Abstract
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. 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. 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. 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. 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.
Highlights
Friedreich’s ataxia is the most common inherited ataxia in the white population, affecting between 1 in 30 000 and 1 in 50 000 people.[1,2] It usually presents in childhood with a relentlessly progressive, predominantly sensory ataxia and dysarthria, and is associated with deafness, visual impairment, diabetes, and hypertrophic cardiomyopathy.[3]
We identified no reports of clinical studies investigating the use of histone deacetylase (HDAC) inhibitors in patients with Friedreich’s ataxia
Interpretation In this exploratory study, we have identified safe and well-tolerated doses of nicotinamide, which when given to patients with Friedreich’s ataxia led to partial reversal of the abnormal heterochromatinisation of the FXN gene and restoration of frataxin concentration towards asymptomatic levels
Summary
Friedreich’s ataxia is the most common inherited ataxia in the white population, affecting between 1 in 30 000 and 1 in 50 000 people.[1,2] It usually presents in childhood with a relentlessly progressive, predominantly sensory ataxia and dysarthria, and is associated with deafness, visual impairment, diabetes, and hypertrophic cardiomyopathy (a frequent cause of premature mortality).[3]. In 97% of cases, Friedreich’s ataxia is caused by the pathological expansion of a GAA triplet repeat within the first intron of both alleles of the frataxin (FXN) gene, which results in partial silencing of the gene, leading to frataxin protein deficiency.[4,5] Most clinical trials so far have focused on ameliorating the downstream effects of frataxin deficiency, with little success in modifying the natural history of the disease.[6] Mariotti and colleagues[7] assessed the use of erythropoietin to upregulate frataxin, but did not report a significant effect. We focus on a novel treatment aimed at correcting the primary defect, FXN gene silencing
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