Patel, Parth Mrugeshkumar; (2025) Exploring the Endothelial and Neuroinflammatory Facets of Spinal Muscular Atrophy and the Role of MicroRNAs as Biomarkers and Therapeutic Targets. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder caused by homozygous deletions or mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive degeneration of motor neurons (MNs). Although traditionally considered a pure MN-specific disease, increasing evidence highlights the contribution of non-neuronal cells and organs to SMA pathogenesis. MicroRNAs (miRNAs) have recently emerged as powerful regulators of gene expression and as promising biomarkers of treatment response in patient biofluids. A major focus of this study was to investigate the involvement of miRNA in SMA disease pathogenesis and how miRNA modulation through antagomirs could offer therapeutic benefits in SMA. This study investigated two microRNA-targeting strategies using distinct human cell models. An antagomir targeting microglia enriched miRNA-125b-5p was employed to suppress NF-κB mediated pro-inflammatory responses. In THP-1-derived human macrophages, miRNA-125b-5p inhibition correlated with reduced TNF-α and IL-1β transcript levels. Separately, the role of miRNA-613 in regulating SMN2 exon 7 inclusion was examined in patient-derived fibroblasts. Treatment with a miRNA-613 antagomir significantly decreased SMN2 exon-7 skipping, although technical challenges in miRNA quantification limited evaluation of its therapeutic potential. In addition, this research examined endothelial dysfunction associated with SMN deficiency. RNA sequencing of SMN-deficient human endothelial cells was performed to investigate alternative splicing events and explore how reduced SMN levels may affect transcript diversity and key cellular functions such as migration. Exon 25 of the human RALGAPB gene showed consistent skipping in SMN-deficient cells generated using a synthetic antisense oligonucleotide (ASO) targeting the SMN1/2 genes. Although this splicing change seems to be specific to human cell lines, more investigation is needed to determine whether it might be caused by an off-target effect of the ASO. Collectively, this study provides insight into SMA as a multi-system disorder and highlights the therapeutic potential of miRNA modulation.

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