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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.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5-mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich's ataxia.

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Reata Announces that The FDA Has Asked The Company to Request a Pre-NDA Meeting for Omaveloxolone for the Treatment of Friedreich’s Ataxia

FARA Co-Founder and President, Ron Bartek and FARA CEO, Jennifer Farmer said, "Thank you to the entire global Friedreich's ataxia community- individuals with FA, family, friends, clinicians, and researchers- who shared their voices as part of the FA Community Petition: Allow Individuals with Friedreich's Ataxia Access to Omaveloxolone which was sent to Reata Pharmaceuticals and the Food and Drug Administration (FDA).

The FDA's request for a Pre- NDA meeting demonstrates the power of the community’s unified voice. Thank you to the FDA for demonstrating flexibility, being open to additional data analysis, and considering the patient voice in the drug development process. We are also grateful to Reata Pharmaceuticals for their steadfast commitment to the omaveloxolone program in FA. FARA looks forward to working with both Reata and the FDA in the next steps of the process and keeping the community informed."

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Reverse phase protein array reveals correlation of retinoic acid metabolism with cardiomyopathy in Friedreich's ataxia

This study utilized a sensitive and high-throughput proteomic technique, reverse phase protein array (RPPA), to attain protein expression profiles of primary fibroblasts obtained from Friedreich's ataxia (FRDA) patients and unaffected controls. The RPPA was designed to detect 217 proteins or phosphorylated proteins by individual antibody, and the specificity of each antibody was validated prior to the experiment. Among sixty-two fibroblast samples (44 FRDA and 18 controls) analyzed, 30 proteins/phosphoproteins were significantly changed in FRDA fibroblasts compared to control cells (p<0.05), mostly representing signaling molecules and metabolic enzymes. As expected, frataxin (FXN) was significantly downregulated in FRDA samples, thus serving as an internal control for assay integrity. Extensive bioinformatic analyses were conducted to correlate differentially expressed proteins with critical disease parameters (e.g. selected symptoms, age of onset, GAA sizes, FXN levels, FARS scores). Results identified altered expression of members of the integrin family of proteins specifically associated with hearing loss in FRDA. Also, RPPA data, combined with results of transcriptome profiling, uncovered defects in the retinoic acid (RA) metabolism pathway in FRDA samples. Moreover, expression of ALDH1A3 differed significantly between cardiomyopathy positive and negative FRDA cohorts, demonstrating that metabolites such as retinol, retinal or RA could become potential predictive biomarkers of cardiac presentation in FRDA.

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Drp1-dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia

Mitochondria alter their morphology in response to various stresses; however, such alterations to morphology may be homeostatic or maladaptive depending upon the tissue and disease state. Numerous neurodegenerative diseases exhibit excessive mitochondrial fragmentation, and reversing this phenotype improves bioenergetics for diseases in which mitochondrial dysfunction is a secondary feature of the disease. This paper demonstrates that frataxin deficiency causes excessive mitochondrial fragmentation that is dependent upon Drp1 activity in Friedreich ataxia cellular models. Drp1 inhibition by the small peptide TAT-P110 reverses mitochondrial fragmentation but also decreases ATP levels in frataxin-knockdown fibroblasts and FRDA patient fibroblasts, suggesting that fragmentation may provide a homeostatic pathway for maintaining cellular ATP levels. The cardiolipin-stabilizing compound SS-31 similarly reverses fragmentation through a Drp1-dependent mechanism, but it does not affect ATP levels. The combination of TAT-P110 and SS-31 does not affect FRDA patient fibroblasts differently from SS-31 alone, suggesting that the two drugs act through the same pathway but differ in their ability to alter mitochondrial homeostasis. In approaching potential therapeutic strategies for FRDA, an important criterion for compounds that improve bioenergetics should be to do so without impairing the homeostatic response of mitochondrial fragmentation.

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Scoliosis in Friedreich's ataxia: longitudinal characterization in a large heterogeneous cohort

The objective of this study was to characterize the incidence and progression of scoliosis in the natural history of Friedreich's ataxia (FRDA) and document the factors leading to the requirement for corrective surgery. Data on the prevalence of scoliosis and scoliosis surgery from up to 17 years of follow-up collected during a large natural history study in FRDA (1116 patients at 4928 visits) were summarized descriptively and subjected to time to event analyses. Well over 90% of early or typical FRDA patients (as determined by age of onset) developed intermediate to severe scoliosis, while patients with a later onset (>14 years) had no or much lower prevalence of scoliosis. Diagnosis of scoliosis occurs during the onset of ataxia and in rare cases even prior to that. Major progression follows throughout the growth phase and puberty, leading to the need for surgical intervention in more than 50% of individuals in the most severe subgroup. The youngest patients appear to delay surgery until the end of the growth period, leading to further progression before surgical intervention. Age of onset of FRDA before or after reaching 15 years sharply separated severe and relatively mild incidence and progression of scoliosis. Scoliosis is an important comorbidity of FRDA. This comprehensive documentation of scoliosis progression in this natural history study provides a baseline for comparison as novel treatments become available.

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