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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.

Safety and feasibility of upper limb cardiopulmonary exercise test in Friedreich ataxia

This study aims to explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and to compare the results with sex, age, and body mass index (BMI) matched cohort of healthy controls (HC). Cardiopulmonary exercise test was performed using an upper limbs cycle ergometer on fasting subjects. Peak oxygen uptake (peak VO2) was recorded as the mean value of VO2 during a 20 s period at the maximal effort of the test at an appropriate respiratory exchange rate. The ventilatory anaerobic threshold (AT) was detected by the use of the V-slope method. The investigators performed echocardiography with an ultrasound system equipped with a 2.5 MHz multifrequency transducer for complete M-mode, two-dimensional, Doppler, and Tissue Doppler Imaging analyses. 55 FRDA and 54 healthy matched controls (HC) were studies. Peak VO2 showed a significant 31% reduction in FRDA patients compared to HC (15.2 ± 5.7 vs. 22.0 ± 6.1 mL/kg/min; P < 0.001). Peak workload was reduced by 41% in FRDA (42.9 ± 12.5 vs. 73.1 ± 21.2 W; P < 0.001). In FRDA patients, peak VO2 is inversely correlated with the Scale for Assessment and Rating of Ataxia score, disease duration, and 9HPT performance, and directly correlated with activities of daily living. The AT occurred at 48% of peak workload time in FRDA patients and at 85% in HC (P < 0.001). Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

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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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