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Nusinersen Modulates Neuroinflammation in Severe SMA, Study Says

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Researchers of the multicenter study looked at the effect of nusinersen among 48 patients with spinal muscular atrophy (SMA) from 2 Italian hospitals, finding more active immune systems among the patients with SMA1, the most severe form of the disorder.

Treatments for spinal muscular atrophy (SMA) that affect the immune system may help improve symptoms of the disorder, suggest findings from a recent study, which indicate that nusinersen counteracts neuroinflammation in infants with the disorder.

Researchers of the multicenter study looked at the effect of nusinersen among 48 patients with SMA from 2 Italian hospitals, finding more active immune systems among the patients with SMA1, the most severe form of the disorder.

“Current SMA therарies increase expression of SMN protein through multiple mechanisms and induce significant clinical improvement in SMA patients treated pre-symptomatically, while delayed treatment often results in a more variable clinical response,” wrote the researchers. “However, the metabolic effects of these drug treatments are poorly defined and may shed light on strengths and limitations governing therapeutic efficacy as well as disease mechanisms.”

Across the 18 patients with SMA1, nusinersen resulted in a significant reduction in CSF levels of some, though not all, of the neuroinflammatory molecules that were increased at baseline. Before treatment, these patients had significant increases across several pro-inflammatory cytokines, including IL-6, IFN-γ, TNF-α, IL-2, IL-8, IL-12, IL-17, MIP-1α, MCP-1, and Eotaxin compared with the 19 patients with SMA2 and 11 patients with SMA3. Levels of neurotrophic factors PDGF-BB and VEGF were also higher among the patients with SMA1 at baseline.

The increases observed at baseline, wrote the researchers, suggest that dysregulation is present across a wide array of cytokines, rather than concentrated amongst a few, in patients with the most severe form of the disease. The patients with SMA2 and SMA3 showed similar levels as the 4 controls included in the study.

“Our study reveals a remarkable increase in the CSF levels of potent pro-inflammatory cytokines that is specific to SMA1 patients relative to individuals affected by milder forms of the disease,” wrote the researchers of their retrospective findings. “These findings highlight an immunological disease feature of severe SMA, which links the magnitude of SMN protein deficiency to neuroinflammation. Consistent with a potential contribution to SMA pathogenesis, increased levels of the same neuroinflammatory cytokines have been documented in the CSF of patients with other neurodegenerative disease.”

CSF samples taken 64 and 302 days following the first injection of nusinersen showed that levels of IL-2, IL-4, IL-7, IL-9, IL-12, IL-17, VEGF, eotaxin and TNF-α significantly decreased following treatment. The finding suggests that IL-6, IL-8, IFN-γ, MCP1, MIP-1α, and PDGF-BB may be refractory to nusinersen treatment in these patients.

Among patients with SMA2, the treatment yielded increases in CSF levels of IL-8, G-CSF, MCP-1, MIP-1α, and MIP-1β compared with levels at baseline. For patients with SMA3, anti- IL-1ra was the only inflammatory molecule impacted by nusinersen treatment, levels of which decreased following treatment.

Reference

Nuzzo T, Russo R, Errico F, et al. Nusinersen mitigates neuroinflammation in severe spinal muscular atrophy patients. Commun Med. Published online February 15, 2023. doi:10.1038/s43856-023-00256-2

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