化方法根據製造商的指南進行。
"分離的"意為改變或去除自天然狀態。例如,天然存在於動物中的核酸或肽不是"分離的",但與其天然狀態的共存材料部分或完全分離的相同核酸或肽是"分離的"。分離的核酸或蛋白可以以基本上純化的形式存在,或者可以存在於非天然環境(諸如,例如遺傳修飾細胞)中。
術語"天然存在的"、"天然的"或"野生型"用於描述自然界中可以發現的不同於人工產生的對象。例如,可以從自然界來源中分離並且未經實驗室人員有意修飾的存在於生物體(包括病毒)中的蛋白或核苷酸序列是天然存在的。
術語"基因組"指的是生物體的完整遺傳材料。
如在本描述和隨後的申請專利範圍中所使用的,除非上下文另有規定,否則詞語"包括"和"包含",或其變體諸如"具有"、"包括(includes)"、"包括(including)"、"包含(comprises)"或"包含(comprising)"將理解為含有包括指定的整數或整數組,但不排除任何其他的整數或整數組的意思。
蛋白 ( 肽 )如本描述中所使用的,術語"肽"、"多肽"和"蛋白"可交換地使用,並且它們指的是由通過肽鍵共價連接的胺基酸殘基組成的化合物。蛋白或肽必須至少包含兩個胺基酸,並且在可以構成蛋白或肽的序列的胺基酸最大數量上不作限制。多肽包括包含通過肽鍵相互連接的兩個或更多個胺基酸的任何肽或蛋白。如本描述中所使用的,該術語指的是短鏈(其在本領域中通常也被稱為例如肽、寡肽和寡聚物)和較長鏈(其在本領域中一般被稱為蛋白,其有許多類型)兩者。"多肽"尤其包括例如生物活性片段、基本上同源的多肽、寡肽、同二聚體、異二聚體、多肽的變體、修飾的多肽、衍生物、類似物、融合蛋白。多肽包括天然肽、重組肽、合成肽或其組合。
核酸分子術語"核酸"、"核酸序列(nucleic sequence)"、"核酸序列(nucleic acid sequence)"、"多核苷酸"、"寡核苷酸"、"多核苷酸序列"和"核苷酸序列"在本描述中可交換地使用,意為修飾或未修飾的、確定核酸的片段或區域的、包含或不包含非天然核苷酸的以及為雙鏈DNA或RNA、單鏈DNA或RNA或所述DNA的轉錄產物的核苷酸的精確序列。
如本描述中所使用的,作為非限制性實例,多核苷酸包括通過本領域可用的任何手段獲得的所有核酸序列,作為非限制性實例,所述手段包括重組手段,即使用普通的選殖技術和PCR等,從重組文庫或細胞基因組中選殖核酸序列,以及通過合成手段。
此處還應包括,本發明不涉及在其天然染色體環境中(即在天然狀態中)的核苷酸序列。本發明的序列已經經過分離和/或純化,即它們通過例如複製被直接或間接地取樣,它們的環境已經被至少部分地修改。因此,這裏還應提及通過重組遺傳學例如通過宿主細胞獲得,或通過化學合成獲得的分離的核酸。
除非另有指示,否則術語核苷酸序列包括其互補物。因此,具有特定序列的核酸應理解為包括具有其互補序列的其互補鏈的核酸。
腺相關病毒 (AAV)細小病毒科(Parvoviridae family)的病毒是小的包含DNA的動物病毒。細小病毒科可以分為兩個亞科:細小病毒亞科(Parvovirinae)(其成員感染脊椎動物)和濃核病毒亞科(Densovirinae)(其成員感染昆蟲)。到2006年,已有11種腺相關病毒的血清型被描述(Mori, S. ET AL., 2004, "Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein", Virology, Т. 330 (2): 375-83)。所有已知的血清型都可以感染來自多種組織類型的細胞。組織特異性由衣殼蛋白血清型確定,因此,通過分配所期望的血清型來構建基於腺相關病毒的載體。細小病毒和細小病毒亞科的其他成員進一步的信息在文獻(Kenneth I. Berns, "Parvoviridae: The Viruses and Their Replication", 病毒學領域(Fields Virology)中的第69章(1996年第三版))中描述。
所有已知AAV血清型的基因組組織非常相似。AAV的基因組是長度小於約5000個核苷酸(nt)的線性、單鏈DNA分子。反向末端重複(ITR)在非結構蛋白(Rep)和結構蛋白(Cap)的複製的獨特編碼核苷酸序列的兩側。Cap基因編碼形成衣殼的VP蛋白(VP1、VP2和VP3)。末端145個核苷酸是自身互補的並且其被組織以使得可以形成能量穩定的分子內雙鏈體(該雙鏈體形成T形髮夾)。這類髮夾結構起病毒DNA複製起點的功能,充當細胞DNA聚合酶複合物的引物。哺乳動物細胞中野生型AAV (wtAAV)感染後,Rep基因(例如Rep78和Rep52)分別使用P5啓動子和P19啓動子表達,並且兩種Rep蛋白在病毒基因組的複製中均具有一定的功能。Rep開放閱讀框(Rep ORF)中的剪接事件導致實際上四種Rep蛋白(例如Rep78、Rep68、Rep52和Rep40)的表達。然而,已經證明編碼Rep78和Rep52蛋白的未剪接mRNA足以在哺乳動物細胞中產生AAV載體。
載體如本文所使用的術語"載體"意為能夠轉運與其連接的另一核酸的核酸分子。此外,本文中術語"載體"指的是能夠轉運核酸的病毒顆粒。
如本描述中所使用的,術語"表達"定義為由其啓動子驅動的特定核苷酸序列的轉錄和/或翻譯。
用途"基因療法"是將基因插入到受試者的細胞和/或組織中以治療疾病(典型地為遺傳疾病),其中用功能等位基因替換有缺陷的突變等位基因。
"治療(treat)"、"治療(treating)"和"治療(treatment)"指的是减輕或消除生物學病症和/或其伴隨症狀的至少一種的方法。如本文所使用的,"减輕"疾病、病症或狀況意為降低疾病、病症或狀況的症狀的嚴重性和/或發生頻率。此外,本文中提及"治療"包括提及治愈性、姑息性和預防性治療。
在一個方面,治療的受試者或患者是哺乳動物,優選人受試者。所述受試者可以是任何年齡的雄性或雌性。
術語"病症"意為將受益於用本發明的化合物的治療的任何狀況。
"疾病"是受試者的健康狀態,其中受試者不能維持體內平衡,並且其中如果疾病沒有得到改善,則受試者的健康繼續惡化。
術語"受試者"、"患者"、"個體"等在本描述中可交換使用,並且它們指的是適用本描述中所述方法的任何動物。在某些非限制性實施方案中,受試者、患者或個體是人。所述受試者可以是任何年齡的雄性或雌性。
"治療有效量"或"有效量"指的是所施用的治療劑的量,其將在一定程度上緩解所治療疾病的一種或多種症狀。
詳述說明 核酸在一個方面,本發明涉及用於產生基因療法病毒產物的分離的核酸,所述分離的核酸包含編碼具有胺基酸序列MAMSSGGSGGGVPEQEDSVLFRRGTGQSDDSDIWDDTALIKAYDKAVASFKHALKNGDICETSGKPKTTPKRKPAKKNKSQKKNTAASLQQWKVGDKCSAIWSEDGCIYPATIASIDFKRETCVVVYTGYGNREEQNLSDLLSPICEVANNIEQNAQENENESQVSTDESENSRSPGNKSDNIKPKSAPWNSFLPPPPPMPGPRLGPGKPGLKFNGPPPPPPPPPPHLLSCWLPPFPSGPPIIPPPPPICPDSLDDADALGSMLISWYMSGYHTGYYMGFRQNQKEGRCSHSLN (SEQ ID NO: 1)的SMN1蛋白(運動神經元存活蛋白)的核酸和編碼微RNA miR-23a的核酸。
在一些實施方案中,以上核酸被用於產生基因療法病毒產物,該病毒產物為本發明的表達載體或本發明的基於AAV9的重組病毒。
"分離的"核酸分子是鑒定的且與至少一種核酸分子-雜質(前者典型地結合在天然來源的核酸酶核酸中)分離的核酸分子。分離的核酸分子與其在天然條件下發現的形式或集合不同。因此,分離的核酸分子與在天然條件下存在於細胞中的核酸分子不同。
在一些實施方案中,分離的核酸是DNA。
如本領域的技術人員可以瞭解的,由於遺傳密碼的冗餘性,因此多種不同的DNA序列可以編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白。產生編碼相同胺基酸序列的這些備選的DNA序列完全在本領域受過訓練的人員的技能範圍內。這類變體DNA序列在本發明的範圍內。
在一些實施方案中,編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的分離的核酸包括以下核苷酸序列:
ATGGCCATGAGCAGCGGCGGCAGCGGCGGCGGCGT
GCCTGAGCAAGAGGACAGCGTGCTGTTCAGAAGAGGCACCGGCCAGAGCGACGACAGCGACATCTGGGACGACACCGCCCTGATCAAGGCCTACGACAAGGCCGTGGCCAGCTTCAAGCACGCCCTGAAGAACGGCGACATCTGCGAGACCAGCGGCAAGCCCAAGACCACCCCCAAGAGAAAGCCCGCCAAGAAGAACAAGAGCCAGAAGAAGAACACCGCCGCCAGCCTGCAGCAGTGGAAGGTGGGCGACAAGTGCAGCGCCATCTGGAGCGAGGACGGCTGCATCTACCCCGCCACCATCGCCAGCATCGACTTCAAGAGAGAGACCTGCGTGGTGGTGTACACCGGCTACGGCAACAGAGAGGAGCAGAACCTGAGCGACCTGCTGAGCCCCATCTGCGAGGTGGCCAACAACATCGAGCAGAACGCCCAAGAGAACGAGAACGAGAGCCAAGTGAGCACCGACGAGAGCGAGAACAGCAGAAGCCCCGGCAACAAGAGCGACAACATCAAGCCCAAGAGCGCCCCCTGGAACAGCTTCCTGCCCCCTCCCCCCCCTATGCCCGGCCCTAGACTGGGCCCTGGCAAGCCTGGCCTGAAGTTCAACGGCCCCCCCCCCCCTCCTCCTCCTCCTCCTCCTCACCTGCTGAGCTGCTGGCTGCCCCCCTTCCCCAGCGGCCCTCCTATCATCCCTCCTCCCCCCCCCATCTGCCCCGACAGCCTGGACGACGCCGACGCCCTGGGCAGCATGCTGATCAGCTGGTACATGAGCGGCTACCACACCGGCTACTACATGGGCTTCAGACAGAACCAGAAGGAGGGCCGGTGCAGCCACAGCCTGAAC (SEQ ID NO: 2)。
在一些實施方案中,分離的核酸包括具有以下核苷酸序列的微RNA miR-23a:
GGCCGGCUGGGGUUCCUGGGGAUGGGAUUUGCUUCCUGUCACAAAUCACAUUGCCAGGGAUUUCCAACCGACC (SEQ ID NO: 3)。
在一些實施方案中,分離的核酸包括編碼微RNA miR-23a的核酸,該核酸包括以下核苷酸序列:
CATGCAAGTTGCTGTAGCCTCCTTGTCCCGCATGGG
CCCTCTAGGTATCTCTGCCTCTCCAGTCCTGGGGCTGGAACGGAGGGCACAGCTAGGCTCCAGCTCCCCGTGTGGTGGCTCCTGCATATGAGAAAAGAGCTTCCCTGTGATCAAAGGAAGCATCTGGGGACCTGGAGGGGAGGTGTCCCCAAATCTCATTACCTCCTTTGCTCTCTCTCTCTTTCTCCCCTCCAGGTGCCAGCCTCTGGCCCCGCCCGGTGCCCCCCTCACCCCTGTGCCACGGCCGGCTGGGGTTCCTGGGGATGGGATTTGCTTCCTGTCACAAATCACATTGCCAGGGATTTCCAACCGACCCTGAGCTCTGCCACCGAGGATGCTGCCCGGGGACGGGGTGGCAGAGAGGCCCCGAAGCCTGTGCCTGGCCTGAGGAGCAGGGCTTAGCTGCTTGTGAGCAGGGTCCACACCAAGTCGTGTTCACAGTGGCTAAGTTCCGCCCCCCAGGCCCTCACCTCCTCTGGCCTTGCCGCCTGTCCCCTGCTGCCGCCTGTCTGCCTGCCATCCTGCTGCCTGGCCTCCCTGGGCTCTGCCTCCCGTGCCTACTGAGCTGAAACACAGTTGGTTTGTGTACACTGGCTCAGTTCAGCAGGAACA (SEQ ID NO: 4)。
