CN113846122A - 一种过表达snca的腺相关病毒载体aav-snca、制备方法及其应用 - Google Patents

一种过表达snca的腺相关病毒载体aav-snca、制备方法及其应用 Download PDF

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CN113846122A
CN113846122A CN202110939639.6A CN202110939639A CN113846122A CN 113846122 A CN113846122 A CN 113846122A CN 202110939639 A CN202110939639 A CN 202110939639A CN 113846122 A CN113846122 A CN 113846122A
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马开利
吴正存
黄璋琼
唐东红
高家红
易红昆
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Abstract

本发明公开一种过表达SNCA的腺相关病毒载体AAV‑SNCA、制备方法及其应用，属于生物技术和医药领域，其技术方案包括构建过表达SNCA的腺相关病毒载体AAV‑SNCA和高滴度的AAV‑SNCA病毒滴度包装制备，将过表达SNCA的腺相关病毒载体AAV‑SNCA制备成针剂运用在膀胱癌治疗中，可以有效抑制肿瘤生长。

Description

一种过表达SNCA的腺相关病毒载体AAV-SNCA、制备方法及其 应用
技术领域
本发明属于生物技术和医药领域，特别涉及一种过表达SNCA的腺相关病毒载体AAV-SNCA、制备方法及其应用。
背景技术
近些年，基因疗法在肿瘤治疗领域取得了重大突破，作为递送基因疗法的有力工具，腺相关病毒(AAV)具有免疫原性地、安全性高、扩散性强等特点备受关注。截止到目前，在ClinicalTrial.gov上已有164项干预临床试验中使用重组AAV载体。作为泌尿系统中第一恶性肿瘤-膀胱癌，位列我国男性恶性肿瘤发病率第七，而且呈逐年上升趋势。膀胱癌的传统治疗方法主要有手术和化疗。手术不可能完全切除所有的肿瘤，因此很容易发生术后复发。化疗会同时损伤癌细胞和正常细胞，对患者造成严重的副作用。临床上，治疗膀胱癌的药物是通过尿道灌注而不是进入血液，通过膀胱镜检查观察和取样进行治疗试验有很多的局限性。因此，需要寻找可靠的治疗靶点，采用基因载体传递靶基因制备成针剂进行治疗成为一种高效、安全的治策策略。
编码α突触核蛋白的基因SNCA，是第一个被报道其突变参与自发性PD病理进程的基因，在PD中扮演着重要的角色。SNCA的正常功能尚不清楚，研究发现与突触可塑性、多巴胺能神经递质传递、囊泡循环、脂质代谢，分子伴侣活性，与多种蛋白质之间发生相互作用。另外，越来越多的研究报道SNCA还可能参与抗凋亡和促凋亡过程，氧化应激，钙调节与线粒体内稳态，细胞周期重组等生命过程近些年，已有研究报道SNCA参与宫颈癌、结肠癌、黑色素瘤。脑癌和肺腺癌的发生。
发明内容
为了显著抑制膀胱癌肿瘤的生长的同时减少治疗膀胱癌的副作用，本发明提供一种过表达SNCA的腺相关病毒载体AAV-SNCA、制备方法及其应用。
为了实现上述目的，本发明通过以下技术方案予以实现：
一种过表达SNCA的腺相关病毒载体AAV-SNCA，其碱基序列如SEQ ID NO：1所示。
进一步地，一种过表达SNCA的腺相关病毒载体AAV-SNCA的制备方法，包括以下步骤：
(1)将人源SNCA的基因序列设计PCR扩增引物，引入酶切位点SalⅠ和 Xhol，采用腺相关病毒过表达质粒pAAV-IRES-hrGFP为骨架，构建入人源SNCA 基因序列构建质粒，质粒命名为AAV-SNCA；
(2)将过表达SNCA的AAV-SNCA进行病毒包装和纯化，所述病毒滴度为1×1013vectorgenome(V.G.)/ml。
进一步地，所述过表达SNCA的腺相关病毒载体AAV-SNCA在制备治疗膀胱癌的制剂中的应用。
有益效果：
通过TCGA数据库筛查，发现在膀胱癌中SNCA的表达显著下调，提示其可能参与膀胱癌的发生发展。因此通过AAV载体递送SNCA至小鼠膀胱癌肿瘤模型中，通过治疗实验发现其能显著抑制肿瘤的生长。过表达SNCA的腺相关病毒载体AAV-SNCA制备成针剂应用在抗膀胱癌肿瘤，可以成为一种理想的膀胱癌基因治疗策略。
附图说明
图1为采用Westernblotting检测AAV-SNCA与对照组的病毒基因表达结果图；
图2为本发明的动物实验流程图；
图3为治疗过程肿瘤生长情况统计图；
图4为治疗过程红外成像系统监测肿瘤生长情况图；
