Repeated SMA Treatment With Nusinersen Does Not Result in Consistent Increase in Immune Responses

Results of a new study published in the European Journal of Paediatric Neurology show that continuous treatment for spinal muscular atrophy (SMA) with nusinersen does not result in unwanted immune responses.

The findings, say the researchers, confirm that repeated intrathecal injections of the gene-targeting therapy are safe, adding to the limited data on the long-term effect and safety of the treatment approach in neurological diseases.

“At the same time, the number of genetic therapies for neurological diseases in advanced stages of clinical development and requiring intrathecal delivery is rapidly increasing,” wrote the researchers. “Because SMA is at the forefront of these developments, and we occasionally noticed elevated CSF [cerebrospinal fluid] leukocytes in the cohort of children with SMA receiving nusinersen, we decided to focus on characterising expression profiles of inflammatory markers in response to repeated intrathecal injections.”

Initial screening from 3 patients receiving nusinersen revealed elevated leukocyte counts in the CSF without exhibiting signs of inflammation, leading the group to further analyze a group of 38 patients to better identify potential inflammatory markers associated with treatment.

Among the larger group, the researchers found no further association between the inflammatory markers—IL-1B, IL-6, IL-10, and tumor necrosis factor α—and nusinersen. Across all 7 markers, the group found no consistent association between the levels of these markers and the duration of nusinersen treatment.

There was a high level of variability among levels of ANG1, and there was no apparent association between ANG1 levels and treatment timepoint nor SMA type. Levels of C5A and MCP1—a neuroprotective protein previously associated with SMA—hit particularly high levels in the youngest patients, though they decreased shortly after treatment initiation.

“Interestingly, protein levels in CSF have previously been found to be increased in young infants (up to 6 months) compared to older children and adolescents, independent of underlying pathology,” wrote the researchers.

“Possible explanations for increased protein levels in young infants are birth trauma, an immature blood-brain barrier or different CSF flow rate. This observation is an example of our limited knowledge about reference values for CSF of (very) young children. In addition to basic reference values such as leukocyte counts and protein levels, reference values for specific proteins (including C5A, MCP1 and ANG1) have not been reported for the age groups investigated in our current study.”

The researchers flagged the small number of patients with type 1 SMA included in their cohort, limiting their ability to analyze this finding further. However, in type 2 and 3 patients, MCP1 expression increased with the duration of treatment, particularly in patients with type 3, with significant increases compared with baseline. This finding suggests a possible neuroprotective effect of nusinersen, explained the researchers. Meanwhile, C5A levels remained stable throughout treatment, with no significant changes.

Reference

Scheijmans F, Cuppen I, Zwartkruis M, et al. Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment. Eur J Paediatr Neurol. 2022;42:34-41. doi:10.1016/j.ejpn.2022.12.003