title: Safety and efficacy of valproic acid treatment in SCA3/MJD patients.
abstract: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is one of 10 known polyglutamine (polyQ) diseases. In Drosophila and rat models of polyQ diseases, histone deacetylation (HDAC) inhibitors improved locomotor function and survival time by increasing histone acetylation levels and modulating gene expression. Valproic acid (VPA) is a pan-HDAC inhibitor used clinically to treat bipolar and seizure disorders. We evaluated the clinical safety and efficacy of VPA treatment for SCA3/MJD patients.
  
  
  
  First, a randomized, open-label, dose-escalation method was used to evaluate tolerance to single-dose VPA administration in 12 SCA3/MJD patients. Patients were randomly assigned to three groups of four subjects, each with an oral dosage of 400 mg, 600 mg, or 800 mg (twice daily (bid) for one day). VPA was well-tolerated for one-dose by all patient groups. Second, a randomized, double-blind, placebo-controlled, dose-controlled study evaluated the safety and efficacy of multi-dose VPA (oral administration, twice daily (bid) for 12 weeks) in 36 SCA3/MJD patients. Patients received either low-dose VPA (800 mg/day), high-dose VPA (1200 mg/day), or placebo (n = 12 subjects per group). Symptoms were evaluated using the Scale for Assessment and Rating of Ataxia (SARA).
  
  
  
  Multi-dose VPA treatment improved SARA measures of locomotor function. Major adverse effects included dizziness and loss of appetite.
  
  
  
  VPA is a potentially beneficial agent for the treatment of SCA3/MJD. These results also provide insight into possible future therapeutics for polyQ diseases.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China; Department of Neurology, Xiangya 3rd Hospital, Central South University, Changsha, Hunan 410013, People's Republic of China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Lei
authors.affiliation: Clinical Pharmacology Center, Xiangya 3rd Hospital, Central South University, Changsha, Hunan 410013, People's Republic of China.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
authors.affiliation: Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Song
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, People's Republic of China; State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, People's Republic of China.
authors.forename: Bei-Sha
authors.initials: BS
authors.lastname: Tang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, People's Republic of China; State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, People's Republic of China. Electronic address: jianghong73868@126.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D017827:Machado-Joseph Disease / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D016896:Treatment Outcome; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid
keywords: Efficacy; PolyQ disease; Spinocerebellar ataxia type 3/Machado-Joseph disease; Tolerability; Valproic acid