Phase II open label study of valproic acid in spinal muscular atrophy

Kathryn J. Swoboda, Charles B. Scott, Sandra P. Reyna, Thomas W. Prior, Bernard LaSalle, Susan L. Sorenson, Janine Wood, Gyula Acsadi, Thomas Owen Crawford, John T. Kissel, Kristin J. Krosschell, Guy D'Anjou, Mark B. Bromberg, Mary K. Schroth, Gary M. Chan, Bakri Elsheikh, Louise R. Simard

Research output: Contribution to journalArticle

Abstract

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≤0.001); however, significant improvement was almost entirely restricted to participants

Original languageEnglish (US)
Article numbere5268
JournalPLoS One
Volume4
Issue number5
DOIs
StatePublished - May 14 2009

Fingerprint

valproic acid
Spinal Muscular Atrophies of Childhood
Spinal Muscular Atrophy
muscular atrophy
Valproic Acid
Labels
Outcome Assessment (Health Care)
Carnitine
Photon Absorptiometry
Controlled Clinical Trials
Body Composition
Natural History
Bone Density
Action Potentials
Weight Gain
Fats
dual-energy X-ray absorptiometry
hepatotoxicity
carnitine
bone density

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Swoboda, K. J., Scott, C. B., Reyna, S. P., Prior, T. W., LaSalle, B., Sorenson, S. L., ... Simard, L. R. (2009). Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One, 4(5), [e5268]. https://doi.org/10.1371/journal.pone.0005268

Phase II open label study of valproic acid in spinal muscular atrophy. / Swoboda, Kathryn J.; Scott, Charles B.; Reyna, Sandra P.; Prior, Thomas W.; LaSalle, Bernard; Sorenson, Susan L.; Wood, Janine; Acsadi, Gyula; Crawford, Thomas Owen; Kissel, John T.; Krosschell, Kristin J.; D'Anjou, Guy; Bromberg, Mark B.; Schroth, Mary K.; Chan, Gary M.; Elsheikh, Bakri; Simard, Louise R.

In: PLoS One, Vol. 4, No. 5, e5268, 14.05.2009.

Research output: Contribution to journalArticle

Swoboda, KJ, Scott, CB, Reyna, SP, Prior, TW, LaSalle, B, Sorenson, SL, Wood, J, Acsadi, G, Crawford, TO, Kissel, JT, Krosschell, KJ, D'Anjou, G, Bromberg, MB, Schroth, MK, Chan, GM, Elsheikh, B & Simard, LR 2009, 'Phase II open label study of valproic acid in spinal muscular atrophy', PLoS One, vol. 4, no. 5, e5268. https://doi.org/10.1371/journal.pone.0005268
Swoboda KJ, Scott CB, Reyna SP, Prior TW, LaSalle B, Sorenson SL et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One. 2009 May 14;4(5). e5268. https://doi.org/10.1371/journal.pone.0005268
Swoboda, Kathryn J. ; Scott, Charles B. ; Reyna, Sandra P. ; Prior, Thomas W. ; LaSalle, Bernard ; Sorenson, Susan L. ; Wood, Janine ; Acsadi, Gyula ; Crawford, Thomas Owen ; Kissel, John T. ; Krosschell, Kristin J. ; D'Anjou, Guy ; Bromberg, Mark B. ; Schroth, Mary K. ; Chan, Gary M. ; Elsheikh, Bakri ; Simard, Louise R. / Phase II open label study of valproic acid in spinal muscular atrophy. In: PLoS One. 2009 ; Vol. 4, No. 5.
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