Abstract
The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme‐linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.
Highlights
PNfH and neurofilament light chain (NfL) levels dosed at baseline in the CFS of spinal muscular atrophy (SMA) type 3 patients were comparable to those observed in controls (n = 9, age: 29.0 [22.054.5] year-old) and were far below the average values described in patients affected by either SMA type 1 (6.874 ng/mL and >10 000 pg/ mL, respectively) or amyotrophic lateral sclerosis (5.270 ng/mL and 2961 pg/mL11) (Figure 2A and 2)
In this explorative study on a small cohort of SMA type 3 patients, we report our preliminary findings on the effects of Nusinersen administration on motor function over the short-term and describe changes over time in the cerebrospinal fluid (CSF) concentration of both phosphorylated neurofilaments heavy chain (pNfH) and NfL, which were assessed as potential biomarkers of treatment response
A recent post hoc analysis of data from the CS2/CS12 study, which included a subset of ambulant patients with SMA type 2 and 3 treated with Nusinersen, showed an improvement in motor performance at 35 months from treatment start.[13]
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. 3.2 | Neurofilaments in the CSF pNfH and NfL levels dosed at baseline in the CFS of SMA type 3 patients were comparable to those observed in controls (n = 9, age: 29.0 [22.054.5] year-old) and were far below the average values described in patients affected by either SMA type 1 (6.874 ng/mL and >10 000 pg/ mL, respectively) or amyotrophic lateral sclerosis (5.270 ng/mL and 2961 pg/mL11) (Figure 2A and 2). No significant correlation was observed between the pre-post–difference in HFMSE scores and the change of either pNfH or NfL over time (Figure 3B and 3) Baseline values of both pNfH and NfL in the patient with SMA type 1 were much higher than those observed in healthy controls (6.874 ng/ mL and >10 000 pg/mL, respectively), in accordance with existing data. | 3037 from the literature.[7,12] Levels of both neurofilament types showed a progressive and rapid reduction, and at 6 months from treatment start they were comparable to those of healthy individuals (data not shown)
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