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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. The authors report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene. The identified missense mutation has been reported previously in two Friedreich's ataxia (FRDA) cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from this family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. This family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that may have important implications on understanding the pathogenesis of these neurological disorders.

Read the entire article HERE

Targeting NRF2 for the Treatment of Friedreich's Ataxia: A Comparison among Drugs

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich's Ataxia (FRDA) and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, the authors compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.

Read the entire article HERE

Cerebellum and cognition in Friedreich ataxia: a voxel-based morphometry and volumetric MRI study

The aim of this study was to investigate the correlation between cerebellar volume and cognition in Friedreich ataxia (FRDA). Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis. FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03). With two different image analysis techniques, the authors confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding knowledge about the physiopathology of cognitive impairment in FRDA.

Read the entire article HERE

Predictors of Left Ventricular Dysfunction in Friedreich's Ataxia in a 16-Year Observational Study

In Friedreich's ataxia (FRDA) lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. The authors aimed to identify patients likely to develop worsening LVEF at an early stage. The study included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years. At baseline, left ventricular (LV) hypertrophy was present in 53%, with LVEF 65 ± 7%, LV end diastolic diameter (LVEDD) 43 ± 5 mm, septal wall thickness (SWT) 11.8 ± 2.7 mm, and posterior wall thickness 11.1 ± 2.5 mm. After a mean follow-up of 13 ± 6 years, LVEF ≤ 50% was observed in 12 patients. The main determinants of LVEF ≤ 50% were GAA repeat number on the shorter allele (odds ratio [OR] 1.007, 95% confidence interval [CI] 1.003-1.012, p = 0.002), LVEDD (OR 1.217, 95% CI 1.058-1.399, p = 0.006), and SWT (OR 1.352, 95% CI 1.016-1.799, p = 0.04). High-risk patients were predicted 5 years before LVEF ≤ 50% occurred: area under the curve of 0.91, 95% CI 0.85-0.97. Patients with GAA repeats > 800 were categorized as high risk, patients with 500 < GAA < 800 were high risk if LVEDD was ≥ 52.6 mm and SWT was ≥ 13.3 mm, and patients with GAA < 500 were low risk if LVEDD was < 52.6 mm and SWT was < 13.3 mm. Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.

Read the entire article HERE

Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide

Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells (iPSCs). To analyse the benefits provided by this approach, the authors focused on two compounds, resveratrol and nicotinamide, for which clinical testing in Friedreich ataxia was not successful. These compounds were selected because they were able to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells, but the authors showed that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.

Read the entire article HERE

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