Learning to walk: challenges for spinal muscular atrophy clinical trials.

摘要

Spinal muscular atrophy (SMA) is a genetically determined neuronopathy and usually presents in childhood. SMA has a broad range of phenotypes: severe early infancy onset (type I, Werdnig-Hoffman disease, non-sitters), later infancy onset, intermediate variety (type II, sitters, non-walkers), and childhood to adulthood onset (type III, Kugelberg-Welander, walkers).1,2 In addition to progressive limb and truncal weakness, dysphagia, aspiration, and respiratory insufficiency are predictable life-threatening comorbidities of the infantile type I and II forms.3 As yet, no effective drug therapy has been found for human SMA. Advances in molecular genetics led to the discovery of the causative mutation in the Survival Motor Neuron (SMN) 1 gene and elucidation of the rescue of an otherwise lethal condition by a nearly identical homologue gene, SMN2.4 The number of copies of this SMN2 gene is inversely associated with disease severity, and this gene dosing observation has led to treatment strategies targeting SMN2.5 These strategies for SMA include induction of SMN2 gene expression, modulation of splicing of SMN2-derived transcripts, and stabilization of SMN protein.6 Each approach will in theory generate more SMN protein and might ameliorate the accelerated motor neuron loss and progressive muscular atrophy. In vitro or animal model studies of valproate, phenylbutyrate, and hydroxyurea have demonstrated promising results and each is now in clinical trials.7