Potent and durable gene modulation in heart and muscle with chemically defined lipophilic siRNAs

Abstract Small interfering RNAs (siRNAs) hold promise for treating cardiac and muscular diseases, but robust and scalable delivery remains a hurdle. While biologic–siRNA conjugates (e.g. antibodies) are in clinical development, their manufacturing is complex. Lipophilic siRNAs are readily chemically synthesized at scale and support effective heart and muscle delivery. Here, we refine siRNA chemical design for enhanced potency and durability to support clinically relevant silencing. Targeting myostatin (MSTN), a key gene in muscle-wasting, a single subcutaneous dose in mice achieved potent silencing (80% inhibition up to 6 weeks, 30% up to 14 weeks). Biweekly dosing led to over 95% MSTN reduction for half-a-year with no observed toxicity. This resulted in muscle growth, increased lean mass, and improved grip strength. Phenotypical benefits extended beyond direct target silencing, suggesting prolonged effects. The siRNA scaffold was effective across multiple muscle groups, with its modularity confirmed by three additional targets. Optimized dosing extended durability to 20 weeks without compromising phenotypic outcomes. As a proof of concept, MSTN inhibition with siRNAs successfully combated muscle wasting in an inflammatory myopathy model (cardiotoxin). These findings pave the way for long-lasting gene modulation in heart and muscle, offering new therapeutic strategies for muscular diseases.