MIR-181A/B INHIBITION AS A NEW STRATEGY FOR MITOCHONDRIAL DISEASE TREATMENT

Mitochondrial diseases (MDs) are a group of rare inherited disorders caused by defective oxidative phosphorylation (OXPHOS) and defined by a wide range of clinical phenotypes. MDs show extreme genetic heterogeneity, which makes the development of efficient treatments particularly difficult. Indeed, despite recent progress, no effective therapies are currently available. Gene/mutation-independent approaches targeting downstream affected pathways are highly needed, considering their genetic heterogeneity. In this context, microRNAs (miRNAs) emerge as promising therapeutic agents due to their ability to simultaneously regulate different pathways. In particular, miR-181a and miR-181b (collectively referred to as miR-181a/b) are two miRNAs involved in mitochondrial processes, and their downregulation has recently been demonstrated to exert a protective action on different MD models associated with neuronal degeneration. This study further investigates the effects of miR-181a/b inhibition in MD contexts and evaluates the feasibility of translating this approach into clinical applications by testing a therapeutic technology to achieve long-term miR-181a/b downregulation in vivo. We assessed the efficacy of our therapeutic approach in different MD models: the Ndufs4 knockout (KO) mouse, which serves as a Leber’s Hereditary Optic Neuropathy (LHON) and Leigh syndrome (LS) model, two of the most prevalent MDs, and the rotenone-induced mouse model, an additional in vivo model of LHON. Notably, our results demonstrate that the downregulation of miR-181a/b consistently ameliorates various phenotypes across all tested conditions. Furthermore, the therapeutic strategy targeting miR-181a/b in vivo exhibited a highly safe and specific profile, paving the way for clinical application.