改进型复制缺陷性腺病毒（HDAd）转基因载体特异性及稳定性研究
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摘要
背景：自我复制缺陷性腺病毒(HDAd)和慢病毒(LV)是转基因治疗中极具吸引力的病毒载体。在质粒载体中的测试已经确认人工合成的启动子AUSEx3具有肌细胞特异性表达的特点。本实验以两种不同的病毒为模板构建含有启动子AUSEx3的基因载体,检测其组织特异性及转基因表达的稳定性。细胞核支架/基质结合区(Scaffold/matrix-attached regions, S/MAR)基因,在基因表达中具有非常重要的作用,能增加质粒转基因的表达水平,可以预防转基因沉默,通过构建含有S/MAR的HDAd,检测S/MAR在HDAd中是否仍具有防止转基因衰退的作用。
方法：构建两种表达β-半乳糖苷酶的HDAd载体,分别受AUSEx3或者CMV(或CAG)启动子调控；构建两种表达绿色荧光蛋白(GFP)的慢病毒,分别受AUSEx3或者CMV调控,在非肌源性细胞(HeLa, Jurkat,293A, A549)、成肌细胞和肌管细胞中比较转基因的表达情况。构建两种表达GFP的HDAd载体,一个含有S/MAR基因,一个没有,在HeLa细胞中培养,比较GFP表达。
结果：在非肌源性细胞中,AUSEx3调控转基因表达是CAG或CMV表达值的1%或更少,AUSEx3在A549细胞中表达范围是CAG或CMV表达值的5-12%。AUSEx3在成肌细胞表达为0.5%和29%,与CAG或CMV相比,具有显著差异性(p<0.05)。但在肌管细胞中,AUSEx3与CMV基因表达具有同样强度,说明AUSEx3在肌细胞中是个很强的启动子。在体内实验中,AUSEx3转基因在肺、肝和脾中的表达值是CAG表达值的2%或者更少,但在肌肉中是10%。胫骨前肌(tibialis anterior)注射AUSEx3-HDAd,28%的肌纤维β-半乳糖苷酶表达阳性。在慢病毒稳定性实验中,AUSEx3调控的GFP表达也比CMV持久。另一个实验中,持续的检测发现,具有S/MAR转基因的HeLa细胞GFP表达下降比例要比没有S/MAR转基因的HeLa细胞小且慢。
结论：经过两种病毒载体(慢病毒载体和辅助腺病毒载体)测试证明,AUSEx3是很强的肌细胞特异性启动子。并且其基因片段小(504bp),非常适合作为肌源性转基因治疗的启动子。S/MAR在HDAd中具有防止基因沉默的作用。
Background Gutless adenovirus (HDAd) and lentiviral vectors (LV) are attractive vectors for gene therapy of muscle diseases. Because the organization of their DNA after transduction (episomal vs. integrated) differs, we have investigated if the strength, specificity and the stability of△USEx3, a novel muscle-specific promoter previously tested with plasmid, were maintained in the context of these vectors. Scaffold/matrix-attached regions (S/MAR) implicated in a variety of important functions related to gene expression Furthermore, the presence of this S/MAR in the plasmid backbone has been shown to increase transgene expression level and to prevent silencing. We will test the effects of incorporating into the HDAd a S/MAR, to test if it still prevent transgene silencing.
Methods Two HDAds expressing β-galactosidase regulated either by△USEx3or the CMV enhancer/β-actin promoter (CAG), and two LVs expressing the green fluorescent protein regulated by△USEx3or CMV were constructed. Gene expression was compared in non-muscle cells (HeLa, Jurkat,293A, A549), C2C12myoblasts and myotubes. HDAds were also tested in mice after injection in the tibialis anterior muscle and intravenous injection. The Lvs was tested in different time point. Two HDAds,expressing GFP, with or without S/MAR, were transfected in HeLa cells and compared the GFP expression.
Results In non-muscle cells, gene expression from△USEx3was1%or less the value of CAG and CMV, except in A549where it ranged between5-12%. In myoblasts, it was0.5%and29%the value of CAG and CMV respectively. In myotubes, AUSEx3was as strong as CMV, but10times weaker than CAG, a powerful promoter in muscle. In vivo, the activity of AUSEx3in the lung, liver and spleen was2%or less the CAG value, whereas in skeletal muscle it was10%. Despite the lower activity of AUSEx3,28%of muscle fibres of injected tibialis anterior were positive for β-galactosidase. The curve of the△USEx3is more stable in the context of LVs. With the time passed the HeLa cells with S/MAR decreased expression of the GFP protein was Slower and less pronounced.
