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.
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