Potential Biomarkers Predict Disease Severity and Treatment Response in SMA

Pro-inflammatory cytokine levels may correlate with disease severity in spinal muscular atrophy (SMA) as well as patient responses to nusinersen, according to new research published in Clinical Neurology and Neurosurgery.¹

Since nusinersen’s approval for SMA in the last decade, many patients’ overall quality of life and motor functioning have drastically improved across the globe; however, not all patient responses have been equal and some derived little benefits at all.² This research evaluating the impact of SMA treatments have suggested, the present authors contend, that some of the underlying mechanisms of SMA or these medications are still ill-understood.

SMA spinal muscular atrophy | Image Credit: © AGPhotography - stock.adobe.com

Neuroinflammation has demonstrated to be involved SMA’s pathogenesis; however, its associations with better or poorer responses to the novel gene modification therapies has not been sufficiently studied.¹ The current authors hypothesized that cytokine levels may act as a neuroinflammatory biomarker in patients with SMA. Identifying biomarkers in SMA could subsequently grant clinicians the opportunity to predict disease progression and potentially the efficacy of the treatments they receive. To add to this literature and draw further conclusions on this theory, they analyzed the cerebral spinal fluid (CSF) of patients with SMA with the aim of distinguishing biomarkers that correlated with nusinersen outcomes.

Between September 2021 and May 2022, a total of 15 patients with either type II or type III SMA were recruited at the Nanjing Medical University, Nanjing, China, where the study was also conducted. Prior to their enrollment, none had been given disease-modifying treatment; nusinersen therapy during this study was their first encounter with these medications.

A 12 mg dose of nusinersen was received intrathecally on day 1, as well as days 14, 28, and 63, subsequent maintenance doses that were given every 4 months that followed. Additionally, patients’ CSF (monocyte chemoactive protein 1 [MCP1], IL-10, and tumor necrosis factor–α [TNF-α] levels) and motor function measures were assessed at baseline, day 63, and again at the 6-month mark post-nusinersen injection. The Hammersmith Functional Rating Scale Expanded (HFMSE), 6-minute walk test (6MWT), Revised Upper Limb Module (RULM), the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and the World Health Organization (WHO) motor milestones (independent walking/standing/sitting, assisted walking/standing, crawling) were used in this evaluation.

Patients with SMA type II were aged 4 years on average, and those with SMA type III were 19.5 years. No individuals with type II group had the ability to walk whereas 33.3% of those with type III could walk at the start of the study.

The WHO motor milestone scores registered a median of 8. Nusinersen treatment after 6 months contributed to 33.3% (n = 5) patients achieving an additional motor milestone. Scoring measures from the HFMSE test in 14 patients had significant improvements at the 63-day mark (P = .003), with patients scores increasing by 4.43 points on average. At the 6-month mark, these scores had increased by an average of 5.21 points vs baseline (P = .0004).

At 63 days and 6 months, RULM scores also significantly increased by 3.77 (P = .005) and 2.85 (P = .007) following the nusinersen injection. 6MWT distances largely improved at 63 days (3m); however, the researchers observed these results slightly diminish by 6 months (-1m). Only 1 patient with type II SMA exhibited improvements to their CHOP INTEND scores.

Following treatment with nusinersen, significant growth in MCP1 expression was observed (P = .016) as well as a significant decline TNF-α (P = .021). IL-10 concentrations trended upward throughout treatment but these levels did not reach statistical significance.

Prior to treatment initiation, higher concentrations of IL-10 were significantly associated with lower performance on the HFMSE (P = .033). Additionally, the researchers observed that decreases in IL-10 levels were significantly linked to RULM improvements at the 6-month mark (P = .007).

“The highlight of the present investigation is that it was a real-world study of a rare diseases. The levels of pro-inflammatory cytokines decreased, while those of protective factors that inhibit inflammation increased during nusinersen treatment in the CSF of patients with SMA,” the authors concluded. “The cytokines in the CSF identified in this study may serve as potential biomarkers for future investigations to monitor disease progression and treatment efficacy.”

References

1. Cheng X, Li YN, Fan YB, et al. Cytokines in cerebrospinal fluid as a prognostic predictor after treatment of nusinersen in SMA patients. Clin Neurol Neurosurg. 2024;244:108462. doi:10.1016/j.clineuro.2024.108462

2. Mercuri E, Pera MC, Scoto M, Finkel R, Muntoni F. Spinal muscular atrophy - insights and challenges in the treatment era. Nat Rev Neurol. 2020;16(12):706-715. doi: 10.1038/s41582-020-00413-4