SMA valiant trial: A prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy

Spinal muscular atrophy (SMA) is unique among human genetic disorders in that a genomic duplication at the causative gene locus (the survival of motor neuron or SMN locus) has resulted in a nearly identical gene, SMN2, which lies centromeric to the SMN1 gene.1–3 This gene differs from SMN1 mainly by a single C-to-T nucleotide substitution at the splice junction of exon 7. Although this mutation does not affect the amino acid sequence, it does alter mRNA splicing in favor of transcripts lacking exon 7. Due to alternative splicing, however, a small amount of full-length SMN transcript is produced by the SMN2 gene so that SMN2 copy number is a major determinant of phenotype.4–11 Murine models of SMA reflect the protective effect of SMN2 copy number on phenotypic severity,12 suggesting that pharmacologic or genetic strategies to increase production of full-length transcript from SMN2 might be an effective therapeutic strategy.1–3,13–16 Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor that increases SMN expression in SMA patient-derived cell lines as well as in SMA patients.17–23 SMA mice treated with VPA have improved gross motor function and survival compared with controls. These positive effects are also reflected in larger compound muscle action potentials (CMAPs) on electrophysiological studies and less degeneration of spinal motor neurons and improved neuromuscular junction innervation.23 Four open-label trials of VPA in humans with SMA all suggested a benefit in strength, motor function, or both.24–26 One study of 7 ambulatory adults in particular found a 49% improvement in baseline strength tested with hand-held myometry after treatment with VPA for a mean of 8 months.24 These encouraging results led the Project Cure SMA Group to perform a series of controlled clinical trials with VPA in various SMA populations.27–29 We report here the results of a double-blind clinical trial of a 6-month treatment course of VPA versus placebo in a cohort of ambulatory SMA adults.