Serum circulating cell-free messenger RNA profile response to risdiplam treatment in adult patients with late-onset spinal muscular atrophy.

Abstract

SMN-enhancing therapies have improved outcomes in adult late-onset spinal muscular atrophy (loSMA), but minimally invasive biomarkers that reflect systemic disease and treatment effects are lacking. In this retrospective cohort study, we profiled circulating cell-free messenger RNA (ccfmRNA) in serum samples from 17 adults with loSMA type 2 (n = 14) and type 3 (n = 3) and healthy controls (n = 12) using the NanoString neuroimmunology panel before (T0) and after 8-10 (T1) and 12-14 (T2) months of risdiplam treatment. A separate exploratory subgroup of patients switching from nusinersen to risdiplam (n = 7) was analysed at comparable time points. Differential ccfmRNA expression, gene ontology and network analyses were performed. At baseline, adult loSMA showed a distinct inflammatory and stress-related ccfmRNA signature and reduced expression of selected glial- and vascular-associated transcripts compared to controls. Risdiplam partially normalized immune and proteostasis transcripts, whereas glial and vascular modules remained persistently dysregulated. Exploratory subgroup analyses suggested larger transcriptional deviations in type 2 than in type 3, although these findings are limited by small sample size. In switcher patients, additional transcriptional changes involving epigenetic- and lipid-associated pathways were observed and should be regarded as hypothesis-generating. Serum ccfmRNA profiles distinguish adult loSMA from controls and capture risdiplam-associated molecular responses. These findings support the concept that serum ccfmRNA profiling may provide a useful exploratory framework for studying disease-associated and treatment-associated molecular changes in adult loSMA.