Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on Spinal Muscular Atrophy type 3 patients

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.

Keywords: Nusinersen; neurofilaments; pharmacodynamics biomarker; spinal muscular atrophy.

Figure 1

Evaluation of standardized motor scales in SMA type 3 patients. Individual scores at the 6 min walking test (A) and at the Hammersmith Functional Motor Scale Expanded (B) at baseline (pre) and after five injections (post) of Nusinersen

Figure 2

Cerebrospinal fluid (CSF) concentrations of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL). Levels of pNfH (A) and NfL (D) in the CSF of SMA type 3 patients (SMA‐3) and controls (median [IQR]). Correlation between pNfH levels and either age at treatment (B) or duration of disease (C). The same analyses for NfL are also displayed (E‐F). 4 of 12 pNfH (A) and 2 of 12 NfL (D) values at baseline were below the detection limit

Figure 3

Cerebrospinal fluid (CSF) concentrations of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) at baseline and after treatment with Nusinersen. Individual CSF pNFH levels (A) and NfL levels (C) of SMA type 3 patients at baseline (Pre) and after five injections (Post) of Nusinersen (6‐month follow‐up) (n = 12); four patients had undetectable pNfH levels both at baseline and during follow‐up, while two patients displayed a similar baseline value of NfL (201.1 and 202.7 pg/mL) that became undetectable in both cases at the end of the follow‐up. Correlation between the change in pNfH (B) or NfL (D) values and variations in HFMSE scores over time (n = 12); two patients displayed identical differences in HFMSE scores (4 points) and differences in pNfH levels (0 ng/mL)