VP.52 Identification of a novel cytokine profile in serum and CSF of pediatric and adult SMA patients and its modulation upon nusinersen treatment

Abstract

Multisystem involvement in SMA has gained prominence since different therapeutic options are emerging making the way for new SMA phenotypes, and consequent challenges in clinical care. Defective immune organs have been found in preclinical models of SMA, suggesting an involvement of the immune system in the disease. However, the immune state in SMA patients have not been investigated so far. Here, we aimed to longitudinally assess for the first time the expression levels of immunity factors, pre- and post- nusinersen therapy, in serum and CSF of SMA type 1 to type 3 patients. A Bio-Plex ProTM Human Cytokine 13-plex Immunoassay was used to measure cytokines in serum and cerebrospinal fluid (CSF) of 21 pediatric and 12 adult SMA patients before and after 6 months of therapy with nusinersen. We detected a significant increase in IL-1β, IL-4, IL-6, IL-10, IFN-γ, IL-17A, IL-22, IL-23, IL-31, IL-33, in serum of pediatric and adult SMA patients at baseline, when compared to the pediatric reference ranges, and to the adult healthy controls. Only pediatric patients showed also a significant increase in TNF-α and IL-17F levels at baseline. IL-4, IFN-γ, Il-22, IL-23, IL-33 decreased in serum of pediatric SMA patients after 6 months of therapy when compared to baseline values. A significant decrease in IL-4, IL-6, INF-γ, and IL-17A was detected in serum of adult SMA patients after treatment. CSF of both pediatric and adult SMA patients displayed detectable levels of all 13 cytokines with no significant differences after 6 months of treatment with nusinersen. Notably, a higher baseline expression of IL-23 in serum correlated with a worse motor function outcome after treatment in pediatric patients. Also, after six months of treatment, patients presenting a higher IL-10 concentration on serum showed a better HFMSE score. The results of our analysis indicated that there is an inflammatory, cell-mediated, signature in serum of pediatric and adult SMA patients, that changes upon SMN2 modulating treatment, and the presence of inflammatory mediators in CSF. Our findings contribute to the comprehension of SMA pathogenesis.