Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment

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. T...

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Published in:	European journal of paediatric neurology Vol. 42; pp. 34 - 41
Main Authors:	Scheijmans, F.E.V., Cuppen, I., Zwartkruis, M.M., Signoria, I., van Ekris, C., Asselman, F., Wadman, R.I., Knol, E.F., van der Pol, W.L., Groen, E.J.N.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-01-2023
Subjects:	Biomarker Child Child, Preschool Gene therapy Humans Inflammation Injections, Spinal - methods MCP1/CCL2 Multiplex immunoassay Muscular Atrophy, Spinal - drug therapy Oligonucleotides - therapeutic use Spinal Muscular Atrophies of Childhood - drug therapy Spinal muscular atrophy Biomarker Multiplex immunoassay Inflammation Gene therapy MCP1/CCL2 Spinal muscular atrophy
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Summary:	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. •Nusinersen treatment did not lead to consistent increase of inflammatory markers (IL-10, IL-1b, IL-6, MCP1, C5a, Ang1).•Increased IL10 concentrations were associated with rare cases of increased CSF leukocyte counts.•MCP1 (CCL2) showed a modest increase with treatment over time in older children with SMA type 2 and 3.•IL10 is a putative candidate to monitor immune response during treatment.•MCP1 is interesting biomarker candidate to follow treatment efficacy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1090-3798 1532-2130
DOI:	10.1016/j.ejpn.2022.12.003