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Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Official URL:https://doi.org/10.1016/S0140-6736(14)60382-2
PubMed:View item in PubMed
Creators Name:Libri, V. and Yandim, C. and Athanasopoulos, S. and Loyse, N. and Natisvili, T. and Law, P.P. and Chan, P.K. and Mohammad, T. and Mauri, M. and Tam, K.T. and Leiper, J. and Piper, S. and Ramesh, A. and Parkinson, M.H. and Huson, L. and Giunti, P. and Festenstein, R.
Journal Title:Lancet
Journal Abbreviation:Lancet
Volume:384
Number:9942
Page Range:504-513
Date:9 August 2014
Keywords:Chromatin, Drug Dose-Response Relationship, Friedreich Ataxia, Genetic Epigenesis, Great Britain, Iron-Binding Proteins, Niacinamide, Treatment Outcome, Vitamin B Complex
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. FINDINGS: 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. INTERPRETATION: 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.
ISSN:0140-6736
Publisher:Elsevier / Lancet (U.K.)
Item Type:Article

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