Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients

Objective The antisense oligonucleotide nusinersen (spinraza) regulates splicing of the survival motor neuron 2 ( SMN2) messenger RNA to increase SMN protein expression and has improved ventilator free survival and motor function outcomes in infantile onset forms of SMA, treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. Methods 34 SMA patients were included. We applied next-generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE), was conducted at baseline and 6 months post initiation of nusinersen therapy to assess motor function. Patients changing by ≥ 3 or ≤0 points in the HFMSE total score were considered as responders or non-responders, respectively. Results Lower baseline levels of two muscle microRNAs (miR-206 and miR-133), alone or in combination, predicted the pre-determined clinical response to nusinersen after 6 months therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. Conclusions Lower miR-206 and miR-133 in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinsersen in later onset SMA patients and call to test the ability of miRNAs to predict more sustained long-term benefit.