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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.

High Levels of Frataxin Overexpression Lead to Mitochondrial and Cardiac Toxicity in Mouse Models

Cardiac dysfunction is the main cause of premature death in Friedreich ataxia (FA). Adeno-associated virus (AAV)-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administered, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level but significant toxicity to the mitochondria and heart above 20-fold. The authors show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of the mitochondria respiratory chain and ultrastructure, which leads to cardiomyocyte subcellular disorganization, cell death, and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriate vector expression level, long-term safety, and biomarkers to monitor such events.

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The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, the authors evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.

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An Overview of the Ferroptosis Hallmarks in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is caused by reduced levels of frataxin, a mitochondrial protein involved in the synthesis of iron-sulfur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. Here the authors describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.

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Assessment of Disease Progression in Friedreich Ataxia using an Instrumented Self Feeding Activity

In Friedreich ataxia (FRDA), it is important to monitor the progression of ataxia over periods of time for clinical and therapeutic interventions. This study was aimed at investigating the use of the instrumented measurement scheme of utilizing a motion detecting spoon in a self-feeding activity to quantify the longitudinal effect of FRDA on upper limb function. Forty individuals diagnosed with FRDA (32.8±14.9 years old) were recruited in a 12-month longitudinal study consisting of equal number of males and females (20). A set of biomarkers was extracted from the temporal and texture analysis of the movement time series data that objectively detected subtle changes during follow-up testing. The results indicated that both analyses generated features that resembled clinical ratings. Although the diagnosis and severity related performances were readily observed by temporal features, the longitudinal progression was better captured by the textural features (p = 0.029). The estimation of severity by mean of random forest regression model and LASSO exhibited a high degree of parity with the standard clinical scale (rho = 0.73, p < 0.001).

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Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich's ataxia

Numerous studies of mitochondrial dysfunction in Friedreich's ataxia have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, this study finds that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7-15% to the total frataxin protein present in mouse tissues. The authors have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich's ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

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