An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder characterized by motor neuron loss.
• Nusinersen, an antisense oligonucleotide, treats SMA by enhancing SMN protein production through SMN2 gene modulation.
• Early and reliable biomarkers are needed for monitoring treatment response in SMA patients.

Purpose of the Study:

• To identify early genetic markers for clinical monitoring of SMA patients undergoing nusinersen treatment.
• To investigate changes in microRNA (miRNA) and messenger RNA (mRNA) expression and their interactions in SMA.
• To explore potential molecular pathways involved in SMA pathogenesis.

Main Methods:

• A 10-month transcriptomics study involving 10 adult SMA patients treated with nusinersen and age-matched healthy controls (HC).
• High-throughput next-generation sequencing (HT-NGS) coupled with bioinformatics and biostatistics analysis.
• Analysis of SMN2/SMN1 expression ratio, differentially expressed genes (DEGs), and miRNA expression profiles.

Main Results:

• The SMN2/SMN1 expression ratio served as an early indicator of nusinersen efficacy, increasing with clinical improvement and decreasing with stable disease.
• Of 147 differentially expressed genes at baseline, 38 showed restored expression by study end (T10).
• Confirmed dysregulation of miR-146a-5p, miR-324-5p, and miR-423-5p in SMA; miR-146a-5p was identified as a SMN1 target, potentially contributing to motor neuron loss.

Conclusions:

• The SMN2/SMN1 expression ratio is a promising early biomarker for nusinersen efficacy in SMA.
• Transcriptomic analysis revealed gene expression restoration and confirmed specific miRNA dysregulations in SMA patients.
• NOTCH, NF-kappa B, and Toll-like receptor signaling pathways are implicated in SMA pathogenesis.