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Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-01-17 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00722
Bregje Leyman 1 , Hanne Huysmans 1 , Séan Mc Cafferty 1, 2 , Francis Combes 1, 2 , Eric Cox 3 , Bert Devriendt 3 , Niek N. Sanders 1, 2
Affiliation  

Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA. The self-replicating mRNA tended to induce the highest protein expression, followed by pDNA, modified mRNA, and unmodified mRNA. Interestingly, the self-replicating mRNA was able to maintain its high expression levels during at least 12 days. In contrast, the expression of pDNA and the nonreplicating mRNAs dropped after respectively one and two days. Six days after intradermal electroporation a dose-dependent expression was observed for all vectors. Again, also at lower doses, the self-replicating mRNA tended to show the highest expression. All the mRNA vectors, including the modified mRNA, induced elevated levels of mRNA encoding cytokines and chemokines in the porcine skin after intradermal electroporation, while no such response was noticed after intradermal electroporation of the pDNA vector.

中文翻译:

猪皮内电穿孔后复制mRNA,非复制mRNA和pDNA的表达动力学和免疫刺激活性的比较

合成mRNA作为基于pDNA的基因治疗的替代方法正变得越来越流行。当前,已经开发了多种合成的mRNA平台。在这项研究中,我们研究了猪皮内注射pDNA,自我复制的mRNA,修饰的和未修饰的mRNA后的表达动力学以及编码细胞因子和趋化因子水平的mRNA的变化。自复制的mRNA倾向于诱导最高的蛋白表达,其次是pDNA,修饰的mRNA和未修饰的mRNA。有趣的是,自我复制的mRNA能够在至少12天内维持其高表达水平。相反,分别在第一天和第二天后,pDNA和非复制性mRNA的表达下降。皮内电穿孔六天后,所有载体均观察到剂量依赖性表达。再次,同样在较低剂量下,自我复制的mRNA倾向于表现出最高的表达。所有的mRNA载体,包括修饰的mRNA,在皮内电穿孔后诱导猪皮肤中编码细胞因子和趋化因子的mRNA水平升高,而在pDNA载体的皮内电穿孔后未观察到这种反应。
更新日期:2018-01-17
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