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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.

Pathology of Intercalated Discs in Friedreich Cardiomyopathy

Friedreich ataxia (FA) is best known for its neurological phenotype, but the most common cause of death is heart disease. This paper describes the FA heart based on studies from post-mortem tissue. The pathogenesis of FA cardiomyopathy includes failure to clear iron from myocytes, chronic inflammation, fiber necrosis, and scarring. On cross section, heart fibers are significantly enlarged and excessively lobulate. In the longitudinal dimension, the pathogenesis also involves modifications of intercalated discs (ICDs), the plasma membrane specializations that connect heart fibers end-to-end. The authors show that some of the unusual features of the FA heart likely precede active cardiac disease, and may or may not be able to be resolved by increasing frataxin later in disease.

Read the entire article HERE

FARA Announces Catabasis Pharmaceuticals as the Recipient of the Kyle Bryant Translational Research Award to Evaluate CAT-4001 as a Potential Therapy for Friedreich’s Ataxia

Downingtown, PA and Cambridge, MA (January 19, 2016) - The Friedreich’s Ataxia Research Alliance (FARA) and Catabasis Pharmaceuticals, Inc. (NASDAQ:CATB) announce that Catabasis Pharmaceuticals is the recipient of the Kyle Bryant Translational Research Award. Catabasis is a clinical-stage drug development company built on a pathway pharmacology technology platform. The two year award will be for the Evaluation of CAT-4001 in Frataxin-deficient mouse models and dorsal root ganglia neurons to enable its therapeutic development for Friedreich's ataxia. This work will be led by Dr. Andrew Nichols at Catabasis along with collaborators Dr. Mark Payne at Indiana University and Dr. Jordi Magrane at Weill Cornell College of Medicine who are expected to perform testing in the Friedreich’s ataxia (FA) animal models.

Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia

This is a large international, collaborative study that reviews both the clinical and frataxin protein differences among 111 individuals with FA who are compound heterozygous for a point mutation on one gene and a GAA repeat expansion on the other FXN gene. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses. In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provides a definitive resource for investigating disease pathogenesis in FRDA.

Read more here:

Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

This publication includes a description and characterization of 18 fibroblast lines derived from FA patients with diverse GAA repeat lengths. This is the largest collection of these cell lines. Researchers can contact the study authors or FARA if they are interested in learning more accessing these cell lines. In addition, this comprehensive analysis revealed that the GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. Furthermore, no long-range silencing effects were detected across a large portion of chromosome 9. Additionally, results of chromatin immunoprecipitation studies confirmed that histone modifications associated with repressed transcription are confined to the FXN locus. Finally, deep sequencing of FXN pre-mRNA molecules revealed a pronounced defect in the transcription elongation rate in FRDA cells when compared to controls. These results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.

Read more: Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

Frataxin levels in peripheral tissue in Friedreich ataxia

Have you ever given a blood sample or cheek swab sample for research? This study shares results of frataxin protein measures from more than >500 individuals with FA, including some specific results on frataxin levels in in individuals who have point mutations. This study finds that there was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood.

Read more: Frataxin levels in peripheral tissue in Friedreich ataxia

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