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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.


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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Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions

This paper reviews some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.

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An unusual combination of large Eustachian valve in a young patient with Friedreich's ataxia cardiomyopathy

A 20-year-old male with Friedreich ataxia (FA) presented with dyspnea and palpitations over the prior 2 days. Atrial fibrillation with rapid ventricular response and inverted T waves in leads III, aVF, V5, V6 were found on the electrocardiogram. The transthoracic echocardiogram, with the patient being in atrial fibrillation, showed concentric hypertrophy and left ventricular ejection fraction of approximately 50%. Surprisingly, an incomplete membrane into the right atrium was noted. Cardiac magnetic resonance imaging was performed and documented the presence of large Eustachian valve in the presence of cardiomyopathy.

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Generation of a Friedreich's Ataxia patient-derived iPSC line USFi001-A

This paper presents the generation of an induced pluripotent stem cell (iPSC) line from an FA patient with a homozygous GAA expansion in intron 1 of the FXN gene. The IPSCs display pluripotent cell morphology, expression of pluripotency markers, normal karyotype, and the capability to differentiate into all three germ layers.

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The Oxford-Harrington Rare Disease Centre initiates first disease priority area: Friedreich's Ataxia

The Oxford-Harrington Rare Disease Centre is redoubling efforts to develop a therapeutics programme for Friedreich’s Ataxia.

Friedreich’s Ataxia (FA) is a debilitating, life-shortening, degenerative neuromuscular rare disorder, with onset during childhood. Despite high levels of existing medical research around FA, significant further progress is needed to advance new treatments.

The Oxford-Harrington Rare Disease Centre (OHC) has the expertise and capability to contribute to the major effort underway aimed at developing effective treatments for FA in the near future. The OHC combines the University of Oxford and the Harrington Discovery Institute's world-leading strengths in research and therapeutics development. The OHC was formed to set the science and innovation agenda, driving cutting-edge rare disease breakthroughs to address the unmet need in rare disease across the globe and to deliver major clinical impact for patients. Friedreich’s Ataxia is a compelling initial focus area given this goal.

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