title: Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study.
abstract: BACKGROUND
  Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia.
  
  
  METHODS
  In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2-8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809.
  
  
  RESULTS
  Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5-6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes.
  
  
  CONCLUSIONS
  Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted.
  
  
  BACKGROUND
  Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.
authors.affiliation: Leonard Wolfson Experimental Neurology Centre, University College London, London, UK; National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Libri
authors.affiliation: Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Cihangir
authors.initials: C
authors.lastname: Yandim
authors.affiliation: National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
authors.forename: Stavros
authors.initials: S
authors.lastname: Athanasopoulos
authors.affiliation: National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Loyse
authors.affiliation: Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Theona
authors.initials: T
authors.lastname: Natisvili
authors.affiliation: Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Pui Pik
authors.initials: PP
authors.lastname: Law
authors.affiliation: Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Ping Kei
authors.initials: PK
authors.lastname: Chan
authors.affiliation: National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Mohammad
authors.affiliation: Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Mauri
authors.affiliation: School of Biological Sciences, University of Hong Kong, Hong Kong, China.
authors.forename: Kin Tung
authors.initials: KT
authors.lastname: Tam
authors.affiliation: Nitric Oxide Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.affiliation: Nitric Oxide Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Piper
authors.affiliation: Intensive Care Department, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Aravind
authors.initials: A
authors.lastname: Ramesh
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parkinson
authors.affiliation: National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK.
authors.forename: Les
authors.initials: L
authors.lastname: Huson
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK. Electronic address: r.festenstein@imperial.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Festenstein
mesh_terms: D000328:Adult; D002843:Chromatin / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005260:Female; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D033862:Iron-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage*; D016896:Treatment Outcome; D006113:United Kingdom; D014803:Vitamin B Complex / Q000008:administration & dosage*; D055815:Young Adult; D000096923:Frataxin
chemical_list: D002843:Chromatin; D033862:Iron-Binding Proteins; D009536:Niacinamide; D014803:Vitamin B Complex; D000096923:Frataxin