Objective: Recent advances in therapeutics have improved prognosis forseverely affected spinal muscular atrophy (SMA) type 1 and 2 patients, whilethe best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and providepotential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age- and gendermatched controls (n = 34). Methods: We performed the first large-scale wholeblood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes.Results: The primary downregulated KEGG pathway in adult SMA type 3patients was "Regulation of Actin Cytoskeleton,” and downregulated expressionof key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patientderived fibroblasts had lower expression of these genes compared to controlfibroblasts from unaffected first-degree relatives. Overexpression of SMN levelsusing an AAV vector in fibroblasts did not normalize ROCK1, RHOA, andACTB mRNA expression, indicating the involvement of additional genes incytoskeleton dynamic regulation. Interpretation: Our findings from wholeblood and patient-derived fibroblasts suggest SMA type 3 patients havedecreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology

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