41 | SRT2104 improves muscle and cognitive outcomes and has the potential to enhance μDys gene therapy in Duchenne muscular dystrophy

Laura Lociuro¹, A. Arcari², O. Gjana¹, G. Scolari¹, S.R. Casati^1|2, S. Zecchini², M. Giovarelli², C. Perrotta², C. De Palma¹ | ¹Department of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano, Segrate (MI), Italy; ²Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Italy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene. The lack of functional dystrophin disrupts the dystrophin-glycoprotein complex, leading to progressive structural degeneration and functional impairment of myofibers. Currently, no cure is available. Although AAV-mediated micro-dystrophin (μDys) gene therapy is among the most promising strategies, its efficacy is still limited by the pathological dystrophic muscle environment, characterized by chronic inflammation and sarcolemma fragility, which compromises μDys engraftment and long-term stability. To enhance therapeutic outcomes, we are investigating a combined approach based on μDys gene therapy and pharmacological activation of Sirtuin1 (SIRT1), a NAD-dependent deacetylase involved in muscle homeostasis and regeneration. In previous work, we demonstrated that SRT2104, a clinically advanced SIRT1-activator, improves functional, metabolic, and histological parameters in mdx mice after 12 weeks of treatment. Importantly, we also observed improvements in specific neurocognitive markers, a relevant finding considering the cognitive deficits often associated with DMD. Given its broad effects on DMD-dysregulated pathways, SRT2104 represents a promising candidate to support μDys therapy by improving muscle condition and potentially allowing a reduction in viral vector dose. To explore this synergistic potential, we selected a dose of AAV9-μDys capable of restoring ≥20% of dystrophin expression, and we are currently testing different administration schedules of SRT2104 and μDys to define the optimal therapeutic window. Specifically, a time-course study is ongoing to determine the optimal timing for gene delivery following SRT2104-mediated stabilization of the muscle environment. This strategy aims not only to boost the efficacy of μDys gene therapy but also to reduce the risks associated with high AAV doses, toward a safer, more sustainable DMD treatment.