Intravenous and oral administration of the synthetic RNA drug, TY1, reverses heart failure with preserved ejection fraction in mice.

Summary

In a two-hit obese-hypertensive mouse model, TY1 reversed HFpEF phenotypes without weight loss, suppressing myocardial MAPK stress signaling and downstream inflammatory, fibrotic, and hypertrophic pathways. Notably, an oral micellar formulation recapitulated the intravenous effects, with no evident toxicity.

Key Findings

• Intravenous TY1 reversed cardiac and systemic HFpEF manifestations in obese-hypertensive mice without inducing weight loss.
• TY1 suppressed myocardial stress-induced MAP kinase signaling and downstream inflammatory, fibrotic, and hypertrophic gene programs.
• An oral micellar formulation of TY1 reproduced the intravenous benefits, with no toxicity; effects were not seen with scrambled control RNA.

Clinical Implications

If translatable, TY1 or related ncRNAs could offer a disease-modifying, potentially oral therapy for HFpEF by targeting cell stress and inflammatory signaling. This could shift management from symptomatic relief to upstream pathobiology.

Limitations

• Preclinical murine study without large-animal or human validation.
• Mechanistic dissection beyond MAPK suppression (e.g., direct cGAS/STING engagement in HFpEF) remains to be fully elucidated.

Future Directions

Evaluate pharmacokinetics, durability, and safety in large-animal models; elucidate precise upstream targets; and design early-phase clinical trials for HFpEF.