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.

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

“…Similar results were confirmed in plasma in the ENDEAR study in symptomatic SMA type I patients [ 85 ]. In older patients with less severe forms of SMA, the role of NFs has not yet been confirmed probably as consequence of a slower disease progression [ 86 , 87 ]. SMN protein regulates RNA metabolism and biogenesis of microRNA (miRNA), which are gene expression modulators, and their dysregulation is implicated in a variety of neuromuscular diseases.…”

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…Independent studies exploring this aspect showed a consistent range of HFMSE score: between 0 and 20 for type 2 and between 25 and 66 for type 3 patients [ 27 , 28 , 29 ]. A larger range was recorded for the type 3 patients followed up by Walter and colleagues [ 18 ].…”

“…Results differed between SMA types 2 and 3, with a higher average HFMSE increase for SMA type 3 patients. Interestingly, no correlation was observed between the age at treatment and the evolution of the functional score during the treatment [ 19 , 29 ].…”

“…In particular, the phosphorylation, abundant on the NF-H, ensures protection from degradation [ 133 ]. Although NFs seem to be reliable biomarkers for SMA infants, as their level is reduced upon Nusinersen treatment and this is generally correlated with an improved motor function [ 134 ], few recent publications have described contradicting results for the use of NFs as biomarkers for adult SMA patients’ response to therapy [ 29 , 135 ]. Eleven SMA type 3 patients (all adults—38.5 years mean age) analyzed for their pNF-H content in blood and CSF showed no change after administration of the Nusinersen loading doses [ 136 ].…”

Przegląd metod oceny funkcjonalnej analizujących motorykę małą i dużą u chorych z rdzeniowym zanikiem mięśni

“…Od 1 stycznia 2019 roku w Polsce wprowadzono leczenie przy wykorzystaniu nusinersenu (spinraza)pierwszego leku leczącego przyczynę SMA. Lek ten jest oligonukleotydem modyfikującym wadliwy splicing pre--mRNA genu SMN2 [1,4,7,8]. Ze względu na ciągłą konieczność rehabilitacji oraz świadomości stopnia progresji choroby konieczne jest używanie przez fizjoterapeutów zwalidowanych narzędzi diagnostycznych oceniających poziom funkcjonalny dziecka z SMA.…”