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FARA Funded Research

Your generous support has funded all the research listed below.


For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice

Dimethyl fumarate (DMF) dose-dependently increases mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia. Here the authors tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of Friedreich's Ataxia. DMF was first dosed at 0-320 mg/kg in C57BL6 mice and the authors observed significant toxicity above 160 mg/kg orally, defining the Maximum Tolerated Dose, MTD. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the Maximum Effective Dose, MED. The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for Multiple Sclerosis (480 mg/day) and Psoriasis (720 mg/day). In the FXNKD mouse model of Friedreich's ataxia, which has a doxycycline-induced deficit of frataxin protein, the authors observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4, and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. 110 mg/kg oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat Friedreich's ataxia or other mitochondrial diseases.

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Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia

Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene, which results in transcriptional deficiency via epigenetic silencing. Most patients are homozygous for alleles containing > 500 triplets, but a subset (~20%) have at least one expanded allele with 500 triplets, a significantly higher prevalence of unmethylated epialleles (median=9.8%) was observed in patients with at least one allele containing 20%) and later onset (>15y). The higher prevalence in mild FRDA of somatic FXN epialleles devoid of DNA methylation is consistent with variegated epigenetic silencing mediated by expanded triplet-repeats. The proportion of unsilenced somatic FXN genes is an unrecognized phenotypic determinant in FRDA, and has implications for the deployment of effective therapies.

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Omaveloxolone: potential new agent for Friedreich ataxia

There are no approved therapies for Friedreich ataxia (FRDA), but elucidation of the pathophysiology of FRDA suggest that agents that increase the activity of the transcription factor Nrf2 may provide a mechanism for ameliorating disease progression or severity. In this work, The authors review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.

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Hand Dexterity and Pyramidal Dysfunction in Friedreich Ataxia, A Finger Tapping Study

Loss of hand dexterity has a profound impact on disability in patients with cerebellar, pyramidal, or extrapyramidal diseases. Analysis of multiple finger tapping (FT) parameters can contribute to identify the underlying physiopathology, while providing a quantitative clinical assessment tool, particularly in patients not reliably evaluated using clinical rating scales. This study used an automated method of FT analysis in Friedreich ataxia (FRDA) to disentangle cerebellar (prominent FT rate variability), extrapyramidal (FT progressive amplitude reduction without slowing of tapping rate), and pyramidal (progressive decrease of FT rate and amplitude) contribution to upper limb loss of dexterity. FT parameters were then related to FRDA clinical parameters and upper limbs motor evoked potential (MEPs). Twenty-four FRDA patients and matched healthy subjects performed FT with the dominant hand for 90 seconds. FT rate, FT rate variability, FT amplitude, and linear regressions of FT movement parameters were automatically computed. Eleven patients underwent MEPs, measured at the first dorsal interosseous of the dominant hand to determine central motor conduction time (CMCT). FRDA patients had slower and more regular FT rate than controls. Eleven FRDA patients showed FT rate slowing. Those patients had longer disease duration and higher Scale for the Assessment and Rating of Ataxia (SARA) scores. Seven patients with FT rate slowing had MEP and all displayed prolonged CMCT, whereas the 4 other patients with constant FT rate had normal CMCT. This study provides evidence for a prominent involvement of pyramidal dysfunction in upper limb dexterity loss as well as a potential outcome measure for clinical studies in FRDA.

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Developing an Instrumented Measure of Upper Limb Function in Friedreich Ataxia

Upper limb function for people with Friedreich ataxia determines capacity to participate in daily activities. Current upper limb measures available do not fully capture impairments related to Friedreich ataxia. This group has developed an objective measure, the Ataxia Instrumented Measure-Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials. A prospective longitudinal study evaluated the capacity of the AIM-S to detect change in upper limb function over 48 weeks. Friedreich ataxia clinical severity, performance on the Nine-Hole Peg Test and Box and Block Test and responses to a purpose-designed questionnaire regarding acceptability of AIM-S were recorded. Forty individuals with Friedreich ataxia and 20 control participants completed the baseline assessment. Thirty individuals with Friedreich ataxia completed the second assessment. The sensitivity of the AIM-S to detect deterioration in upper limb function was greater than other measures. Patient-reported outcomes indicated the AIM-S reflected a daily activity and was more enjoyable to complete than other assessments. The AIM-S is a more accurate, less variable measure of upper limb function in Friedreich ataxia than existing measures. The AIM-S is perceived by individuals with Friedreich ataxia to be related to everyday life and will permit individuals who are non-ambulant to be included in future clinical trials.

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