图5为处死小鼠后的肿瘤测量图；
图6为处死小鼠后的肿瘤体重图；
图7为采用Westernblotting检测肿瘤组织中SNCA表达情况。
具体实施方式
下面结合实施例和附图对本发明做进一步说明。
实施例1
构建过表达SNCA的腺相关病毒载体AAV-SNCA。
通过NCBI公布的人源SNCA的基因序列设计PCR扩增引物，同时引入酶切位点SalⅠ和Xhol。采用腺相关病毒(AAV)过表达质粒pAAV-IRES-hrGFP 为骨架，构建入人源SNCA基因序列，通过测序方法确认构建正确的质粒命名为AAV-SNCA。将此重组中质粒采用瞬时转染的方法转染293T细胞48h后，提取蛋白。同时转染空质粒(AAV-对照)作为对照采用Westernblotting方法验证 AAV-SNCA的表达，验证结果见附图1。
实施例2
进行高滴度的AAV-SNCA病毒滴度包装。
对已验证表达无误的质粒送往上海和元生物有限公司进行病毒的包装和纯化。病毒滴度为1×1013vectorgenome(V.G.)/ml。
实施例3
小鼠膀胱癌模型构建。
本项目采用细胞株T24进行小鼠膀胱癌细胞的构建。取生长对数期的T24 细胞，经胰酶消化后，以4:1的比例混合基质胶，制备成107个细胞/ml浓度的细胞悬液。采用1ml规格的胰岛素注射针，准确吸取100μl细胞悬液，注射于裸鼠(5-8周龄雄鼠，体重在20g左右)右侧腹股沟。进针尽量深一些，注射完后停针5s左右后再抽出针头。
实施例4
AAV-SNCA注射进行膀胱癌治疗。
裸鼠接种细胞10d，肿瘤生长大概在3mm左右，将成裸鼠随机分成两组，实验组采用微量进样针在肿瘤部位注射5μl体积的AAV-SNCA病毒，对照组注射等体积的空质粒对照病毒(AAV-对照)。每隔三天重复注射治疗一次，连续治疗4次。同时采用游标卡尺量取肿瘤的长度和宽度，通过计算公式V＝L*W2监测肿瘤的生长情况，生长情况见附图3，另外利用小动物活体成像系统监测肿瘤生长情况，见附图4。待最大组肿瘤长至1.5cm时，处死裸鼠并取肿瘤采用分析天平进行称量并分别取材检测，称量结果见附图5，和附图6。同时取治疗后的肿瘤提取蛋白后采用Westernblot方法检测SNCA的表达情况，相比较注射对照病毒组，注射AAV-SNCA组肿瘤中显著表达SNCA蛋白，结果见附图7。
实施例3和4的实验流程图见附图2。
序列表
<110> 中国医学科学院医学生物学研究所
<120> 一种过表达SNCA的腺相关病毒载体AAV-SNCA、制备方法及其应用
<130> 20210812
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 420
<212> DNA
<213> 人工合成
<400> 1
atggatgtat tcatgaaagg actttcaaag gccaaggagg gagttgtggc tgctgctgag 60
aaaaccaaac agggtgtggc agaagcagca ggaaagacaa aagagggtgt tctctatgta 120
ggctccaaaa ccaaggaggg agtggtgcat ggtgtggcaa cagtggctga gaagaccaaa 180
gagcaagtga caaatgttgg aggagcagtg gtgacgggtg tgacagcagt agcccagaag 240
acagtggagg gagcagggag cattgcagca gccactggct ttgtcaaaaa ggaccagttg 300
ggcaagaatg aagaaggagc cccacaggaa ggaattctgg aagatatgcc tgtggatcct 360
gacaatgagg cttatgaaat gccttctgag gaagggtatc aagactacga acctgaagcc 420

Claims (3)

1.一种过表达SNCA的腺相关病毒载体AAV-SNCA，其特征在于：其核苷酸序列如SEQ IDNO：1所示。
2.根据权利要求1所述过表达SNCA的腺相关病毒载体AAV-SNCA的制备方法，其特征在于包括以下步骤：
（1）将人源SNCA的基因序列设计PCR扩增引物，引入酶切位点SalⅠ和Xhol，采用腺相关病毒过表达质粒pAAV-IRES-hrGFP为骨架，构建入人源SNCA基因序列，质粒命名为AAV-SNCA；
（2）将过表达SNCA的AAV-SNCA进行病毒包装和纯化，所述病毒滴度为1×1013vectorgenome(V.G.)/ml。
3.权利要求1所述过表达SNCA的腺相关病毒载体AAV-SNCA在制备治疗膀胱癌的制剂中的应用。
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