以上編碼微RNA miR-23a的具有核苷酸序列SEQ ID NO: 4的核酸為加工前的核酸。
加工後,編碼微RNA miR-23a的核酸具有以下核苷酸序列:
GGCCGGCTGGGGTTCCTGGGGATGGGATTTGCTTCCTGTCACAAATCACATTGCCAGGGATTTCCAACCGACC (SEQ ID NO:5)。
在一些實施方案中,分離的核酸在5'端至3'端方向包括以下元件:
編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的核酸,和
編碼微RNA miR-23a的核酸。
表達盒 表達載體在一個方面,本發明涉及包含以上核酸的任一種的表達盒。
如本文所使用的,術語"表達盒"特別地指的是在適當的設置中,能夠觸發包括於所述表達盒中的編碼感興趣的多肽的多核苷酸的表達的DNA片段。當引入到宿主細胞中時,表達盒尤其能夠參與細胞機制以將編碼感興趣的多肽的多核苷酸轉錄為RNA,其然後典型地被進一步加工並最終被翻譯為感興趣的多肽。表達盒可以包含於表達載體中。
如本文所使用的,術語"表達…的盒"或"表達盒"特別地指的是在適當的設置中,能夠觸發包括於所述表達盒中的編碼感興趣的多肽的多核苷酸的表達的DNA片段。當引入到宿主細胞中時,表達盒尤其能夠參與細胞機制以將編碼感興趣的多肽的多核苷酸轉錄為RNA,其然後典型地被進一步加工並最終被翻譯為感興趣的多肽。表達盒可以包含於表達載體中。
本發明的表達盒包含啓動子作為元件。如本文所使用的術語"啓動子"特別地指的是促進與啓動子可操作地連接的多核苷酸的轉錄的DNA元件。啓動子可以進一步形成啓動子/增強子元件的一部分。儘管"啓動子"和"增強子"元件之間的物理界限並不總是清楚的,但術語"啓動子"典型地指的是核酸分子上的位點,該位點與RNA聚合酶和/或任何相關因子結合並且在該位點處轉錄起始。增強子在時間以及空間上加強啓動子活性。已知本領域中許多啓動子在各式各樣的細胞類型中是轉錄活性的。啓動子可以分為兩類,組成性地起功能的啓動子和通過誘導或去阻遏調節的啓動子。這兩類都適合用於蛋白表達。用於在真核細胞中,並且特別是在哺乳動物細胞中多肽的高水平產生的啓動子應該是強的,並且優選在各式各樣的細胞類型中有活性。能夠在許多細胞類型中驅動表達的強組成型啓動子在本領域中是眾所周知的,以及因此本文中沒有必要對其進行詳細描述。根據本發明的思想,優選使用巨細胞病毒(CMV)啓動子。源自人巨細胞病毒(hCMV)的即刻早期(IE)區域的啓動子或啓動子/增強子特別適合作為本發明的表達盒中的啓動子。例如,人巨細胞病毒(hCMV)即刻早期(IE)區域以及源自其的功能表達誘導片段和/或功能表達增強片段已經在ЕР0173177和ЕР0323997中公開,並且在本領域中是眾所周知的。因此,可以將hCMV即刻早期(IE)區域的幾個片段用作啓動子和/或啓動子/增強子。根據本發明的一個實施方案,在本發明的表達盒中使用人CMV啓動子。
在一些實施方案中,表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,左側(第一個) ITR (反向末端重複)具有以下核酸序列:
cctgcaggcagctgcgcgctcgctcgctcactgaggccgcccgggcgtcgggcgacctttggtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcct (SEQ ID NO: 10)。
在一些實施方案中,CMV (巨細胞病毒)增強子具有以下核酸序列:
cgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgCcaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatg (SEQ ID NO: 11)。
在一些實施方案中,CMV (巨細胞病毒)啓動子具有以下核酸序列:
gtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttgGcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagct (SEQ ID NO: 12)。
在一些實施方案中,hBG1 (血紅蛋白γ1亞基)基因的內含子具有以下核酸序列:
cgaatcccggccgggaacggtgcattggaacgcggattccccgtgccaagagtgacgtaagtaccgcctatagagtctataggcccacaaaaaatgctttcttcttttaatatacttttttgtttatcttatttctaatactttccctaatctctttctttcagggcaataatgatacaatgtatcatgcctctttgcaccattctaaagaataacagtgataatttctgggttaaggcaatagcaatatttctgcatataaatatttctgcatataaattgtaactgatgtaagaggtttcatattgctaatagcagctacaatccagctaccattctgcttttattttatggttgggataaggctggattattctgagtccaagctaggcccttttgctaatcatgttcatacctcttatcttcctcccacagctcctgggcaacgtgctggtctgtgtgctggcccatcactttggcaaagaattgggat (SEQ ID NO: 13)。
在一些實施方案中,hGH1 (人生長激素1基因)多聚腺苷酸化信號具有以下核酸序列:
acgggtggcatccctgtgacccctccccagtgcctctcctggccctggaagttgccactccagtgcccaccagccttgtcctaataaaattaagttgcatcattttgtctgactaggtgtccttctataatattatggggtggaggggggtggtatggagcaaggggcaagttgggaagacaacctgtagggcctgcggggtctattgggaaccaagctggagtgcagtggcacaatcttggctcactgcaatctccgcctcctgggttcaagcgattctcctgcctcagcctcccgagttgttgggattccaggcatgcatgaccaggctcagctaatttttgtttttttggtagagacggggtttcaccatattggccaggctggtctccaactcctaatctcaggtgatctacccaccttggcctcccaaattgctgggattacaggcgtgaaccactgctcccttccctgtcctt (SEQ ID NO: 14)。
在一些實施方案中,SV40啓動子(猴病毒40啓動子)具有以下核酸序列:
TGCATCTCAATTAGTCAGCAACCATAGtcccgcccctaactccgcccatcccgcccctaactccgcccagttccgcccattctccgccccatcgctgactaattttttttatttatgcagaggccgaggccgcctcggcctctgagctattccagaagtagtgaggaggcttttttggaggcctaggcttttgcaaaaagct (SEQ ID NO: 15)。
在一些實施方案中,SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號)具有以下核酸序列:
aataaaatatctttattttcattacatctgtgtgttggttttttgtgtgaatcgatagtactaacatacgctctccatcaaaacaaaacgaaacaaaacaaactagcaaaataggctgtccccagtgcaaGTGCAGGTGCCAGAACATTTCTCT (SEQ ID NO: 16)。
在一些實施方案中,右側(第二個) ITR具有以下核酸序列:
aggaacccctagtgatggagttggccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcgcgcagctgcctgcagg (SEQ ID NO: 17)。
在一些實施方案中,表達盒包括具有以下核苷酸序列的核酸:
cctgcaggcagctgcgcgctcgctcgctcactgaggccgcccgggcgtcgggcgacctttggtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcctgcggccgcacgcgtctagttattaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgCcaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttgGcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctcgtttagtgaaccgtcagatcgcctggagacgccatccacgctgttttgacctccatagaagacaccgggaccgatccagcctccgcggattcgaatcccggccgggaacggtgcattggaacgcggattccccgtgccaagagtgacgtaagtaccgcctatagagtctataggcccacaaaaaatgctttcttcttttaatatacttttttgtttatcttatttctaatactttccctaatctctttctttcagggcaataatgatacaatgtatcatgcctctttgcaccattctaaagaataacagtgataatttctgggttaaggcaatagcaatatttctgcatataaatatttctgcatataaattgtaactgatgtaagaggtttcatattgctaatagcagctacaatccagctaccattctgcttttattttatggttgggataaggctggattattctgagtccaagctaggcccttttgctaatcatgttcatacctcttatcttcctcccacagctcctgggcaacgtgctggtctgtgtgctggcccatcactttggcaaagaattgggattcgaacatCGATTGTAATTCATGAGCCACCATGGCCATGAGCAGCGGCGGCAGCGGCGGCGGCGTGCCTGAGCAAGAGGACAGCGTGCTGTTCAGAAGAGGCACCGGCCAGAGCGACGACAGCGACATCTGGGACGACACCGCCCTGATCAAGGCCTACGACAAGGCCGTGGCCAGCTTCAAGCACGCCCTGAAGAACGGCGACATCTGCGAGACCAGCGGCAAGCCCAAGACCACCCCCAAGAGAAAGCCCGCCAAGAAGAACAAGAGCCAGAAGAAGAACACCGCCGCCAGCCTGCAGCAGTGGAAGGTGGGCGACAAGTGCAGCGCCATCTGGAGCGAGGACGGCTGCATCTACCCCGCCACCATCGCCAGCATCGACTTCAAGAGAGAGACCTGCGTGGTGGTGTACACCGGCTACGGCAACAGAGAGGAGCAGAACCTGAGCGACCTGCTGAGCCCCATCTGCGAGGTGGCCAACAACATCGAGCAGAACGCCCAAGAGAACGAGAACGAGAGCCAAGTGAGCACCGACGAGAGCGAGAACAGCAGAAGCCCCGGCAACAAGAGCGACAACATCAAGCCCAAGAGCGCCCCCTGGAACAGCTTCCTGCCCCCTCCCCCCCCTATGCCCGGCCCTAGACTGGGCCCTGGCAAGCCTGGCCTGAAGTTCAACGGCCCCCCCCCCCCTCCTCCTCCTCCTCCTCCTCACCTGCTGAGCTGCTGGCTGCCCCCCTTCCCCAGCGGCCCTCCTATCATCCCTCCTCCCCCCCCCATCTGCCCCGACAGCCTGGACGACGCCGACGCCCTGGGCAGCATGCTGATCAGCTGGTACATGAGCGGCTACCACACCGGCTACTACATGGGCTTCAGACAGAACCAGAAGGAGGGCCGGTGCAGCCACAGCCTGAACTGATctagagtcgacctgcagaagcttgcctcgagcagcgctgctcgagagatctacgggtggcatccctgtgacccctccccagtgcctctcctggccctggaagttgccactccagtgcccaccagccttgtcctaataaaattaagttgcatcattttgtctgactaggtgtccttctataatattatggggtggaggggggtggtatggagcaaggggcaagttgggaagacaacctgtagggcctgcggggtctattgggaaccaagctggagtgcagtggcacaatcttggctcactgcaatctccgcctcctgggttcaagcgattctcctgcctcagcctcccgagttgttgggattccaggcatgcatgaccaggctcagctaatttttgtttttttggtagagacggggtttcaccatattggccaggctggtctccaactcctaatctcaggtgatctacccaccttggcctcccaaattgctgggattacaggcgtgaaccactgctcccttccctgtccttctgattttgtaggtaaccacTAGAGAAATGTTCTGGCACCTGCACttgcactggggacagcctattttgctagtttgttttgtttcgttttgttttgatggagagcgtatgttagtactatcgattcacacaaaaaaccaacacacagatgtaatgaaaataaagatattttattgcggccgcTGTTCCTGCTGAACTGAGCCAGTGTACACAAACCAACTGTGTTTCAGCTCAGTAGGCACGGGAGGCAGAGCCCAGGGAGGCCAGGCAGCAGGATGGCAGGCAGACAGGCGGCAGCAGGGGACAGGCGGCAAGGCCAGAGGAGGTGAGGGCCTGGGGGGCGGAACTTAGCCACTGTGAACACGACTTGGTGTGGACCCTGCTCACAAGCAGCTAAGCCCTGCTCCTCAGGCCAGGCACAGGCTTCGGGGCCTCTCTGCCACCCCGTCCCCGGGCAGCATCCTCGGTGGCAGAGCTCAGGGTCGGTTGGAAATCCCTGGCAATGTGATTTGTGACAGGAAGCAAATCCCATCCCCAGGAACCCCAGCCGGCCGTGGCACAGGGGTGAGGGGGGCACCGGGCGGGGCCAGAGGCTGGCACCTGGAGGGGAGAAAGAGAGAGAGAGCAAAGGAGGTAATGAGATTTGGGGACACCTCCCCTCCAGGTCCCCAGATGCTTCCTTTGATCACAGGGAAGCTCTTTTCTCATATGCAGGAGCCACCACACGGGGAGCTGGAGCCTAGCTGTGCCCTCCGTTCCAGCCCCAGGACTGGAGAGGCAGAGATACCTAGAGGGCCCATGCGGGACAAGGAGGCTACAGCAACTTGCATGgccgcagctttttgcaaaagcctaggcctccaaaaaagcctcctcactacttctggaatagctcagaggccgaggcggcctcggcctctgcataaataaaaaaaattagtcagcgatggggcggagaatgggcggaactgggcggagttaggggcgggatgggcggagttaggggcgggaCTATGGTTGCTGACTAATTGAGATGCAgggccgctccaagtacctcccgtaccttaagtgcggaccgagcggccgcaggaacccctagtgatggagttggccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttgcccgggcggcctcagtgagcgagcgagcgcgcagctgcctgcagg (SEQ ID NO: 6)。
在一個方面,本發明涉及包括以上核酸的任一種或以上盒的任一個的表達載體。
在一些實施方案中,載體是質粒,即可以連接額外的DNA段到其中的一段環狀雙鏈DNA。
在一些實施方案中,載體是病毒載體,其中額外的DNA段可以連接到病毒基因組中。
在一些實施方案中,載體能夠在其被引入的宿主細胞中自主複製(例如具有細菌複製起始位點的細菌載體和游離型哺乳動物載體)。在另外的實施方案中,載體(例如非游離型哺乳動物載體)可以在引入到宿主細胞中後整合到宿主細胞的基因組中,並且由此與宿主基因一起被複製。此外,某些載體能夠指導與其可操作地連接的基因的表達。這類載體在本文中稱為"重組表達載體"(或簡稱為"表達載體")。
表達載體包括質粒、逆轉錄病毒、腺病毒、腺相關病毒(AAV)、植物病毒諸如花椰菜花葉病毒、煙草花葉病毒、黏粒、YAC、EBV來源的游離體等。DNA分子可以連接到載體中,以使得載體內的轉錄和翻譯控制序列起到其調節DNA的轉錄和翻譯的預期功能。可以選擇與所使用的表達宿主細胞相容的表達載體和表達控制序列。可以通過標準方法(例如,互補限制性位點的連接,或如果不存在限制性位點,則平端連接)將DNA分子引入到表達載體中。
重組表達載體還可以編碼促進感興趣的蛋白從宿主細胞分泌的前導肽(或信號肽)。可以將感興趣的蛋白的基因選殖到載體中,以使得信號肽與感興趣的蛋白的胺基末端框內連接。前導肽(或信號肽)可以是免疫球蛋白前導肽或其他前導肽(即,非免疫球蛋白前導肽)。
除了根據本發明的SMN1基因和微RNA miR-23a基因之外,根據本發明的載體的重組表達可以攜帶在宿主細胞中控制SMN1基因和微RNA miR-23a基因的表達的調節序列。本領域的技術人員將理解,表達載體的設計,包括調節序列的選擇,可取決於諸如待轉化宿主細胞的選擇、所期望的蛋白的表達水平等因素。對於哺乳動物中的表達宿主細胞,優選的控制序列包括保證哺乳動物細胞中蛋白表達的高水平的病毒元件,諸如源自逆轉錄病毒LTR、巨細胞病毒(CMV)(諸如CMV啓動子/增強子)、猴病毒40 (SV40)(諸如SV40啓動子/增強子)、腺病毒(例如腺病毒主要晚期啓動子(AdMLP))、多瘤病毒的啓動子和/或增強子,和強哺乳動物啓動子,諸如天然免疫球蛋白啓動子或肌動蛋白啓動子。
術語"控制序列"指的是在特定的宿主生物體中表達可操作地連接的編碼序列所必需的DNA序列。例如,適合用於原核生物的控制序列是啓動子、任選的操縱子序列和核糖體結合位點。已知真核細胞包括啓動子、多聚腺苷酸化信號和增強子。
如本描述中所使用的,術語"啓動子"或"轉錄調節序列"或"調節序列"指的是控制一個或多個編碼序列的轉錄的核酸片段,並且其在關於相對於從編碼序列的轉錄起始位點的轉錄方向的閱讀方向的上游定位,並且在結構上通過DNA依賴的RNA聚合酶的結合位點、轉錄起始位點和任何其他DNA序列(包括但不限於轉錄因子結合位點、阻遏蛋白結合位點和激活蛋白結合位點以及本領域技術人員已知的直接或間接地與所述啓動子一起調節轉錄水平的任何其他核苷酸序列)的存在來鑒定。"組成型"啓動子是在典型的生理和發育條件下在大多數組織中有活性的啓動子。"誘導型"啓動子是受到生理或發育調節(例如在化學誘導劑的影響下)的啓動子。"組織特異性"啓動子僅在特定類型的組織或細胞中是有活性的。
如本文所使用的"增強子(enhancers)"或"增強子(enhancer)"可以指的是與編碼重組產物的DNA序列相鄰定位的DNA序列。增強子元件典型地位於啓動子元件的5'方向,或者可以在編碼DNA序列(例如轉錄或翻譯為重組產物的DNA序列)的下游或其內定位。因此,增強子元件可以在編碼重組產物的DNA序列的上游或所述序列的下游的100個鹼基對、200個鹼基對或300個或更多鹼基對處定位。增強子元件可以高於與單個啓動子元件相關的表達水平地增加表達自DNA序列的重組產物的量。本領域的普通技術人員容易得到多種增強子元件。
如本描述中所使用的術語"表達控制序列"指的是實現與其連接的編碼序列的表達和加工所必需的多核苷酸序列。表達控制序列包括:適當的轉錄起始、終止、啓動子和增強子序列;有效的RNA加工信號(諸如剪接)和多聚腺苷酸化信號;穩定細胞質mRNA的序列;增強翻譯效率的序列(即Kozak共有序列);增強蛋白穩定性的序列;以及當期望時,增強蛋白分泌的序列。這類控制序列的性質取決於宿主生物體而不同,在原核生物中,這類控制序列一般包括核糖體結合位點的啓動子和轉錄終止序列,在真核生物中,這類控制序列典型地包括啓動子和轉錄終止序列。術語"控制序列"至少包括其存在對於表達和加工至關重要的所有組分,並且還可以包括其存在是有利的額外的組分,例如前導序列和融合伴侶序列。
在本發明的一個實施方案中,"表達載體"涉及包含兩側是細小病毒序列或反向末端重複(ITR)序列的一個或多個感興趣的多核苷酸序列、感興趣的基因或"轉基因"的載體。
本發明的盒或載體均不包含編碼腺相關病毒的非結構蛋白(Rep)和結構蛋白(Cap)的基因的核苷酸序列。
基於 AAV9 ( 腺相關病毒血清型 9) 的重組病毒在一個方面,本發明涉及用於SMN1基因在目標細胞中的表達的基於AAV9 (腺相關病毒血清型9)的重組病毒,其包括衣殼和以上表達盒的任一個。
如本描述中所使用的術語"基於AAV的重組病毒"(或"基於AAV的病毒樣顆粒"或"AAV重組病毒株"或"AAV重組載體"或"rAAV載體")指的是被封入AAV衣殼內的以上表達盒(或以上表達載體)。
除了其他備選的產物之外,Cap基因還編碼3種衣殼蛋白(VP1、VP2和VP3)。VP1、VP2和VP3以1:1:10的比存在,以形成二十面體衣殼(Xie Q等人. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA, 2002; 99:10405-10410)。這些基因的轉錄從單一的啓動子p40開始。相應蛋白(VP1、VP2和VP3)的分子量分別為87 kDa、72 kDa和62 kDa。所有三個蛋白均翻譯自單一的mRNA。轉錄後,前mRNA可以以兩種不同的方式被剪接,其中較長或較短的內含子被切去以形成各種核苷酸長度的mRNA。
在基於AAV(rAAV)的重組病毒的產生期間,將兩側是ITR的表達盒包裝到AAV衣殼中。如上所提及的AAV的複製所需要的基因不包括在盒中。
將表達盒DNA以大約為3000個核苷酸長的單鏈DNA分子(ssDNA)的形式包裝到病毒衣殼中。一旦細胞被病毒感染,單鏈DNA就會轉換為雙鏈DNA (dsDNA)的形式。dsDNA只能由細胞的蛋白使用,這些蛋白將存在的一個或多個基因轉錄為RNA。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1的衣殼。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1的衣殼,所述AAV9蛋白VP1具有以下胺基酸序列:
MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 7)。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1的衣殼,所述AAV9蛋白VP1具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP2的衣殼。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP2的衣殼,所述AAV9蛋白VP2具有以下胺基酸序列:
TAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 8)。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP2的衣殼,所述AAV9蛋白VP2具有帶有一個或多個點突變的SEQ ID NO: 8的胺基酸序列。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP3的衣殼。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP3的衣殼,所述AAV9蛋白VP3具有以下胺基酸序列:
MASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 9)。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP3的衣殼,所述AAV9蛋白VP3具有帶有一個或多個點突變的SEQ ID NO: 9的胺基酸序列。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1、VP2和VP3的衣殼。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有SEQ ID NO: 9的胺基酸序列的蛋白VP3。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有帶有一個或多個點突變的SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有帶有一個或多個點突變的SEQ ID NO: 9的胺基酸序列的蛋白VP3。
詞組"多個點突變"指的是兩個、三個、四個、五個、六個、七個、八個、九個或十個點置換。
特別優選的實施方案包括本質上保守的置換(突變),即置換發生在根據其側鏈加入的胺基酸家族內。特別地,胺基酸典型地分為四個家族:(1)酸性胺基酸為天冬氨酸和谷氨酸;(2)鹼性胺基酸為賴氨酸、精氨酸、組氨酸;(3)非極性胺基酸為丙氨酸、纈氨酸、亮氨酸、異亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸;和(4)不帶電荷的極性胺基酸為甘氨酸、天冬醯胺、穀氨醯胺、半胱氨酸、絲氨酸、蘇氨酸、酪氨酸。苯丙氨酸、色氨酸和酪氨酸有時被分類為芳香族胺基酸。例如,可以合理預測,獨立地將亮氨酸置換為異亮氨酸或纈氨酸、天冬氨酸置換為谷氨酸、蘇氨酸置換為絲氨酸或類似地將胺基酸保守置換為結構相關的胺基酸對生物學活性將不具有主要影響。例如,感興趣的多肽可以包括多達約5-10個保守或非保守胺基酸置換,只要分子的期望功能保持完整。
在AAV9蛋白VP1、VP2或VP3的序列中帶有使用胺基酸置換的點突變的實施方案是用另一個胺基酸殘基置換AAV9蛋白VP1、VP2或VP3中的至少一個胺基酸殘基。
保守置換顯示在表A的"優選置換"欄中。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1的衣殼,所述AAV9蛋白VP1具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列,和表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有SEQ ID NO: 9的胺基酸序列的蛋白VP3,和表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有帶有一個或多個點突變的SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有帶有一個或多個點突變的SEQ ID NO: 9的胺基酸序列的蛋白VP3,和表達盒在5'端至3'端方向包括以下元件:
左側(第一個) ITR (反向末端重複);
CMV (巨細胞病毒)增強子;
CMV (巨細胞病毒)啓動子;
hBG1基因(血紅蛋白γ1亞基基因)的內含子;
編碼SMN1蛋白的核酸;
hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號);
SV40啓動子(猴病毒40啓動子);
編碼微RNA miR-23a的核酸;
SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和
右側(第二個) ITR。
在一些實施方案中,基於AAV9的重組病毒具有包括AAV9蛋白VP1的衣殼,所述AAV9蛋白VP1具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列,和表達盒包含具有SEQ ID NO: 6的核酸。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有SEQ ID NO: 9的胺基酸序列的蛋白VP3,和表達盒包含具有SEQ ID NO: 6的核酸。
在一些實施方案中,基於AAV9的重組病毒具有包括以下蛋白的衣殼:具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的蛋白VP1、具有帶有一個或多個點突變的SEQ ID NO: 8的胺基酸序列的蛋白VP2和具有帶有一個或多個點突變的SEQ ID NO: 9的胺基酸序列的蛋白VP3,和表達盒包含具有SEQ ID NO: 6的核酸。
藥物組合物在一個方面,本發明涉及用於將SMN1基因遞送至目標細胞的藥物組合物,其包括與一種或多種藥學上可接受的賦形劑組合的以上基於AAV9的重組病毒的任一種。
以上組合物中的活性物質以有效量,例如以生物有效量存在。
在特定的實施方案中,本發明涉及包含在藥學上可接受的載體中或在其他藥劑、佐劑、稀釋劑等中的本發明的基於AAV9的重組病毒的藥物組合物。對於注射,載體將典型地是液體載體。對於其他給藥方法,載體可以是固體或液體,諸如無菌無熱原水或無菌無熱原磷酸鹽緩衝鹽水溶液。對於吸入給藥,載體是可吸入的,並且優選以固體或液體顆粒形式。作為注射介質,優選使用包含注射溶液常用的添加劑(諸如穩定劑、鹽或鹽水和/或緩衝液)的水。
"藥物組合物"意為包含本發明的以上基於AAV9的重組病毒和至少一種組分的組合物,所述組分選自藥學上可接受的以及藥理學相容的賦形劑,諸如填充劑、溶劑、稀釋劑、載體、助劑、分布劑、遞送劑、防腐劑、穩定劑、乳化劑、助懸劑、增稠劑、延長遞送控制劑,其選擇和比例取決於給藥的類型和路徑以及用量。本發明的藥物組合物及其製備方法對本領域的技術人員將無疑是顯而易見的。藥物組合物應優選按照GMP (藥品生產質量管理規範(Good Manufacturing Practice))要求製造。該組合物可以包含緩衝液組合物、張力劑、穩定劑和增溶劑。
"藥學上可接受的"意為不具有生物學或其他負面副作用的材料,例如可以施用給受試者而不引起任何不期望的生物學作用的材料。因此,這類藥物組合物可以在例如離體的細胞轉染中或直接給受試者的本發明的基於AAV9的重組病毒的體內給藥中使用。
本文使用術語"賦形劑"以描述除了本發明的以上成分之外的任何成分。這些是無機或有機性質的物質,其在藥物製造中使用以給予藥品產品必要的理化特性。
"穩定劑"指的是提供活性藥物的物理和/或化學穩定性的賦形劑或兩種或更多種賦形劑的混合物。
術語"緩衝液"、"緩衝液組合物"、"緩衝劑"指的是能夠通過其酸鹼共軛物組分的作用抵抗pH的變化的溶液,其使rAAV9載體產物能夠抵抗pH的變化。一般地,藥物組合物優選具有在從4.0至8.0的範圍中的pH。所使用的緩衝液的實例包括但不限於乙酸鹽、磷酸鹽、檸檬酸鹽、組氨酸、琥珀酸鹽等緩衝液溶液。
如果活性藥物在例如2-8 °C的貯存溫度下在指定的保存期限期間保持其物理穩定性和/或化學穩定性和/或生物學活性,則藥物組合物是"穩定的"。優選地,活性藥物保持物理和化學穩定性兩者以及生物學活性。貯存期基於在加速或自然老化條件下的穩定性測試的結果進行調整。
本發明的藥物組合物可以以現成製劑的形式以單一單位劑量或多個單一單位劑量的形式製造、包裝或廣泛銷售。如本文所使用的術語"單一單位劑量"指的是包含預定量的活性成分的離散量的藥物組合物。活性成分的量典型地等於待在受試者中施用的活性成分的劑量或該劑量的方便部分,例如該劑量的一半或三分之一。
用途本發明的作者驚奇地發現miR-23a在體外增強SMN1的功能作用,並揭示了SMN1和miR-23a在SMA的動物模型中治療該疾病的協同作用。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於將SMN1基因遞送至目標細胞的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的存活的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於將SMN1蛋白提供給患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的用途。
在一個方面,本發明涉及以上基於AAV9的重組病毒的任一種或以上組合物用於在患有脊髓性肌萎縮的受試者中治療脊髓性肌萎縮的用途。
在一個方面,本發明涉及用於在患有運動神經元病症的受試者中調整運動功能的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到受試者的細胞中。
在一個方面,本發明涉及用於將SMN蛋白提供給患有脊髓性肌萎縮的受試者的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到有需要的受試者的細胞中。
在一個方面,本發明涉及用於將SMN1基因遞送至患有脊髓性肌萎縮的受試者的目標細胞的方法,所述方法包含將以上基於AAV9的重組病毒的任一種或以上組合物施用到受試者的細胞中。
在一個方面,本發明涉及用於在受試者中治療脊髓性肌萎縮的方法,所述方法包含將治療有效量的以上基於AAV9的重組病毒的任一種或以上組合物施用到患有脊髓性肌萎縮的受試者中。
SMN1基因的完全功能複製的缺乏指的是在基因組中的SMN1基因的所有複製中的失活突變或缺失,其導致SMN1基因功能的喪失或缺陷。
受試者指的是適用本描述中所提供的技術的任何動物。在某些非限制性實施方案中,受試者是人。所述受試者可以是任何年齡的雄性或雌性。
需要將SMN1基因遞送至目標細胞的受試者,或需要被提供SMN1蛋白的受試者,或需要將SMN1基因遞送至目標細胞的受試者指的是患有脊髓性肌萎縮的受試者或在SMN1基因中具有導致SMN1基因功能的喪失或缺陷的失活突變或缺失的受試者。
示例的給藥方式包括局部施加、鼻內、吸入、經黏膜、經皮、腸內(例如口服、直腸)、腸胃外(例如靜脈內、皮下、皮內、肌肉內)給藥以及直接組織或器官注射。
可以以常規形式,作為液體溶液或懸浮液、適用於在注射前在液體中製備溶液或懸浮液的固體形式或作為乳劑製備注射劑。備選地,可以以局部而不是全身的方式(例如以儲庫(depot)製劑或緩釋製劑)施用本發明的以上基於AAV9的重組病毒。
將基於AAV9的重組病毒以有效量引入到生物體中。優選將基於AAV9的重組病毒以生物有效量引入到生物體中。重組病毒的"生物有效"量是足以引起感染(或轉導)以及細胞中核酸序列的表達的量。如果在體內將病毒施用給細胞(例如,如下所述,將病毒施用給受試者),那麽病毒載體的"生物有效"量是足以引起轉導和目標細胞中核酸序列的表達的量。
本發明的以上基於AAV9的重組病毒的用量將取決於給藥方式、特定的病毒載體,並且它們可以以常規的方式來確定。用於達到治療作用的示例劑量為每公斤至少約10
5、10
6、10
7、10
8、10
9、10
10、10
11、10
12、10
13、10
14、10
15、10
16個轉導單位或更多,優選約10
9至10
15個轉導單位,更優選10
14個轉導單位的病毒滴度。
施用本發明的以上基於AAV9的重組病毒的細胞可以是任何類型的細胞,包括但不限於運動神經元或神經系統的其他組織、上皮細胞(例如皮膚、呼吸道和腸道上皮細胞)、肝細胞、肌肉細胞、胰腺細胞(包括胰島細胞)、肝細胞、脾細胞、成纖維細胞、內皮細胞等。
本發明的以上基於AAV9的重組病毒不用於修飾人生殖系細胞的遺傳完整性。
實施例為了更好地理解本發明,提供以下實施例。這些實施例僅用於說明的目的,並且不應解釋為以任何方式限制本發明的範圍。
本說明書中援引的所有出版物、專利和專利申請均通過引用併入本文。儘管為了清楚理解的目的已經通過說明和實例的方式對前面的發明進行了一些詳細的描述,但是根據本發明的教導,對於本領域的普通技術人員來說將容易顯而易見的是,可以在不背離所附實施方案的精神或範圍的情況下對其進行某些變化和修改。
材料和一般方法 重組 DNA 技術如在Sambrook, J等人, Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989中所述,使用標準方法操作DNA。根據製造商方案使用分子生物學試劑。簡要地,在選擇性抗生素壓力下生長的大腸杆菌(E. coli)細胞中生產質粒DNA用於進一步操作,以便質粒不會在細胞群體中丟失。我們使用商業試劑盒從細胞中分離了質粒DNA,測量了濃度,並通過限制性內切酶處理或PCR擴增將其用於選殖。使用連接酶將DNA片段相互連接並轉化到細菌細胞中用於選殖的選擇和進一步生產。所有所得到的遺傳構建體都通過限制圖譜和完整的Sanger測序來確認。
