Vincenzo Libri1, Cihangir Yandim2, Stavros Athanasopoulos3, Naomi Loyse3, Theona Natisvili2, Pui Pik Law2, Ping Kei Chan2, Tariq Mohammad3, Marta Mauri4, Kin Tung Tam5, James Leiper6, Sophie Piper6, Aravind Ramesh7, Michael H Parkinson8, Les Huson3, Paola Giunti8, Richard Festenstein9. 1. 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. 2. Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK. 3. National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK. 4. Max Delbrück Centre for Molecular Medicine, Berlin, Germany. 5. School of Biological Sciences, University of Hong Kong, Hong Kong, China. 6. Nitric Oxide Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK. 7. Intensive Care Department, Christchurch Hospital, Christchurch, New Zealand. 8. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. 9. 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.
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. FUNDING: 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.
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. FUNDING: 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: Tanya V Aranca; Tracy M Jones; Jessica D Shaw; Joseph S Staffetti; Tetsuo Ashizawa; Sheng-Han Kuo; Brent L Fogel; George R Wilmot; Susan L Perlman; Chiadi U Onyike; Sarah H Ying; Theresa A Zesiewicz Journal: Neurodegener Dis Manag Date: 2016
Authors: Elisabetta Soragni; Wenyan Miao; Marco Iudicello; David Jacoby; Stefania De Mercanti; Marinella Clerico; Filomena Longo; Antonio Piga; Sherman Ku; Erica Campau; Jintang Du; Pablo Penalver; Myriam Rai; Joseph C Madara; Kristopher Nazor; Melinda O'Connor; Anton Maximov; Jeanne F Loring; Massimo Pandolfo; Luca Durelli; Joel M Gottesfeld; James R Rusche Journal: Ann Neurol Date: 2014-09-16 Impact factor: 10.422
Authors: Yogesh K Chutake; Christina Lam; Whitney N Costello; Michael Anderson; Sanjay I Bidichandani Journal: Ann Neurol Date: 2014-08-30 Impact factor: 10.422
Authors: Xiulong Shen; Audrius Kilikevicius; Daniel O'Reilly; Thazha P Prakash; Masad J Damha; Frank Rigo; David R Corey Journal: Bioorg Med Chem Lett Date: 2018-07-21 Impact factor: 2.823