Impact of mRNA chemistry and manufacturing process on innate immune activation

作者：Jennifer Nelson, Elizabeth W. Sorensen, Shrutika Mintri, Amy E. Rabideau, Wei Zheng, Gilles Besin, Nikhil Khatwani, Stephen Su, Edward J. Miracco, William Issa, Stephen Hoge, Matthew G. Stanton, John L. Joyal · 发表于：Science Advances · 年份：2020 · DOI：10.1126/sciadv.aaz6893 · 被引用次数：357 · 研究领域：RNA Interference and Gene Delivery、RNA Research and Splicing、RNA and protein synthesis mechanisms

1-methyl-pseudouridine (1mΨ), synthesized by either a standard process shown to have double-stranded RNA (dsRNA) impurities or a modified process that yields a highly purified mRNA preparation. Our data demonstrate that the lowest stimulation of immune endpoints was with 1mΨ made by the modified process, while mRNA containing canonical uridine was immunostimulatory regardless of process. These findings confirm that uridine modification and the reduction of dsRNA impurities are both necessary and sufficient at controlling the immune-activating profile of therapeutic mRNA.