基因合成期望的基因段製備自通過化學合成製成的寡核苷酸。兩側是獨特的限制性位點的300 bp至1000 bp長的基因段通過在彼此的上面將寡核苷酸複性,接著從邊界引物進行PCR擴增而收集。作為結果,產生了片段的混合物,包括期望的片段。將片段在限制性位點選殖到中間載體中,其後通過DNA測序確認亞選殖片段的DNA序列。
DNA 序列確定DNA序列通過Sanger測序確定。在SnapGene Viewer 4.2或更高版本中分析DNA和蛋白的序列並處理序列數據用於序列創建、作圖(mapping)、分析、注釋和說明。
培養細胞培養物實驗使用HEK293 (人胚腎選殖293)和U-87 MG (人成膠質細胞瘤)細胞系。將細胞在標準條件下在37℃和5%CO
2下,在補充有10% FBS和抗生素的DMEM完全培養基上培養。為了培養HSMC,用膠原(Gibco)預塗布培養塑料。細胞在達到80-90%匯合後進行傳代培養。使用台盼藍(Trypan Blue)染色和血細胞計數器或PI染色和流式細胞術評價細胞活力。
siRNA 細胞轉染與非特異性對照一起從製造商(ThermoFisher Scientific)訂購了對
SMN1基因特異的商業siRNA。
在轉染前一天將細胞系接種到6孔平板中,以使得它們到轉染時達到70-80%匯合。根據製造商的方案,使用商業脂質體轉染試劑盒進行轉染。轉染後24小時,進行轉導(見下文)。轉導後120小時,將細胞用胰蛋白酶溶液或類似物處理、從基質中去除、在磷酸鹽緩衝液中洗滌並收集用於目標基因和蛋白表達的進一步分析。進行酶免疫吸附(ELISA)以控制SMN蛋白敲低的水平。
所有樣品均進行3次實驗重複分析。
基因表達分析使用定量PCR測量SMN1在mRNA水平的表達和
miR-23a的表達。簡要地,我們使用了對編碼SMN1蛋白的核苷酸序列特異的引物和樣品。對於
miR-23a,我們使用了對加工過的
miR-23a特異的用於定量PCR的商業試劑盒(Thermo Fisher Scientific)。使用對
GAPDH持家基因特異的引物和樣品來控制初始RNA水平。使用包含相應基因的擴增序列的線性化質粒DNA的已知複製數量來繪製每組引物和樣品的校準曲線。通過使用校準曲線確定每個樣品中
SMN1和
GAPDH的複製數量來分析表達,其後我們將
SMN1的複製數量相對於10,000個
GAPDH的複製進行歸一化。在相同的實驗內比較不同樣品所得到的值。
SMN 蛋白表達的確定使用Thermo Fisher Scientific試劑盒以確定總蛋白的量。裂解細胞沉澱,將所得到的裂解物與已知濃度下的BSA標準稀釋物一起引入到微板孔中。將工作試劑添加至樣品,並孵育樣品。孵育結束時,我們在酶標儀上測量了在562 nm波長處的吸收。根據BSA標準曲線計算了測試樣品中總蛋白的濃度。接下來,將裂解物稀釋至10 μg/ml的總蛋白濃度。
根據製造商的說明,使用商業Abcam試劑盒通過酶免疫測定(ELISA)評價細胞中SMN蛋白的含量。用測試樣品和已知濃度下的標準品加載塗布有抗SMN抗體的微板孔。孵育和洗滌後,將用於檢測的SMN特異性多選殖抗體添加至每個孔,孵育和洗滌樣品。添加與辣根過氧化物酶共軛的第二抗體,並孵育樣品。洗掉過量的試劑並添加TMB底物。短期孵育後,用終止試劑終止酶促反應。黃色產物的光密度通過分光光度法在450nm波長處測量。使用光密度相對標準品中SMN濃度的校準圖確定測試樣品中SMN的量。
SMN 靶標 Senataxin 蛋白表達的確定 ( 功能測試 )Senataxin蛋白是參與到稱為R環的DNA-RNA結構的拆分中的多功能酶,所述R環在SMN蛋白不存在或低表達的情況下在轉錄期間發生。文獻已經報道了SMN和Senataxin表達水平之間的直接相關,以及Senataxin的間接激活是SMN的功能之一。在這一點上,Senataxin表達的變化被用作SMN的功能測試。
通過蛋白質印漬確定Senataxin表達水平。簡要地,在實驗暴露(轉染、轉導、孵育)後用補充有蛋白酶抑制劑混合物的RIPA緩衝液裂解細胞,由此獲得蛋白裂解物樣品。將樣品施加到10%聚丙烯醯胺變性凝膠上,其後將蛋白轉移到PVDF膜上。
將膜在TBS-T緩衝液中的5%牛血清白蛋白(BSA)溶液中孵育1小時,其後用補充有對Senataxin特異的第一抗體的TBS-T中的1% BSA溶液替換BSA溶液。孵育2小時後,將膜用TBS-T中的1% BSA溶液洗滌3次,並添加補充有1% BSA的TBS-T中的第二抗體溶液。我們使用與酶辣根過氧化物酶共軛的第二抗體。
將第二抗體用TBS-T中的1%BSA溶液洗滌3次,其後使用化學發光底物和凝膠成像系統在膜上檢測蛋白信號。所得到的圖像以數字格式保存,並使用凝膠成像系統的軟件分析信號強度。
黏著斑蛋白持家基因的蛋白信號被用作歸一化的對照。染色以類似的方式進行。
AAV 重組載體病毒顆粒的組裝和純化為了組裝包含
SMN1基因或
GFP對照基因的AAV顆粒,我們使用了HEK293包裝細胞,其中使用聚乙烯亞胺轉染了如下3個質粒:
1. 包含具有轉基因表達盒(
SNM1、
GFP、
SMN1+
miR-23a或
GFP+
miR-23a)的AAV基因組的質粒;
2. 用於AAV9血清型
Cap基因和AAV2血清型
Rep基因的表達的質粒。每個基因使用可變閱讀框編碼幾種蛋白產物;
3. 用於AAV衣殼組裝和包裝所需要的Ad5 (腺病毒血清型5)基因的表達的質粒。
72小時後,將細胞裂解並且使用過濾和色譜法純化和濃縮病毒顆粒。病毒顆粒的滴度用對重組病毒基因組區域特異的引物和樣品通過定量PCR確定,並表示為每1 ml的病毒基因組的複製數量。
細胞培養物的轉導與轉染實驗類似地接種U-87細胞系,用siRNA進行轉染,其後添加帶有病毒顆粒的產物並在120 h後分析細胞。通過測量GFP+細胞的百分比來估算轉導效率。
所使用的培養物用轉導效率檢查進行預測試。簡要地,將AAV9-GFP病毒產物以不同的細胞和病毒顆粒比轉導到細胞系中。病毒顆粒數量與細胞數量的比被稱為感染複數(MOI)。AAV9-GFP病毒的MOI的範圍從50,000到1,000,000。作為結果,為U-87系選擇了400,000的最佳MOI。在該MOI下對所有病毒進行了進一步的U-87轉導工作。
轉導後,如上所述分析基因和蛋白表達。
所有樣品均進行3次實驗重複分析。
病毒產物注射到脊髓性肌萎縮 (SMA) 的小鼠模型中病毒顆粒AAV9-SMN1、AAV9-GFP、AAV9-SMN1-miR-23a和AAV9-GFP-miR-23a用於注射到SMA模型小鼠中。這些小鼠不表達小鼠
Smn基因,但在其基因組中具有人
SMN2基因的一個複製和帶有外顯子7缺失的人
SMN1基因(
SMN1Δ7)的一個複製。在沒有干預或注射安慰劑的情況下,這些小鼠出生,但是出生後體重增加差並且平均21天後死亡。
模型系的小鼠在出生後第1天進行基因分型,其後用安慰劑(不包含病毒顆粒,但包含用於其稀釋的緩衝液的溶液)或病毒的一種以3.2x10
14vg/kg體重的劑量對不包含
Smn基因的複製的小鼠進行全身注射(在尾靜脈中)。其後,將動物保持在標準條件下並每天稱重,並且還繪製存活曲線。注射後90天,將存活的動物處死用於組織分析並結束實驗。
實施例 1. 攜帶重組 AAV 基因組並且編碼 SMN1 、 GFP 和 miR-23a 基因的遺傳構建體的組裝。SMN1基因序列通過用特異性引物與基於HEK293細胞的總RNA合成的cDNA進行擴增而產生,或組裝自一系列寡核苷酸(見上文)。在擴增過程期間,從基因的5'端添加Kozak序列和ClaI限制性位點,並從3'端添加XbaI限制性位點。其後,通過限制性連接酶方法在ClaI和XbaI位點將
SMN1基因的序列選殖到來自CellBiolab (USA)的商業構建體pAAV-GFP Control質粒(VPK-402)中,用
SMN1置換GFP基因,由此產生pAAV-SMN1構建體。
將額外的
miR-23a表達盒插入到先前產生的質粒pAAV-GFP和pAAV-SMN1中。額外的
miR-23a表達盒由啓動子、感興趣的基因(使用PCR從Huh7細胞系的基因組DNA產生的
miR-23a)和多聚腺苷酸化信號組成。通過在PmlI位點線性化受體載體(pAAV-GFP、pAAV-SMN1),接著在黏性末端併入帶有
miR-23a的表達盒來產生目標質粒。
最終載體包含作為重組AAV基因組一部分的基因的表達和組裝所必需的所有元件:
1. 在被包裹(encapsidate)到病毒衣殼中的序列的末端的ITR;
2. 用於目標基因的表達的盒(啓動子、增強子、內含子、Kozak序列、轉基因、多聚腺苷酸化位點);
3. 如果有的話,
miR-23a表達盒(啓動子、編碼
miR-23a正向鏈和反向鏈的基於
miR-30的微RNA盒、多聚腺苷酸化位點);
4. 用於在細菌細胞中產生質粒DNA的細菌複製起點和抗生素抗性基因。
實施例 2. 表達 SMN1 和 miR-23a 的病毒產物的產生質粒pAAV-SMN1、pAAV-GFP、pAAV-SMN1-miR-23a、pAAV-GFP-miR-23a與產生重組AAV病毒顆粒所需要的其他質粒(見上文)一起被用於AAV產生生物過程。所使用的血清型為野生型AAV9或具有各種突變的AAV9。在所有情況下,只有所使用的血清型和衣殼突變(如果有的話)相同時,才比較病毒顆粒的特性。所有基於AAV9的血清型,無論是野生型還是帶有突變,在下文中都稱為AAV9,而不指定突變。
生物過程造成了重組病毒顆粒,將其命名為AAV9-SMN1、AAV9-GFP、AAV9-SMN1-miR-23a、AAV9-GFP-miR-23a。在確定病毒顆粒的滴度後,使用具有相同的400,000的MOI的所有3種產物轉導感受細胞U-87,所述U-87用針對SMN1的siRNA或具有非特異性序列的siRNA預轉染(24小時前)。只有GFP轉導效率至少為70%時,才進行進一步的分析。
成功轉導後,將細胞從基質中去除,在磷酸鹽緩衝液中洗滌,並如上所述在mRNA水平和SMN蛋白水平分析
SMN1的表達。證明了當用病毒AAV9-SMN1和AAV9-SMN1-miR-23a轉導時,
SMN1表達超過了內源mRNA水平(表1,圖1),並在蛋白水平恢復到內源水平(在沒有
SMN1特異性siRNA的對照中觀察到的)(表2,圖2)。
表1.
表2.
此外,我們確定了轉導後樣品中的
miR-23a表達水平。在用病毒AAV9-SMN1-miR-23a、AAV9-GFP-miR-23a轉導的樣品中顯示出顯著過量的
miR-23a表達。在其他樣品中,
miR-23a表達與內源表達沒有不同。針對
SMN1的siRNA的轉染不影響
miR-23a表達(表3,圖3)。
表3.
應該注意的是,用敲低或使用病毒產物恢復對
SMN1表達的改變不影響
miR-23a表達。此外,
miR-23a過量表達對
SMN1表達沒有影響。
實施例 3. 體外轉導後的 SMN1 和 miR-23a 的功能評價使用以上
SMN1敲低和使用用病毒顆粒轉導恢復其表達的實驗設計評估
SMN1和
miR-23a在體外的功能協作。在SMN1的許多功能中,該蛋白質負責轉錄期間發生的DNA-RNA雙鏈體的正確拆分。此外,參與到雙鏈體的拆分的主要蛋白是Senataxin,根據文獻,其由SMN間接激活。因此,Senataxin的激活可以被認為是細胞中SMN活性的功能測試。
通過蛋白質印漬確定樣品中Senataxin表達水平。發現了隨著SMN表達的敲低,Senataxin表達减少至約1/2,並且隨著用病毒AAV9-SMN1恢復SMN表達,其恢復至內源水平。在SMN敲低的情況下,在用對照病毒AAV9 - GFP-miR-23a轉導期間,我們觀察到Senataxin表達有輕微增加的趨勢,但其沒有統計學意義。值得注意的是,在用病毒AAV9-SMN1-miR-23a轉導的情況下,Senataxin表達不僅在內源SMN敲低的背景下恢復至內源水平,而且具有統計學意義地增加到1.5倍-2倍(表4,圖4)。
表4.
這確認了SMN和
miR-23a對Senataxin表達的協同作用,其超過了
miR-23a和SMN兩者單獨對基因調節的作用。
實施例 4.
