title: Spinal Muscular Atrophy Biomarker Measurements from Blood Samples in a Clinical Trial of Valproic Acid in Ambulatory Adults.
abstract: BACKGROUND
  Clinical trials of therapies for spinal muscular atrophy (SMA) that are designed to increase the expression the SMN protein ideally include careful assessment of relevant SMN biomarkers.
  
  
  OBJECTIVE
  In the SMA VALIANT trial, a recent double-blind placebo-controlled crossover study of valproic acid (VPA) in ambulatory adult subjects with SMA, we investigated relevant pharmacodynamic biomarkers in blood samples from SMA subjects by direct longitudinal measurement of histone acetylation and SMN mRNA and protein levels in the presence and absence of VPA treatment.
  
  
  METHODS
  Thirty-three subjects were randomized to either VPA or placebo for the first 6 months followed by crossover to the opposite arm for an additional 6 months. Outcome measures were compared between the two treatments (VPA and placebo) using a standard crossover analysis.
  
  
  RESULTS
  A significant increase in histone H4 acetylation was observed with VPA treatment (p = 0.005). There was insufficient evidence to suggest a treatment effect with either full length or truncated SMN mRNA transcript levels or SMN protein levels.
  
  
  CONCLUSIONS
  These measures were consistent with the observed lack of change in the primary clinical outcome measure in the VALIANT trial. These results also highlight the added benefit of molecular and pharmacodynamic biomarker measurements in the interpretation of clinical trial outcomes.
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Renusch
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Harshman
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Workman
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Wehr
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Prior
authors.affiliation: Department of Neurology, Dhahran Medical Center, Dhahran, Saudi Arabia.
authors.forename: Bakri H
authors.initials: BH
authors.lastname: Elsheikh
authors.affiliation: Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Simard
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Kissel
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Battle
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Parthun
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Freitas
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kolb
keywords: Biomarker; Valproic acid; histone deacetylase; spinal muscular atrophy; survival motor neuron protein