SMA THERAPIES II AND BIOMARKERS: P.266Neurofilament as a potential biomarker for spinal muscular atrophy: rationale based on animal and human studies

Abstract

SMA is an autosomal recessive neuromuscular disorder characterized by degeneration of alpha motor neurons (AHCs) in the spinal cord and brain stem leading to muscular atrophy and weakness. Prognostic and predictive biomarkers are needed to inform SMA treatment. Neurofilaments (NFs) have been proposed as biomarkers in disorders characterized by axonal degeneration, although their clinical utility has not been established. NFs are intermediate filaments uniquely expressed in neuronal cells and are integral components of the cytoskeleton. NFs are differentiated by molecular weight: light (NF-L), medium (NF-M), and heavy (NF-H). About 80% of axonal NFs are highly phosphorylated, conferring resistance to protein degradation. NFs are released into the extracellular fluid during axonal disintegration and are detected in cerebrospinal fluid (CSF) and blood. Advanced detection assays allow robust quantification of NF proteins in the CSF and blood of patients with amyotrophic lateral sclerosis and multiple sclerosis. End stage human SMA pathology is notable for loss of AHCs and ventral root axons, but the timing of degeneration based on disease severity is unknown. Severe SMA mouse models also demonstrate loss of AHCs and denervation of vulnerable muscle groups. In human SMA and mouse models, neuromuscular junctions (NMJs) are structurally immature and contain accumulations of pNFs at the presynaptic terminal, possibly from dysregulation of NF axonal transport with impaired NF degradation. Similar NF accumulations were observed in 70% of diaphragmatic NMJs in SMA Type I infants (age<6 months) versus normal controls. The restoration of NMJ synaptic integrity upon therapeutic restoration of survival motor neuron (SMN) in SMA mice suggests that sufficient SMN expression in the CNS prevents axonal degeneration and NF accumulation in SMA. Assessments of blood and CSF pNF-H levels are promising prognostic and predictive biomarkers for SMA disease activity and/or treatment efficacy.