Abstract
Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology.Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.Results: Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder caused by homozygous loss of function of the SMN1 gene [1]
In SMA patients, full-length SMN protein is produced by a second gene, SMN2, but only in small amounts which are insufficient for normal neuromuscular function [2,3,4,5,6]
Nusinersen was approved for all types of SMA, but approval was primarily based on evidence in infants and children ages 2–15 [7,8,9]
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder caused by homozygous loss of function of the SMN1 gene [1]. In SMA patients, full-length SMN protein is produced by a second gene, SMN2, but only in small amounts which are insufficient for normal neuromuscular function [2,3,4,5,6]. Nusinersen (Spinraza) is an intrathecally-delivered therapy that increases full-length SMN protein production from the SMN2 gene. There is emerging data supporting the use of nusinersen in adults with SMA [10,11,12,13,14,15,16,17]. Limited data from prior studies suggest progressive strength and functional decline over time in all SMA participants including adults [19]. Data on long-term longitudinal changes in several of the standard outcome measures used in ambulatory adults is scant [19, 20]
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