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FARAFARA Cure FA

 

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.

 


 

Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich's ataxia

Friedreich ataxia (FRDA) affects the spatio-temporal parameters (STP) of gait. The aims of this study were: (1) to measure the reproducibility of STP and gait scores in young patients with FRDA and (2) to describe the characteristics of gait parameters in this population.Thirty-six patients (18 males, 18 females) with diagnosis of FRDA (mean age 16.4 ± 4.5 years) were asked to walk barefoot at a self-selected pace along the pressure sensitive walkway (GAITRite®). Three trials were recorded for each patient and repeated 48 h later. Collected data was put into statistical analysis tests to determine reliability and variability of STPs and two other gait scores: The Functional Ambulation Performance score (FAP) and the Gait Variability Index (GVI). All STPs showed strong or very strong reliability (ICC > 0.7) and a low variability. The two parameters showing the lowest reliability (0.71 and 0.74) were the base of support and the foot progression angle. The FAP score and the GVI showed strong reliability (ICC > 0.8). The authors conclude that the GAITRite system allows feasible and reliable measurements of gait parameters in young patients with FRDA. Lower reliability found for the weakest parameters was attributed to the software automatic errors and the ankle laxity noted in every patient.

Read the entire article HERE

Two funded post-doctoral positions are available in the laboratory of Hélène Puccio at the IGBMC in Strasbourg.

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Nonataxia symptoms in Friedreich Ataxia: Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)

This paper describes a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms. The authors studied 650 patients with genetically confirmed FRDA from the large database of the European Friedreich's Ataxia Consortium for Translational Studies. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Logistic regression modeling was used to identify predictors for the presence of the most common clinical features. The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems. This joint European effort demonstrates the multisystem nature of this neurodegenerative disease encompassing most the central nervous, neuromuscular, cardiologic, and sensory systems. A distinct and deeper knowledge of this rare and chronic disease is highly relevant for clinical practice and designs of clinical trials.

Read the entire article HERE

Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion

Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). The genetic cause of the disease is an expanded GAA repeat within the FXN gene. Agents that increase expression of FXN protein are a potential approach to therapy. This group has previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here they test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low Tm values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.

Read the entire article HERE

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models

In Friedreich's Ataxia, increased oxidative stress leads to a chronic depletion of endogenous antioxidants, which affects the survival of the cells and causes neurodegeneration. In particular, cerebellar granule neurons (CGNs) show a significant increase of reactive oxygen species (ROS), lipid peroxidation and lower level of reduced glutathione (GSH). In FRDA, one of the major pathways of oxidant scavengers, the Nrf2 antioxidant pathway, is defective. Previous studies on FRDA-like CGNs showed that the reduced level of frataxin and the oxidative stress induce mitochondrial impairments. By triggering the Nrf2 pathway pharmacologically we determined whether this could promote mitochondrial fitness and counteract oxidative stress. In this work, we sought to investigate the beneficial effect of a promising Nrf2-inducer, omaveloxolone (omav), in CGNs from two FRDA mouse models, KIKO and YG8R, and human fibroblasts from patients. We found that CGNs from both KIKO and YG8R presented Complex I deficiency and that omav was able to restore substrate availability and Complex I activity. This was also confirmed in human primary fibroblasts from FRDA patients. Although fibroblasts are not the major tissue affected, we found that they show significant differences recapitulating the disease; this is therefore an important tool to investigate patients' pathophysiology. Interestingly, we found that patient fibroblasts had an increased level of endogenous lipid peroxidation and mitochondrial ROS (mROS), and lower GSH at rest. Omav was able to reverse this phenotype, protecting the cells against oxidative stress. By stimulating the cells with hydrogen peroxide (H2O2) and looking for potential mitochondrial pathophysiology, we found that fibroblasts could not maintain their mitochondrial membrane potential (ΔΨm). Remarkably, omav was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

Read the entire article HERE

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