Conclusions△USEx3is a robust muscle-specific and stable promoter in the context of LV and HDAd.This, in conjunction with its small size (504bp), make it very attractive for gene therapy of muscle diseases. S/MAR in the HDAd still could prevent transgene silencing
方法：构建两种表达β-半乳糖苷酶的HDAd载体,分别受AUSEx3或者CMV(或CAG)启动子调控；构建两种表达绿色荧光蛋白(GFP)的慢病毒,分别受AUSEx3或者CMV调控,在非肌源性细胞(HeLa, Jurkat,293A, A549)、成肌细胞和肌管细胞中比较转基因的表达情况。构建两种表达GFP的HDAd载体,一个含有S/MAR基因,一个没有,在HeLa细胞中培养,比较GFP表达。
结果：在非肌源性细胞中,AUSEx3调控转基因表达是CAG或CMV表达值的1%或更少,AUSEx3在A549细胞中表达范围是CAG或CMV表达值的5-12%。AUSEx3在成肌细胞表达为0.5%和29%,与CAG或CMV相比,具有显著差异性(p<0.05)。但在肌管细胞中,AUSEx3与CMV基因表达具有同样强度,说明AUSEx3在肌细胞中是个很强的启动子。在体内实验中,AUSEx3转基因在肺、肝和脾中的表达值是CAG表达值的2%或者更少,但在肌肉中是10%。胫骨前肌(tibialis anterior)注射AUSEx3-HDAd,28%的肌纤维β-半乳糖苷酶表达阳性。在慢病毒稳定性实验中,AUSEx3调控的GFP表达也比CMV持久。另一个实验中,持续的检测发现,具有S/MAR转基因的HeLa细胞GFP表达下降比例要比没有S/MAR转基因的HeLa细胞小且慢。
结论：经过两种病毒载体(慢病毒载体和辅助腺病毒载体)测试证明,AUSEx3是很强的肌细胞特异性启动子。并且其基因片段小(504bp),非常适合作为肌源性转基因治疗的启动子。S/MAR在HDAd中具有防止基因沉默的作用。
Background Gutless adenovirus (HDAd) and lentiviral vectors (LV) are attractive vectors for gene therapy of muscle diseases. Because the organization of their DNA after transduction (episomal vs. integrated) differs, we have investigated if the strength, specificity and the stability of△USEx3, a novel muscle-specific promoter previously tested with plasmid, were maintained in the context of these vectors. Scaffold/matrix-attached regions (S/MAR) implicated in a variety of important functions related to gene expression Furthermore, the presence of this S/MAR in the plasmid backbone has been shown to increase transgene expression level and to prevent silencing. We will test the effects of incorporating into the HDAd a S/MAR, to test if it still prevent transgene silencing.
Methods Two HDAds expressing β-galactosidase regulated either by△USEx3or the CMV enhancer/β-actin promoter (CAG), and two LVs expressing the green fluorescent protein regulated by△USEx3or CMV were constructed. Gene expression was compared in non-muscle cells (HeLa, Jurkat,293A, A549), C2C12myoblasts and myotubes. HDAds were also tested in mice after injection in the tibialis anterior muscle and intravenous injection. The Lvs was tested in different time point. Two HDAds,expressing GFP, with or without S/MAR, were transfected in HeLa cells and compared the GFP expression.
Results In non-muscle cells, gene expression from△USEx3was1%or less the value of CAG and CMV, except in A549where it ranged between5-12%. In myoblasts, it was0.5%and29%the value of CAG and CMV respectively. In myotubes, AUSEx3was as strong as CMV, but10times weaker than CAG, a powerful promoter in muscle. In vivo, the activity of AUSEx3in the lung, liver and spleen was2%or less the CAG value, whereas in skeletal muscle it was10%. Despite the lower activity of AUSEx3,28%of muscle fibres of injected tibialis anterior were positive for β-galactosidase. The curve of the△USEx3is more stable in the context of LVs. With the time passed the HeLa cells with S/MAR decreased expression of the GFP protein was Slower and less pronounced.
Conclusions△USEx3is a robust muscle-specific and stable promoter in the context of LV and HDAd.This, in conjunction with its small size (504bp), make it very attractive for gene therapy of muscle diseases. S/MAR in the HDAd still could prevent transgene silencing
引文
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