P.372CSF miRNAs as biomarkers to indicate the clinical response to Spinraza treatment for patients with spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, due to Survival Motor Neuron gene 1 (SMN1) gene mutatinos. Spinraza (Nusinersen, an antisense-oligonucleotide (AON) drug, is the only approved treatment for SMA. Although the majority of patients show a significant clinical improvement in response to Spinraza, some show minimal or no improvement. We here aim to determine if micro-RNAs (miRNAs) in the cerebrospinal fluid (CSF) can be used as biomarkers to predict the clinical outcomes of type I SMA patients in response to Spinraza treatment. 13 miRNAs were identified in a discovery profiling performed in CSF samples of type I SMA patients at pre- (n=10) and 2 months (n=10) post-Spinraza treatment. Further validation was performed in CSF samples from clinical responders (n=8) and non-responding (n=5) type I SMA patients, based on the improvement in CHOP-INTEND motor scores at 10 months post- treatment. 5 miRNAs were significantly changed during the course of treatment between responder and non-responder groups. A miRNA-target gene protein interaction network was created. The shortest paths between candidate miRNAs and SMN1 and SMN2 genes were identified, the central targets identified using network centrality algorithms. 3 miRNAs were isolated with 10 central target proteins linking them to SMN with less than 2 intermediary nodes. Interestingly, some of the target proteins have been previously linked to SMA pathogenesis. Our data suggest that CSF miRNAs could play a role as biomarkers to monitor SMA patients' responses to Spinraza treatment. Encouragingly, the link between candidate miRNAs and the SMA-related target proteins suggests a functional relevance to the disease. This may allow the identification of novel pathways for therapeutic intervention.