Journal Article Epublish
PubMed: 42798856 DOI: 10.1093/braincomms/fcag352
Serum circulating cell-free messenger RNA profile response to risdiplam treatment in adult patients with late-onset spinal muscular atrophy.
Brain Commun 8(5):fcag352
Authors: Markus Leo, Linda-Isabell Schmitt, Kai Christine Liebig, Stefanie Hezel, Svenja Neuhoff, Andreas Roos, Tobias Ruck, Christoph Kleinschnitz, Tim Hagenacker
Affiliations
- Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Essen 45147, Germany.
- Department of Neurology, Ruhr University Bochum, BG University Hospital Bergmannsheil, Bochum 44789, Germany. BG University Hospital Bergmannsheil, Heimer Institute for Muscle Research, Bochum 44789, Germany. Department of Neuropediatrics, Centre for Neuromuscular Disorders in Children, University Children's Hospital Essen, University Medicine Essen, Essen 45147, Germany.
- Department of Neurology, Ruhr University Bochum, BG University Hospital Bergmannsheil, Bochum 44789, Germany.
- BG University Hospital Bergmannsheil, Heimer Institute for Muscle Research, Bochum 44789, Germany.
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.
MeSH
Muscular Atrophy, Cells, Genes, Serum, Atrophy, Rna, Messenger, Biomarkers, Therapeutics, Muscular Atrophy, Spinal, Liquid Biopsy, Spine