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

Abstract

Objective: The antisense oligonucleotide nusinersen (spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase survival motor neuron (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: This is a multi-center longitudinal cohort study including a total of 34 type II or III SMA patients. We applied unbiased next-generation sequencing to identify cell-free microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers to predict response to nusinersen. Motor function, assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE), was considered the primary clinical outcome. HFMSE was conducted at baseline and 6 months post initiation of nusinersen therapy. Patients with an improvement ≥ 3 points or no change or decline < 0 points in the HFMSE total score were considered to be responders or non-responders, respectively. Results: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133), alone or in combination, were associated with 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.

Molecular markers of disease severity and response to nusinersen therapy in 5q spinal muscular atrophy (literature review)

“…Уровень экспрессии miR-133b и -206 снизился в процессе лечения, однако не оказывал влияния на исходы [35]. Другая команда ученых проводила нетаргетированное исследование уровня миРНК в ЦСЖ [36]. В данном исследовании у 34 пациентов со СМА II и III типов не удалось обнаружить значимого изменения уровня миРНК в процессе лечения.…”