SMN1 和 miR-23a 在治療 SMA 小鼠模型動物中的協同作用在出生後第一天以3.6x10
14vg/kg的劑量將病毒產物AAV9-SMN1和AAV9-SMN1-miR-23a注射到SMA模型小鼠的尾靜脈中。我們使用了不含病毒顆粒的溶液(安慰劑)和一組由於它們的
Smn表達而不具有SMA表型的野生型同胞小鼠。接下來,在所有組中建立了小鼠的存活功能。在達到可以確定所有組的中位存活時間的點後,計算中位數。
在用病毒AAV9-SMN1-miR-23a注射的組中SMA表型得到的矯正最多。該組的中位存活時間為55天。該結果與用病毒AAV9-SMN1注射的組顯著不同,該組中中位存活時間為21天。對於注射安慰劑的小鼠,中位數為出生後16天(圖5)。該結果顯示
SMN1和
miR-23a在SMA的動物模型中治療該疾病的協同作用。
表A | ||
原始殘基 | 示例置換 | 優選置換 |
Ala (A) | Val; Leu; Ile | Val |
Arg(R) | Lys; Gin; Asn | Lys |
Asn(N) | Gin; His; Asp, Lys; Arg | Gin |
Asp (D) | Glu; Asn | Glu |
Cys (C) | Ser; Ala | Ser |
Gln(Q) | Asn; Glu | Asn |
Glu (E) | Asp; Gin | Asp |
Gly(G) | Ala | Ala |
His (H) | Asn; Gin; Lys; Arg | Arg |
Ile (I) | Leu; Val; Met; Ala; Phe; 正亮氨酸 | Leu |
Leu (L) | 正亮氨酸; Ile; Val; Met; Ala; Phe | Ile |
Lys (K) | Arg; Gin; Asn | Arg |
Met (M) | Leu; Phe; Ile | Leu |
Phe(F) | Trp; Leu; Val; Ile; Ala; Tyr | Tyr |
Pro (P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr (T) | Val; Ser | Ser |
Trp(W) | Tyr; Phe | Tyr |
Tyr(Y) | Trp; Phe; Thr; Ser | Phe |
Val (V) | Ile; Leu; Met; Phe; Ala; 正亮氨酸 | Leu |
樣品名稱 | 相對於 GAPDH 複製數量進行歸一化的平均 mRNA 複製數量 | 標準偏差 |
無siRNA,無病毒 | 0.00275 | 0.00021 |
siNeg | 0.00168 | 0.00009 |
siSMN1 | 0.0002 | 0.00002 |
siNeg + AAV9-GFP | 0.00203 | 0.00033 |
siSMN1 + AAV9-GFP | 0.00039 | 0.00006 |
siNeg + AAV9-GFP-miR-23a | 0.00185 | 0.00028 |
siSMN1 + AAV9-GFP-miR-23a | 0.00039 | 0.00001 |
siNeg + AAV9-SMN1 | 0.10363 | 0.01045 |
siSMN1 + AAV9-SMN1 | 0.33121 | 0.01495 |
siNeg + AAV9-SMN1-miR-23a | 0.24863 | 0.01715 |
siSMN1 + AAV9-SMN1-miR-23a | 0.34258 | 0.0705 |
樣品名稱 | 相對於總蛋白 (μg) 進行歸一化的平均 SMN 量 (pg) | 標準偏差 |
無siRNA,無病毒 | 83.37 | 8.58 |
siNeg | 73.43 | 5.53 |
siSMN1 | 5.45 | 1.36 |
siNeg + AAV9-GFP | 67.95 | 12.41 |
siSMN1 + AAV9-GFP | 5.4 | 1.02 |
siNeg + AAV9-GFP-miR-23a | 71.82 | 3.16 |
siSMN1 + AAV9-GFP-miR-23a | 4.8 | 1.23 |
siNeg + AAV9-SMN1 | 116.4 | 1.85 |
siSMN1 + AAV9-SMN1 | 69.15 | 5.71 |
siNeg + AAV9-SMN1-miR-23a | 99.95 | 7.1 |
siSMN1 + AAV9-SMN1-miR-23a | 91.13 | 4.93 |
樣品名稱 | miR-23a 的平均歸一化量 (%) | 標準偏差 |
無siRNA,無病毒 | 100 | 12 |
siNeg | 95 | 10 |
siSMN1 | 113 | 13 |
siNeg + AAV9-GFP | 124 | 12.41 |
siSMN1 + AAV9-GFP | 107 | 11 |
siNeg + AAV9-GFP-miR-23a | 843 | 33 |
siSMN1 + AAV9-GFP-miR-23a | 768 | 26 |
siNeg + AAV9-SMN1 | 116.4 | 16 |
siSMN1 + AAV9-SMN1 | 77 | 8 |
siNeg + AAV9-SMN1-miR-23a | 803 | 15 |
siSMN1 + AAV9-SMN1-miR-23a | 920 | 19 |
樣品名稱 | Senataxin 的平均歸一化量 (%) | 標準偏差 |
無siRNA,無病毒 | 100 | 15 |
siNeg | 109 | 17 |
siSMN1 | 46 | 8 |
siNeg + AAV9-GFP | 115 | 11 |
siSMN1 + AAV9-GFP | 53 | 12 |
siNeg + AAV9-GFP-miR-23a | 98 | 14 |
siSMN1 + AAV9-GFP-miR-23a | 73 | 19 |
siNeg + AAV9-SMN1 | 124 | 21 |
siSMN1 + AAV9-SMN1 | 110 | 13 |
siNeg + AAV9-SMN1-miR-23a | 196 | 17 |
siSMN1 + AAV9-SMN1-miR-23a | 168 | 7 |
[圖1]是顯示使用siRNA敲低(knockdown)
SMN1並通過AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a病毒轉導後
SMN1在mRNA水平的表達的圖。用20 nmol/l對SMN1特異的siRNA (或對照siRNA)轉染U-87細胞,其後由病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a在MOI=400,000下轉導它們。轉導後120 h,通過定量PCR (n=3)確定每個樣品中
SMN1基因的複製數量。還確定了
GAPDH持家基因的複製數量。所有獲得的
SMN1水平均相對於每個樣品中
GAPDH基因的複製量進行歸一化。提供的是
SMN1的歸一化平均複製數量的數據,顯示標準偏差。
[圖2]是顯示使用siRNA敲低
SMN1並通過病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a轉導後SMN在蛋白水平的表達的圖。用20 nmol/l對SMN1特異的siRNA (或對照siRNA)轉染U-87細胞,其後由病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a在MOI=400,000下轉導它們。轉導後120 h,使用ELISA (n=3)確定了每個樣品中SMN蛋白的量。所有所得到的SMN蛋白的量(以pg為單位)均相對於每個樣品中蛋白的總量(以μg為單位)進行歸一化。提供的是SMN蛋白的歸一化平均量的數據,顯示標準偏差。
[圖3]是顯示使用siRNA敲低
SMN1並通過病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a轉導後
miR-23a表達的圖。用20 nmol/l對SMN1特異的siRNA (或對照siRNA)轉染U-87細胞,其後由病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a在MOI=400,000下轉導它們。轉導後120 h,使用ΔΔC
T方法,通過定量PCR (n=3)確定了每個樣品中相對於
GAPDH基因的複製數量的
miR-23a的量。提供的是
miR-23a的歸一化平均量的數據,顯示標準偏差。取未轉染和未轉導對照中的
miR-23a的相對量為100 %。
[圖4]是顯示使用siRNA敲低
SMN1並通過病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a轉導後Senataxin表達的圖。用20 nmol/l對野生型SMN1特異的siRNA (或對照siRNA)轉染U-87細胞,其後由病毒AAV9-GFP、AAV9-GFP-miR-23a、AAV9-SMN1和AAV9-SMN1-miR-23a在MOI=400,000下轉導它們。轉導後120 h,使用蛋白質印漬確定了每個樣品中相對於黏著斑蛋白(Vinculin)蛋白的量的Senataxin的量。提供的是顯示帶有標準偏差(n=3)指示的在實驗樣品中相對於黏著斑蛋白的Senataxin的歸一化表達的圖。取未轉染和未轉導對照中的Senataxin的相對量為100 %。
對於圖1至4:
siNEG是siRNA的陰性對照,
siSMN1是用於SMN1的siRNA。
[圖5]是顯示用病毒AAV9-SMN1和AAV9-SMN1-miR-23a注射的SMA模型小鼠的存活曲線的圖。還顯示了注射安慰劑的動物和野生型對照小鼠(來自與實驗小鼠相同的一窩)的存活曲線。
<![CDATA[<110> 俄羅斯聯邦商亞那拜恩有限公司(Limited Liability Company <<ANABION>>)]]> <![CDATA[<120> SMN1和miR-23a在治療脊髓性肌萎縮中的協同作用]]> <![CDATA[<140> TW 111104139]]> <![CDATA[<141> 2022-01-28]]> <![CDATA[<150> RU2021102051]]> <![CDATA[<151> 2021-01-29]]> <![CDATA[<160> ]]>17 <![CDATA[<170> BiSSAP 1.3.6]]> <![CDATA[<210> 1]]> <![CDATA[<211> 294]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> SMN1蛋白的胺基酸序列]]> <![CDATA[<400> 1]]> Met Ala Met Ser Ser Gly Gly Ser Gly Gly Gly Val Pro Glu Gln Glu 1 5 10 15 Asp Ser Val Leu Phe Arg Arg Gly Thr Gly Gln Ser Asp Asp Ser Asp 20 25 30 Ile Trp Asp Asp Thr Ala Leu Ile Lys Ala Tyr Asp Lys Ala Val Ala 35 40 45 Ser Phe Lys His Ala Leu Lys Asn Gly Asp Ile Cys Glu Thr Ser Gly 50 55 60 Lys Pro Lys Thr Thr Pro Lys Arg Lys Pro Ala Lys Lys Asn Lys Ser 65 70 75 80 Gln Lys Lys Asn Thr Ala Ala Ser Leu Gln Gln Trp Lys Val Gly Asp 85 90 95 Lys Cys Ser Ala Ile Trp Ser Glu Asp Gly Cys Ile Tyr Pro Ala Thr 100 105 110 Ile Ala Ser Ile Asp Phe Lys Arg Glu Thr Cys Val Val Val Tyr Thr 115 120 125 Gly Tyr Gly Asn Arg Glu Glu Gln Asn Leu Ser Asp Leu Leu Ser Pro 130 135 140 Ile Cys Glu Val Ala Asn Asn Ile Glu Gln Asn Ala Gln Glu Asn Glu 145 150 155 160 Asn Glu Ser Gln Val Ser Thr Asp Glu Ser Glu Asn Ser Arg Ser Pro 165 170 175 Gly Asn Lys Ser Asp Asn Ile Lys Pro Lys Ser Ala Pro Trp Asn Ser 180 185 190 Phe Leu Pro Pro Pro Pro Pro Met Pro Gly Pro Arg Leu Gly Pro Gly 195 200 205 Lys Pro Gly Leu Lys Phe Asn Gly Pro Pro Pro Pro Pro Pro Pro Pro 210 215 220 Pro Pro His Leu Leu Ser Cys Trp Leu Pro Pro Phe Pro Ser Gly Pro 225 230 235 240 Pro Ile Ile Pro Pro Pro Pro Pro Ile Cys Pro Asp Ser Leu Asp Asp 245 250 255 Ala Asp Ala Leu Gly Ser Met Leu Ile Ser Trp Tyr Met Ser Gly Tyr 260 265 270 His Thr Gly Tyr Tyr Met Gly Phe Arg Gln Asn Gln Lys Glu Gly Arg 275 280 285 Cys Ser His Ser Leu Asn 290 <![CDATA[<210> 2]]> <![CDATA[<211> 882]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 編碼SMN1蛋白的核酸序列]]> <![CDATA[<400> 2]]> atggccatga gcagcggcgg cagcggcggc ggcgtgcctg agcaagagga cagcgtgctg 60 ttcagaagag gcaccggcca gagcgacgac agcgacatct gggacgacac cgccctgatc 120 aaggcctacg acaaggccgt ggccagcttc aagcacgccc tgaagaacgg cgacatctgc 180 gagaccagcg gcaagcccaa gaccaccccc aagagaaagc ccgccaagaa gaacaagagc 240 cagaagaaga acaccgccgc cagcctgcag cagtggaagg tgggcgacaa gtgcagcgcc 300 atctggagcg aggacggctg catctacccc gccaccatcg ccagcatcga cttcaagaga 360 gagacctgcg tggtggtgta caccggctac ggcaacagag aggagcagaa cctgagcgac 420 ctgctgagcc ccatctgcga ggtggccaac aacatcgagc agaacgccca agagaacgag 480 aacgagagcc aagtgagcac cgacgagagc gagaacagca gaagccccgg caacaagagc 540 gacaacatca agcccaagag cgccccctgg aacagcttcc tgccccctcc cccccctatg 600 cccggcccta gactgggccc tggcaagcct ggcctgaagt tcaacggccc ccccccccct 660 cctcctcctc ctcctcctca cctgctgagc tgctggctgc cccccttccc cagcggccct 720 cctatcatcc ctcctccccc ccccatctgc cccgacagcc tggacgacgc cgacgccctg 780 ggcagcatgc tgatcagctg gtacatgagc ggctaccaca ccggctacta catgggcttc 840 agacagaacc agaaggaggg ccggtgcagc cacagcctga ac 882 <![CDATA[<210> 3]]> <![CDATA[<211> 73]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 微RNA miR-23a]]> <![CDATA[<400> 3]]> ggccggcugg gguuccuggg gaugggauuu gcuuccuguc acaaaucaca uugccaggga 60 uuuccaaccg acc 73 <![CDATA[<210> 4]]> <![CDATA[<211> 648]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 編碼微RNA miR-23a 的核酸序列(加工前)]]> <![CDATA[<400> 4]]> catgcaagtt gctgtagcct ccttgtcccg catgggccct ctaggtatct ctgcctctcc 60 agtcctgggg ctggaacgga gggcacagct aggctccagc tccccgtgtg gtggctcctg 120 catatgagaa aagagcttcc ctgtgatcaa aggaagcatc tggggacctg gaggggaggt 180 gtccccaaat ctcattacct cctttgctct ctctctcttt ctcccctcca ggtgccagcc 240 tctggccccg cccggtgccc ccctcacccc tgtgccacgg ccggctgggg ttcctgggga 300 tgggatttgc ttcctgtcac aaatcacatt gccagggatt tccaaccgac cctgagctct 360 gccaccgagg atgctgcccg gggacggggt ggcagagagg ccccgaagcc tgtgcctggc 420 ctgaggagca gggcttagct gcttgtgagc agggtccaca ccaagtcgtg ttcacagtgg 480 ctaagttccg ccccccaggc cctcacctcc tctggccttg ccgcctgtcc cctgctgccg 540 cctgtctgcc tgccatcctg ctgcctggcc tccctgggct ctgcctcccg tgcctactga 600 gctgaaacac agttggtttg tgtacactgg ctcagttcag caggaaca 648 <![CDATA[<210> 