High Expression of SMN circ4-2b-3 in SMA I Children Treated with Nusinersen is Associated with Improved Motor Outcomes.

Spinal muscular atrophy (SMA) is a neuromuscular disorder resulting in the loss of α-motor neurons. Nusinersen is an antisense oligonucleotide administered intrathecally to SMA patients that corrects the splicing defect of SMN2. Not all SMA patients respond equally to the therapy and work is in progress to identify biomarkers that may help stratify to SMA patients. In this study, we evaluated the expression of SMN circular RNAs (circRNAs) as potential biomarkers of the disease. This monocentric study was conducted at Fondazione Policlinico A. Gemelli in collaboration with Catholic University of Sacred Heart between December 2019 and March 2023. The inclusion criteria comprised having a diagnosis of SMA I and being treated with Nusinersen. The quantitative analysis of SMN circ4-2b-3 was conducted analyzing patients' serum-derived exosomes. The study included 19 type I SMA patients. Among several SMN circRNAs expressed in SMA cells, only SMN circ4-2b-3 was also detected in exosomes isolated from both type I SMA cell lines and patient-derived serum. High copy number of SMN circ4-2b-3 occurred in a small subgroup of type I SMA patients who were defined as super-responders, based on their response to the Nusinersen therapy. The levels of this circRNA remained high over time. Our results suggest that SMN circ4-2b-3 is a potential biomarker to predict the therapeutic response of type I SMA patients to Nusinersen. However, since other super-responders had a lower number of SMN circ4-2b-3 copies, these findings should be confirmed in larger cohorts.