Loomis Kristin H, Kirschman Jonathan L, Bhosle Sushma, Bellamkonda Ravi V, Santangelo Philip J
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, USA.
J Mater Chem B. 2016 Mar 7;4(9):1619-1632. doi: 10.1039/c5tb01753j. Epub 2015 Oct 13.
Synthetic mRNA has recently shown great potential as a tool for genetic introduction of proteins. Its utility as a gene carrier has been demonstrated in several studies for both the introduction of therapeutic proteins and subunit vaccines. At one point, synthetic mRNA was believed to be too immunogenic and labile for pharmaceutical purposes. However, the development of several strategies have enabled mRNA technology to overcome these challenges, including incorporation of modified nucleotides, codon optimization of the coding region, incorporation of untranslated regions into the mRNA, and the use of delivery vehicles. While these approaches have been shown to enhance performance of some mRNA constructs, gene-to-gene variation and low efficiency of mRNA protein production are still significant hurdles. Further mechanistic understanding of how these strategies affect protein production and innate immune activation is needed for the widespread adoption for both therapeutic and vaccine applications. This review highlights key studies involved in the development of strategies employed to increase protein expression and control the immunogenicity of synthetic mRNA. Areas in the literature where improved understanding is needed will also be discussed.
合成mRNA最近作为一种导入蛋白质的基因工具显示出巨大潜力。在多项关于导入治疗性蛋白质和亚单位疫苗的研究中，已证明其作为基因载体的效用。曾有一度，合成mRNA被认为对于制药用途而言免疫原性过高且不稳定。然而，多种策略的发展使mRNA技术能够克服这些挑战，包括掺入修饰核苷酸、对编码区进行密码子优化、将非翻译区掺入mRNA以及使用递送载体。虽然这些方法已显示出可提高某些mRNA构建体的性能，但基因间差异和mRNA蛋白质生产效率低下仍是重大障碍。对于治疗和疫苗应用的广泛采用而言，需要对这些策略如何影响蛋白质生产和先天免疫激活有更深入的机制理解。本综述重点介绍了在开发用于提高蛋白质表达和控制合成mRNA免疫原性的策略过程中涉及的关键研究。还将讨论文献中需要进一步深入理解的领域。
