Extracellular vesicles as biomarkers of disease progression and therapeutic response in patients with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating genetic disorder characterized by loss of motor neurons and muscle atrophy. In the most severe form, affected infants experience progressive weakness and, if untreated, typically do not survive beyond 2 years of age. Although several disease-modifying therapies are currently available, treatment response varies and there are no clinically available molecular biomarkers to accurately assess therapeutic efficacy. Extracellular vesicles (EVs) are small, membrane-bound nanoparticles released from all cell types, and contain a diverse cargo reflective of their cell of origin. We have followed a cohort of adults with SMA type 3 over 2 years of treatment with nusinersen. At baseline prior to treatment, individuals with SMA exhibit a trend toward increased concentration of nanoparticles in blood plasma and cerebrospinal fluid relative to healthy controls, and a significant decrease in plasma nanoparticle concentration following treatment. We identified several proteins commonly associated with EVs that were significantly different between individuals with SMA and healthy controls, and 21 EV-associated proteins with significantly altered levels in plasma over the course of nusinersen treatment. These findings suggest that nanoparticles and several EV-associated marker proteins hold promise as potential biomarkers for disease state and treatment response in individuals undergoing nusinersen therapy.