DNA ministrings: highly safe and effective gene delivery vectors.
DNA ministrings: highly safe and effective gene delivery vectors.
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DOI：
10.1038/mtna.2014.16
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发表时间：
2014-05-27
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--
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--
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传统的质粒DNA载体在基因治疗中发挥着重要作用，但它们也有相当大的局限性：它们可能引起不良的免疫反应，因为它们含有用于在原核生物中维持和扩增的细菌序列，它们的生物利用度由于它们的分子大小而受到损害，并且它们可能具有基因毒性。我们构建了一个体内平台来生产迷你串 DNA（迷你线性共价闭合 DNA 载体），该载体不含不需要的细菌序列，仅编码感兴趣的基因和必要的真核表达元件。与亲本质粒前体和同基因环状共价闭合 DNA 对应物相比，用编码增强型绿色荧光蛋白的小链 DNA 转染快速和缓慢分裂的人类细胞，可显着改善转染、生物利用度和细胞质动力学。整合到人类细胞基因组中的小串 DNA 导致染色体破坏和可能致癌载体整合体的细胞凋亡；因此，它们可能比质粒和环状 DNA 载体更安全。
Conventional plasmid DNA vectors play a significant role in gene therapy, but they also have considerable limitations: they can elicit adverse immune responses because of bacterial sequences they contain for maintenance and amplification in prokaryotes, their bioavailability is compromised because of their large molecular size, and they may be genotoxic. We constructed an in vivo platform to produce ministring DNA—mini linear covalently closed DNA vectors—that are devoid of unwanted bacterial sequences and encode only the gene(s) of interest and necessary eukaryotic expression elements. Transfection of rapidly and slowly dividing human cells with ministring DNA coding for enhanced green fluorescent protein resulted in significantly improved transfection, bioavailability, and cytoplasmic kinetics compared with parental plasmid precursors and isogenic circular covalently closed DNA counterparts. Ministring DNA that integrated into the genome of human cells caused chromosomal disruption and apoptotic death of possibly oncogenic vector integrants; thus, they may be safer than plasmid and circular DNA vectors.
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