Staple oligomers induce a stable RNA G-quadruplex structure for protein translation inhibition in therapeutics

Le résumé fourni par la source

Gene-silencing mechanisms using RNA interference (RNAi) and antisense oligomers have drawn attention to nucleic acid medicines. However, several challenges remain such as low in vivo stability and inadequate target selectivity. Here we report a versatile and highly selective method for suppressing gene expression with a short oligonucleotide. The oligonucleotide, a Staple oligomer, hybridizes specifically to a target mRNA and artificially induces a higher-order structure, an RNA G-quadruplex (rG4), on the mRNA. This results in the rG4 effectively suppressing the target protein's translation. The method is validated by successfully regulating translation of TPM3, MYD88 and TRPC6 mRNAs in a cell-free system and in living mammalian cells. Unlike RNAi and antisense technologies, the present technology does not require cooperation with bioprocesses, permitting the quick and easy development of fully non-natural nucleic acid-based Staple oligomers without compromising their effectiveness. In vivo application of the technology to TRPC6 mRNA helps prevent cardiac hypertrophy in thoracic aortic constriction-treated mice without detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.

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