Key result
TRPC6-targeting Staple oligomers prevent cardiac hypertrophy and preserve cardiac function in pressure-overloaded mice.
Why the study?
Existing nucleic acid medicine technologies like RNA interference and antisense oligomers face challenges including in vivo stability, target selectivity, drug delivery, and induced innate immunity.
Does in vivo mRNA hacking with Staple oligomers targeting TRPC6 prevent myocardial hypertrophy in TAC-treated mice?
Does in vivo mRNA hacking with Staple oligomers targeting TRPC6 prevent myocardial hypertrophy in TAC-treated mice?
RNA hacking using Staple oligomers is a novel, highly selective nucleic acid technology that effectively prevents cardiac hypertrophy in vivo without requiring native enzymatic bioprocesses.
Staple oligomer TRPC6 targeting prevents hypertrophy in TAC mice; hypothesis-generating for enzyme-independent RNA repression in human cardiomyopathy.
Summary paragraph The elucidation of gene-silencing mechanisms by RNA interference (RNAi) and antisense oligomers has drawn increasing attention to nucleic acid medicine. However, several challenges remain to be overcome, such as in vivo stability 1 , target selectivity 2,3 , drug delivery 4,5 , and induced innate immunity 6 . Here, we report a new, versatile, and highly-selective method to hack RNA by controlling RNA structure using short oligonucleotides (RNA hacking: RNAh) in living cells. The oligonucleotide, named Staple oligomer, hybridizes specifically to a target mRNA and artificially induces an RNA higher-order structure, RNA G-quadruplex (RGq) 7 , on the mRNA. As a result, the RGq allows effective suppression of the target protein translation. This technology does not require cooperation with bioprocesses including enzymatic reactions as in RNAi or antisense technologies, permitting the introduction of artificial nucleic acids into Staple oligomers to increase their in vivo stability without compromising their effectiveness. The method was validated by translational regulation of the mRNAs of TPM3, MYD88, and TRPC6, in a cell-free system and in living mammalian cells. In vivo application of the technology to TRPC6 mRNA allowed us to prevent cardiac hypertrophy in transverse aortic constriction (TAC)-treated mice with no detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.
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Katsuda et al. (2023) studied Myocardial hypertrophy. Staple oligomers targeting TRPC6 mRNA vs. Sham treatment or TAC without Staple oligomer treatment was evaluated on Myocardial hypertrophy (myocardial weight) and cardiac function (fractional shortening). In vivo application of Staple oligomers targeting TRPC6 mRNA successfully prevented cardiac hypertrophy and maintained cardiac function in transverse aortic constriction (TAC)-treated mice.
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