Assessment of cerebral spinal fluid biomarkers and microRNA-mediated disease mechanisms in spinal muscular atrophy patient samples

Welby E, Rehborg RJ, Harmelink M, and Ebert AD.

Human Molecular Genetics, 2021.

Scientists use bioelectronic assays and other methods to explore potential biomarkers associated with SMA

People receiving intrathecal treatment with nusinersen for spinal muscular atrophy (SMA)—a group of inherited diseases that progressively destroy motor neurons and lead to muscle weakness and atrophy—often show improved motor function, but the effects of the treatment on cellular health are not well understood. In this study, researchers sought to identify biomarkers indicative of neural and glial health by evaluating SMA patients’ cerebrospinal fluid for extracellular RNAs and microRNAs, before and after nusinersen treatment.

Although some improvements in microRNA expression levels related to SMA pathology were observed post treatment, the astrocyte-secreted microRNA-146a—which has demonstrated toxic effects on SMA motor neurons—remained elevated in SMA patient cerebrospinal fluid. To investigate the effects of microRNA-146a in SMA-induced pluripotent stem cell-derived astrocytes, the scientists used mRNA sequencing and Axion’s noninvasive Maestro multielectrode arrays (MEA) platform. The findings demonstrated that microRNA-146a led to a downregulation of extracellular matrix genes associated with synaptic perineuronal nets and changes in spontaneous electrophysiological activity. Overall, the results suggest that extracellular RNAs and microRNAs may be helpful biomarkers for monitoring cellular health during nusinersen treatment and underscore the importance of glial cells in SMA development and therapeutic strategies.