RESUMEN
Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses.