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.
Subject(s)
Friedreich Ataxia/drug therapy , Iron-Binding Proteins/drug effects , Niacinamide/administration & dosage , Vitamin B Complex/administration & dosage , Adult , Chromatin/drug effects , Chromatin/genetics , Dose-Response Relationship, Drug , Epigenesis, Genetic , Female , Friedreich Ataxia/genetics , Humans , Iron-Binding Proteins/biosynthesis , Male , Middle Aged , Treatment Outcome , United Kingdom , Young Adult , FrataxinABSTRACT
Prenatal exposure to maternal cigarette smoking in humans or nicotine in experimental animals is associated with elevated blood pressure in the offspring. This effect may be limited to genetically vulnerable individuals and related to alterations in the kidneys. Here we investigated whether prenatal exposure to nicotine (PEN) alters kidney morphology and gene expression, and whether these effects differ between two genetically distant strains, i.e. spontaneously hypertensive (SHR) and Brown Norway (BN) rats. The results showed that, in SHR but not in BN offspring, PEN decreases kidney glomerular mass and increases renal expression of the angiotensin II type 1b receptor gene; the latter is not mediated through changes in DNA methylation of the proximal promoter of this gene. The results also showed that PEN alters expression of multiple genes involved in the kidney nervous system function, with mostly opposite effects being seen in SHR and BN. These results suggest that, in genetically vulnerable individuals, PEN leads to morphological and molecular changes in the kidneys that may contribute to fetal programming of hypertension.
Subject(s)
Kidney Glomerulus/drug effects , Maternal Exposure/adverse effects , Nicotine/toxicity , Prenatal Exposure Delayed Effects , Receptor, Angiotensin, Type 1/biosynthesis , Animals , Animals, Newborn , Body Weight/drug effects , Body Weight/physiology , Female , Gene Expression Regulation/drug effects , Histocytochemistry , Kidney Glomerulus/metabolism , Logistic Models , Male , Oligonucleotide Array Sequence Analysis , Organ Size/drug effects , Organ Size/physiology , Pregnancy , RNA/chemistry , RNA/genetics , Rats , Rats, Inbred BN , Rats, Inbred SHR , Receptor, Angiotensin, Type 1/geneticsABSTRACT
This article describes a suite of computational approaches suitable for deriving various quantitative phenotypes from structural magnetic resonance (MR) images obtained in rodents and used subsequently in genetic studies of complex traits. We begin by introducing the basic principles of genetic studies of complex traits in experimental models. We then illustrate the use of MR-based computational anatomy in vivo and ex vivo, and in combination with histology. This work was carried out in two inbred strains of rats, namely spontaneously hypertensive rats and Brown Norway rats; these are parental strains of the only existing panel of recombinant inbred strains of rats. The rats were scanned in vivo at two time points (at 8 and 12 weeks of age) and ex vivo (at 12 weeks of age). We describe between-strain differences and across-time changes in brain and kidney volumes, as well as regional variations in brain structure using surface- and deformation-based approaches. We conclude by discussing the power of the population-based computational analysis of MR images, and their fusion with histology, in studies of complex traits.
