Frameshifting with mRNA Therapeutics

N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting
“Here we [MRC researchers at the University of Cambridge] demonstrate that incorporation of N1-methylpseudouridine [a natural archaeal tRNA plus a synthetic nucleoside] into mRNA results in +1 ribosomal frameshifting in vitro and that cellular immunity in mice and humans to +1 frameshifted products from BNT162b2 vaccine mRNA translation occurs after vaccination. . . . . Overall, these data increase our understanding of how modified ribonucleotides affect the fidelity of mRNA translation, and although there are no adverse outcomes reported from mistranslation of mRNA-based SARS-CoV-2 vaccines in humans, these data highlight potential off-target effects for future mRNA-based therapeutics and demonstrate the requirement for sequence optimization.” MORE
Image Credit: Cheng Chang on LinkIn