Enhancing micro-dystrophin gene therapy: the role of SRT2104, a new Sirtuin1-activating compound, for the treatment of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy(DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene. The lack of dystrophin protein disrupts the dystrophin-glycoprotein complex eliciting structural degeneration and functional impairments of myofibers. Currently, there’s no cure for DMD. However, progress has been made in gene therapies to restore dystrophin and among the different trialed strategies, the approach based on AAV-delivered micro-dystrophin (MD) is the last to be approved. Nevertheless, it still presents some limits. Indeed, the dystrophic muscle milieu exhibits chronic inflammation and early sarcolemmal fragility that do not support MD engraftment and its preservation over time. Therefore, to enhance gene therapy efficacy, it is crucial to develop conservative therapies that preserve dystrophic muscles. For this purpose, the NADH-dependent deacetylase Sirtuin1 (SIRT1) might be the suitable target. In mdx mice, SIRT1 overexpression tends to counteract the dystrophic muscular and cardiac phenotype. Among the new SIRT1-activating compounds, SRT2104 has never been tested in DMD. We assessed its efficacy on mdx mice demonstrating that, after 12 weeks of administration, treated mice show functional, metabolic and histological improvements compared to the controls. Overall, given its effects on crucial hallmarks of DMD, SRT2104 could be the proper candidate to sustain MD-based gene therapy in a combined treatment. Noteworthy, this dual approach could also allow to reduce the required AAV dose and, consequently, reduce the dangerous adverse effects related to viral vector immunogenicity. In a dose-response study, we selected the minimum sub-optimal doses of AAV-MD able to restore at least 20% of dystrophin expression in mdx mice and two of these doses have been injected into mice previously treated with SRT2104 to assess whether this can promote a recovery superimposable to the optimal dose of MD, thus demonstrating the advantages of a combined therapy.