5]]> <![CDATA[<211> 73]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 編碼微RNA miR-23a的核酸序列(加工後)]]> <![CDATA[<400> 5]]> ggccggctgg ggttcctggg gatgggattt gcttcctgtc acaaatcaca ttgccaggga 60 tttccaaccg acc 73 <![CDATA[<210> 6]]> <![CDATA[<211> 3972]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 表達盒的核酸序列(完整)]]> <![CDATA[<400> 6]]> cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60 ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120 aggggttcct gcggccgcac gcgtctagtt attaatagta atcaattacg gggtcattag 180 ttcatagccc atatatggag ttccgcgtta cataacttac ggtaaatggc ccgcctggct 240 gaccgcccaa cgacccccgc ccattgacgt caataatgac gtatgttccc atagtaacgc 300 caatagggac tttccattga cgtcaatggg tggagtattt acggtaaact gcccacttgg 360 cagtacatca agtgtatcat atgccaagta cgccccctat tgacgtcaat gacggtaaat 420 ggcccgcctg gcattatgcc cagtacatga ccttatggga ctttcctact tggcagtaca 480 tctacgtatt agtcatcgct attaccatgg tgatgcggtt ttggcagtac atcaatgggc 540 gtggatagcg gtttgactca cggggatttc caagtctcca ccccattgac gtcaatggga 600 gtttgttttg gcaccaaaat caacgggact ttccaaaatg tcgtaacaac tccgccccat 660 tgacgcaaat gggcggtagg cgtgtacggt gggaggtcta tataagcaga gctcgtttag 720 tgaaccgtca gatcgcctgg agacgccatc cacgctgttt tgacctccat agaagacacc 780 gggaccgatc cagcctccgc ggattcgaat cccggccggg aacggtgcat tggaacgcgg 840 attccccgtg ccaagagtga cgtaagtacc gcctatagag tctataggcc cacaaaaaat 900 gctttcttct tttaatatac ttttttgttt atcttatttc taatactttc cctaatctct 960 ttctttcagg gcaataatga tacaatgtat catgcctctt tgcaccattc taaagaataa 1020 cagtgataat ttctgggtta aggcaatagc aatatttctg catataaata tttctgcata 1080 taaattgtaa ctgatgtaag aggtttcata ttgctaatag cagctacaat ccagctacca 1140 ttctgctttt attttatggt tgggataagg ctggattatt ctgagtccaa gctaggccct 1200 tttgctaatc atgttcatac ctcttatctt cctcccacag ctcctgggca acgtgctggt 1260 ctgtgtgctg gcccatcact ttggcaaaga attgggattc gaacatcgat tgtaattcat 1320 gagccaccat ggccatgagc agcggcggca gcggcggcgg cgtgcctgag caagaggaca 1380 gcgtgctgtt cagaagaggc accggccaga gcgacgacag cgacatctgg gacgacaccg 1440 ccctgatcaa ggcctacgac aaggccgtgg ccagcttcaa gcacgccctg aagaacggcg 1500 acatctgcga gaccagcggc aagcccaaga ccacccccaa gagaaagccc gccaagaaga 1560 acaagagcca gaagaagaac accgccgcca gcctgcagca gtggaaggtg ggcgacaagt 1620 gcagcgccat ctggagcgag gacggctgca tctaccccgc caccatcgcc agcatcgact 1680 tcaagagaga gacctgcgtg gtggtgtaca ccggctacgg caacagagag gagcagaacc 1740 tgagcgacct gctgagcccc atctgcgagg tggccaacaa catcgagcag aacgcccaag 1800 agaacgagaa cgagagccaa gtgagcaccg acgagagcga gaacagcaga agccccggca 1860 acaagagcga caacatcaag cccaagagcg ccccctggaa cagcttcctg ccccctcccc 1920 cccctatgcc cggccctaga ctgggccctg gcaagcctgg cctgaagttc aacggccccc 1980 ccccccctcc tcctcctcct cctcctcacc tgctgagctg ctggctgccc cccttcccca 2040 gcggccctcc tatcatccct cctccccccc ccatctgccc cgacagcctg gacgacgccg 2100 acgccctggg cagcatgctg atcagctggt acatgagcgg ctaccacacc ggctactaca 2160 tgggcttcag acagaaccag aaggagggcc ggtgcagcca cagcctgaac tgatctagag 2220 tcgacctgca gaagcttgcc tcgagcagcg ctgctcgaga gatctacggg tggcatccct 2280 gtgacccctc cccagtgcct ctcctggccc tggaagttgc cactccagtg cccaccagcc 2340 ttgtcctaat aaaattaagt tgcatcattt tgtctgacta ggtgtccttc tataatatta 2400 tggggtggag gggggtggta tggagcaagg ggcaagttgg gaagacaacc tgtagggcct 2460 gcggggtcta ttgggaacca agctggagtg cagtggcaca atcttggctc actgcaatct 2520 ccgcctcctg ggttcaagcg attctcctgc ctcagcctcc cgagttgttg ggattccagg 2580 catgcatgac caggctcagc taatttttgt ttttttggta gagacggggt ttcaccatat 2640 tggccaggct ggtctccaac tcctaatctc aggtgatcta cccaccttgg cctcccaaat 2700 tgctgggatt acaggcgtga accactgctc ccttccctgt ccttctgatt ttgtaggtaa 2760 ccactagaga aatgttctgg cacctgcact tgcactgggg acagcctatt ttgctagttt 2820 gttttgtttc gttttgtttt gatggagagc gtatgttagt actatcgatt cacacaaaaa 2880 accaacacac agatgtaatg aaaataaaga tattttattg cggccgctgt tcctgctgaa 2940 ctgagccagt gtacacaaac caactgtgtt tcagctcagt aggcacggga ggcagagccc 3000 agggaggcca ggcagcagga tggcaggcag acaggcggca gcaggggaca ggcggcaagg 3060 ccagaggagg tgagggcctg gggggcggaa cttagccact gtgaacacga cttggtgtgg 3120 accctgctca caagcagcta agccctgctc ctcaggccag gcacaggctt cggggcctct 3180 ctgccacccc gtccccgggc agcatcctcg gtggcagagc tcagggtcgg ttggaaatcc 3240 ctggcaatgt gatttgtgac aggaagcaaa tcccatcccc aggaacccca gccggccgtg 3300 gcacaggggt gaggggggca ccgggcgggg ccagaggctg gcacctggag gggagaaaga 3360 gagagagagc aaaggaggta atgagatttg gggacacctc ccctccaggt ccccagatgc 3420 ttcctttgat cacagggaag ctcttttctc atatgcagga gccaccacac ggggagctgg 3480 agcctagctg tgccctccgt tccagcccca ggactggaga ggcagagata cctagagggc 3540 ccatgcggga caaggaggct acagcaactt gcatggccgc agctttttgc aaaagcctag 3600 gcctccaaaa aagcctcctc actacttctg gaatagctca gaggccgagg cggcctcggc 3660 ctctgcataa ataaaaaaaa ttagtcagcg atggggcgga gaatgggcgg aactgggcgg 3720 agttaggggc gggatgggcg gagttagggg cgggactatg gttgctgact aattgagatg 3780 cagggccgct ccaagtacct cccgtacctt aagtgcggac cgagcggccg caggaacccc 3840 tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag gccgggcgac 3900 caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgca 3960 gctgcctgca gg 3972 <![CDATA[<210> 7]]> <![CDATA[<211> 736]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> AAV9蛋白VP1的胺基酸序列]]> <![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 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> 8]]> <![CDATA[<211> 599]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> AAV9蛋白VP2的胺基酸序列]]> <![CDATA[<400> 8]]> Thr Ala Pro Gly Lys Lys Arg Pro Val Glu Gln Ser Pro Gln Glu Pro 1 5 10 15 Asp Ser Ser Ala Gly Ile Gly Lys Ser Gly Ala Gln Pro Ala Lys Lys 20 25 30 Arg Leu Asn Phe Gly Gln Thr Gly Asp Thr Glu Ser Val Pro Asp Pro 35 40 45 Gln Pro Ile Gly Glu Pro Pro Ala Ala Pro Ser Gly Val Gly Ser Leu 50 55 60 Thr Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp Asn Asn Glu Gly 65 70 75 80 Ala Asp Gly Val Gly Ser Ser Ser Gly Asn Trp His Cys Asp Ser Gln 85 90 95 Trp Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu 100 105 110 Pro Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser Asn Ser Thr Ser 115 120 125 Gly Gly Ser Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp 130 135 140 Gly Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp 145 150 155 160 Trp Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu 165 170 175 Asn Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn 180 185 190 Gly Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe 195 200 205 Thr Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu 210 215 220 Gly Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr 225 230 235 240 Gly Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser 245 250 255 Phe Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn 260 265 270 Asn Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser 275 280 285 Tyr Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp 290 295 300 Gln Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn 305 310 315 320 Gln Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val 325 330 335 Gln Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val 340 345 350 Ser Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly 355 360 365 Ala Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly 370 375 380 Pro Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu 385 390 395 400 Ser Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val 405 410 415 Asp Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr 420 425 430 Asn Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln 435 440 445 Ser Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile 450 455 460 Leu Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro 465 470 475 480 Ile Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro 485 490 495 Leu Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile 500 505 510 Lys Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp 515 520 525 Lys Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val 530 535 540 Glu Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro 545 550 555 560 Glu Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe 565 570 575 Ala Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr 580 585 590 Arg Tyr Leu Thr Arg Asn Leu 595 <![CDATA[<210> 9]]> <![CDATA[<211> 534]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> AAV9蛋白VP3的胺基酸序列]]> <![CDATA[<400> 9]]> Met Ala Ser Gly Gly Gly Ala Pro Val Ala Asp Asn Asn Glu Gly Ala 1 5 10 15 Asp Gly Val Gly Ser Ser Ser Gly Asn Trp His Cys Asp Ser Gln Trp 20 25 30 Leu Gly Asp Arg Val Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro 35 40 45 Thr Tyr Asn Asn His Leu Tyr Lys Gln Ile Ser Asn Ser Thr Ser Gly 50 55 60 Gly Ser Ser Asn Asp Asn Ala Tyr Phe Gly Tyr Ser Thr Pro Trp Gly 65 70 75 80 Tyr Phe Asp Phe Asn Arg Phe His Cys His Phe Ser Pro Arg Asp Trp 85 90 95 Gln Arg Leu Ile Asn Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Asn 100 105 110 Phe Lys Leu Phe Asn Ile Gln Val Lys Glu Val Thr Asp Asn Asn Gly 115 120 125 Val Lys Thr Ile Ala Asn Asn Leu Thr Ser Thr Val Gln Val Phe Thr 130 135 140 Asp Ser Asp Tyr Gln Leu Pro Tyr Val Leu Gly Ser Ala His Glu Gly 145 150 155 160 Cys Leu Pro Pro Phe Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly 165 170 175 Tyr Leu Thr Leu Asn Asp Gly Ser Gln Ala Val Gly Arg Ser Ser Phe 180 185 190 Tyr Cys Leu Glu Tyr Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn 195 200 205 Phe Gln Phe Ser Tyr Glu Phe Glu Asn Val Pro Phe His Ser Ser Tyr 210 215 220 Ala His Ser Gln Ser Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln 225 230 235 240 Tyr Leu Tyr Tyr Leu Ser Lys Thr Ile Asn Gly Ser Gly Gln Asn Gln 245 250 255 Gln Thr Leu Lys Phe Ser Val Ala Gly Pro Ser Asn Met Ala Val Gln 260 265 270 Gly Arg Asn Tyr Ile Pro Gly Pro Ser Tyr Arg Gln Gln Arg Val Ser 275 280 285 Thr Thr Val Thr Gln Asn Asn Asn Ser Glu Phe Ala Trp Pro Gly Ala 290 295 300 Ser Ser Trp Ala Leu Asn Gly Arg Asn Ser Leu Met Asn Pro Gly Pro 305 310 315 320 Ala Met Ala Ser His Lys Glu Gly Glu Asp Arg Phe Phe Pro Leu Ser 325 330 335 Gly Ser Leu Ile Phe Gly Lys Gln Gly Thr Gly Arg Asp Asn Val Asp 340 345 350 Ala Asp Lys Val Met Ile Thr Asn Glu Glu Glu Ile Lys Thr Thr Asn 355 360 365 Pro Val Ala Thr Glu Ser Tyr Gly Gln Val Ala Thr Asn His Gln Ser 370 375 380 Ala Gln Ala Gln Ala Gln Thr Gly Trp Val Gln Asn Gln Gly Ile Leu 385 390 395 400 Pro Gly Met Val Trp Gln Asp Arg Asp Val Tyr Leu Gln Gly Pro Ile 405 410 415 Trp Ala Lys Ile Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu 420 425 430 Met Gly Gly Phe Gly Met Lys His Pro Pro Pro Gln Ile Leu Ile Lys 435 440 445 Asn Thr Pro Val Pro Ala Asp Pro Pro Thr Ala Phe Asn Lys Asp Lys 450 455 460 Leu Asn Ser Phe Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu 465 470 475 480 Ile Glu Trp Glu Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu 485 490 495 Ile Gln Tyr Thr Ser Asn Tyr Tyr Lys Ser Asn Asn Val Glu Phe Ala 500 505 510 Val Asn Thr Glu Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg 515 520 525 Tyr Leu Thr Arg Asn Leu 530 <![CDATA[<210> 10]]> <![CDATA[<211> 130]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 左側(第一個)ITR(反向末端重複)]]> <![CDATA[<400> 10]]> cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60 ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120 aggggttcct 130 <![CDATA[<210> 11]]> <![CDATA[<211> 304]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> CMV(巨細胞病毒)增強子]]> <![CDATA[<400> 11]]> cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60 gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120 atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180 aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240 catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300 catg 304 <![CDATA[<210> 12]]> <![CDATA[<211> 204]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> CMV(巨細胞病毒)啓動子]]> <![CDATA[<400> 12]]> gtgatgcggt tttggcagta catcaatggg cgtggatagc ggtttgactc acggggattt 60 ccaagtctcc accccattga cgtcaatggg agtttgtttt ggcaccaaaa tcaacgggac 120 tttccaaaat gtcgtaacaa ctccgcccca ttgacgcaaa tgggcggtag gcgtgtacgg 180 tgggaggtct atataagcag agct 204 <![CDATA[<210> 13]]> <![CDATA[<211> 493]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hBG1基因(血紅蛋白γ1亞基)的內含子]]> <![CDATA[<400> 13]]> cgaatcccgg ccgggaacgg tgcattggaa cgcggattcc ccgtgccaag agtgacgtaa 60 gtaccgccta tagagtctat aggcccacaa aaaatgcttt cttcttttaa tatacttttt 120 tgtttatctt atttctaata ctttccctaa tctctttctt tcagggcaat aatgatacaa 180 tgtatcatgc ctctttgcac cattctaaag aataacagtg ataatttctg ggttaaggca 240 atagcaatat ttctgcatat aaatatttct gcatataaat tgtaactgat gtaagaggtt 300 tcatattgct aatagcagct acaatccagc taccattctg cttttatttt atggttggga 360 taaggctgga ttattctgag tccaagctag gcccttttgc taatcatgtt catacctctt 420 atcttcctcc cacagctcct gggcaacgtg ctggtctgtg tgctggccca tcactttggc 480 aaagaattgg gat 493 <![CDATA[<210> 14]]> <![CDATA[<211> 479]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hGH1多聚腺苷酸化信號 ]]> (人生長激素的多聚腺苷酸化信號(多聚(A))) <![CDATA[<400> 14]]> acgggtggca tccctgtgac ccctccccag tgcctctcct ggccctggaa gttgccactc 60 cagtgcccac cagccttgtc ctaataaaat taagttgcat cattttgtct gactaggtgt 120 ccttctataa tattatgggg tggagggggg tggtatggag caaggggcaa gttgggaaga 180 caacctgtag ggcctgcggg gtctattggg aaccaagctg gagtgcagtg gcacaatctt 240 ggctcactgc aatctccgcc tcctgggttc aagcgattct cctgcctcag cctcccgagt 300 tgttgggatt ccaggcatgc atgaccaggc tcagctaatt tttgtttttt tggtagagac 360 ggggtttcac catattggcc aggctggtct ccaactccta atctcaggtg atctacccac 420 cttggcctcc caaattgctg ggattacagg cgtgaaccac tgctcccttc cctgtcctt 479 <![CDATA[<210> 15]]> <![CDATA[<211> 202]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> SV40啓動子(猴病毒40啓動子)]]> <![CDATA[<400> 15]]> tgcatctcaa ttagtcagca accatagtcc cgcccctaac tccgcccatc ccgcccctaa 60 ctccgcccag ttccgcccat tctccgcccc atcgctgact aatttttttt atttatgcag 120 aggccgaggc cgcctcggcc tctgagctat tccagaagta gtgaggaggc ttttttggag 180 gcctaggctt ttgcaaaaag ct 202 <![CDATA[<210> 16]]> <![CDATA[<211> 154]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號)]]> <![CDATA[<400> 16]]> aataaaatat ctttattttc attacatctg tgtgttggtt ttttgtgtga atcgatagta 60 ctaacatacg ctctccatca aaacaaaacg aaacaaaaca aactagcaaa ataggctgtc 120 cccagtgcaa gtgcaggtgc cagaacattt ctct 154 <![CDATA[<210> 17]]> <![CDATA[<211> 141]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 天然序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 右側(第二個)ITR]]> <![CDATA[<400> 17]]> aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60 ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120 gagcgcgcag ctgcctgcag g 141
Claims (23)
- 一種用於產生基因療法病毒產物的分離的核酸,所述分離的核酸包含編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白(運動神經元存活蛋白)的核酸和編碼微RNA miR-23a的核酸。
- 根據請求項1所述的分離的核酸,其中所述編碼具有SEQ ID NO: 1的胺基酸序列的SMN1蛋白的核酸包含SEQ ID NO: 2的核苷酸序列。
- 根據請求項1所述的分離的核酸,其中所述微RNA miR-23a具有SEQ ID NO: 3的核苷酸序列。
- 根據請求項1所述的分離的核酸,其中所述編碼微RNA miR-23a的核酸包含SEQ ID NO: 4的核苷酸序列。
- 一種包含根據請求項1-4中任一項所述的核酸的表達盒。
- 根據請求項5所述的表達盒,所述表達盒在5'端至3'端方向包含以下元件: 左側(第一個) ITR (反向末端重複); CMV (巨細胞病毒)增強子; CMV (巨細胞病毒)啓動子; hBG1基因(血紅蛋白γ1亞基基因)的內含子; 編碼SMN1蛋白的核酸; hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號); SV40啓動子(猴病毒40啓動子); 編碼微RNA miR-23a的核酸; SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和 右側(第二個) ITR。
- 根據請求項6所述的表達盒,所述表達盒包含具有SEQ ID NO: 6的核酸。
- 一種包含根據請求項1-4中任一項所述的核酸或根據請求項5-7中任一項所述的表達盒的表達載體。
- 一種用於SMN1基因在目標細胞中的表達的基於AAV9 (腺相關病毒血清型9)的重組病毒,所述基於AAV9的重組病毒包含衣殼和根據請求項5-7中任一項所述的表達盒。
- 根據請求項9所述的基於AAV9的重組病毒,其中所述衣殼包含AAV9蛋白VP1。
- 根據請求項10所述的基於AAV9的重組病毒,其中所述衣殼包含具有SEQ ID NO: 7的胺基酸序列的所述AAV9蛋白VP1。
- 根據請求項10所述的基於AAV9的重組病毒,其中所述衣殼包括具有帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的所述AAV9蛋白VP1。
- 根據請求項9-12中任一項所述的基於AAV9的重組病毒,其中所述衣殼包含具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的所述AAV9蛋白VP1,和所述表達盒在5'端至3'端方向包含以下元件: 左側(第一個) ITR (反向末端重複); CMV (巨細胞病毒)增強子; CMV (巨細胞病毒)啓動子; hBG1基因(血紅蛋白γ1亞基基因)的內含子; 編碼SMN1蛋白的核酸; hGH1多聚腺苷酸化信號(人生長激素基因多聚腺苷酸化信號); SV40啓動子(猴病毒40啓動子); 編碼微RNA miR-23a的核酸; SV40多聚腺苷酸化信號(猴病毒40多聚腺苷酸化信號),和 右側(第二個) ITR。
- 根據請求項10所述的基於AAV9的重組病毒,其中所述衣殼包含具有SEQ ID NO: 7的胺基酸序列或帶有一個或多個點突變的SEQ ID NO: 7的胺基酸序列的所述AAV9蛋白VP1,和所述表達盒包含具有SEQ ID NO: 6的核酸。
- 一種用於將SMN1基因遞送至目標細胞的藥物組合物,所述藥物組合物包含與一種或多種藥學上可接受的賦形劑組合的根據請求項9-14中任一項所述的基於AAV9的重組病毒。
- 一種根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物用於將SMN1基因遞送至目標細胞的用途。
- 一種根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物用於患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的存活的用途。
- 一種根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物用於將SMN1蛋白提供給患有脊髓性肌萎縮和/或不具有SMN1基因的完全功能複製的受試者的用途。
- 一種根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物用於在患有脊髓性肌萎縮的受試者中治療脊髓性肌萎縮的用途。
- 一種用於在患有運動神經元病症的受試者中調整運動功能的方法,所述方法包含將治療有效量的根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物施用到所述受試者的細胞中。
- 一種用於將SMN蛋白提供給患有脊髓性肌萎縮的受試者的方法,所述方法包含將治療有效量的根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物施用到有需要的所述受試者的細胞中。
- 一種用於將SMN1基因遞送至患有脊髓性肌萎縮的受試者的目標細胞的方法,所述方法包含將根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物施用到所述受試者的細胞中。
- 一種用於在受試者中治療脊髓性肌萎縮的方法,所述方法包含將治療有效量的根據請求項9-14中任一項所述的基於AAV9的重組病毒或根據請求項15所述的組合物施用給患有脊髓性肌萎縮的受試者。
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