Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

• Published in: PloS one Vol. 4; no. 5; p. e5268
• Main Authors: Swoboda, Kathryn J., Scott, Charles B., Reyna, Sandra P., Prior, Thomas W., LaSalle, Bernard, Sorenson, Susan L., Wood, Janine, Acsadi, Gyula, Crawford, Thomas O., Kissel, John T., Krosschell, Kristin J., D'Anjou, Guy, Bromberg, Mark B., Schroth, Mary K., Chan, Gary M., Elsheikh, Bakri, Simard, Louise R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.05.2009; Public Library of Science (PLoS)
• Subjects: Absorptiometry, Photon; Acids; Action potential; Adolescent; Adult; Age; Analysis of Variance; Atrophy; Body composition; Body composition (biology); Body Composition - drug effects; Body fat; Body weight gain; Bone composition; Bone density; Bone Density - drug effects; Bone mineral density; Bones; Carnitine; Cell lines; Cerebral palsy; Child; Child, Preschool; Clinical trials; Density; Departments; Depletion; Divalproex; Dual energy X-ray absorptiometry; Electrophysiology; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fatty acids; Genetics and Genomics/Medical Genetics; Genetics and Genomics/Pharmacogenomics; Health aspects; Hepatotoxicity; Human subjects; Humans; In vivo methods and tests; Innervation; Medical research; Medicine; Medicine, Experimental; Metabolism; mRNA; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - pathology; Neurologic Examination; Neurological Disorders/Neuromuscular Diseases; Neurology; Neuromuscular diseases; Oxidation; Pathology; Pediatrics; Pediatrics and Child Health/Developmental and Pediatric Neurology; Product development; Proteins; Respiratory Function Tests; RNA; Rodents; Salt; SMN protein; Spinal muscular atrophy; Survival of Motor Neuron 2 Protein - genetics; Treatment Outcome; Valproic acid; Valproic Acid - administration & dosage; Valproic Acid - adverse effects; Valproic Acid - pharmacology; Valproic Acid - therapeutic use; Young Adult; Canada; Ohio; United States > US; Utah
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005268

Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. ClinicalTrials.gov.