SMN circular RNAs as potential new targets and biomarkers for the therapeutic response in Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a life-threatening disease in infancy. SMA is caused by loss of function mutations in the SMN1 gene, leading to degeneration of motor neurons in the spinal cord and muscle atrophy. Three treatments for SMA have now been approved. While these therapies significantly ameliorate the course of the disease, they do not represent a cure yet. Indeed, not all patients equally respond to them while in some patients the symptoms are only attenuated or stabilized. Furthermore, their long-term efficacy and safety are unknown. Our project proposes to elucidate new molecular mechanisms underlying SMN expression and to evaluate new biomarkers as predictors of SMA course and response to therapies. In particular, we will characterize the function of a new class of circular transcripts produced by the SMN genes (SMN circRNAs) in SMA cells. We will also evaluate the potential of SMN circRNAs to function as biomarkers of the SMA course and of the response of patients to therapies. To this end, we will measure their concentration in body fluids of symptomatic patients undergoing treatments as well as in pre-symptomatic patients that will be identified in the pilot neonatal screen active in our hospital. Furthermore, since experiments we carried out in SMA cells identified a treatment that enhances the efficacy of a SMA therapy (Nusinersen), we will test the efficacy of this combined treatment in a pre-clinical SMA mouse model. Collectively, the results obtainable with our project may pave the ground for improvement of therapeutic strategies for SMA.