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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.

Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation

Cardiac dysfunction pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood in Friedreich's ataxia (FRDA), though are expected to be linked to an energy deficit. The authors modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. These results suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

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Reata Pharmaceuticals Plans NDA Submission for Omaveloxolone in First Quarter of 2022 Following Completion of Pre-NDA Meeting with FDA

Approximately 5,000 Children and Adults in the United States and 22,000 Globally Are Affected with Friedreich’s Ataxia, a Life-Threatening Disease with No Approved Therapies

PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it has completed its pre-New Drug Application (“NDA”) meeting with the United States Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia and reaffirmed its plan to submit an NDA in the first quarter of 2022.

The purpose of the pre-NDA meeting was to discuss the content of Reata’s planned NDA submission. We plan to submit the NDA seeking standard approval for omaveloxolone for the treatment of Friedrich’s ataxia. We are not planning to conduct a second pre-approval clinical study prior to the submission. The FDA indicated that the appropriate approval pathway would be a matter of review after submission of the NDA. In response to our questions about the contents of the filing and because of the seriousness of the indication, the FDA exercised its discretion subject to review to permit us to submit the results of certain nonclinical and clinical studies after approval.

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Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia

This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub-second dynamics of resting-state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA-related changes in resting-state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting-state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12-51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median-split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo-parietal junctions (TPJ). FRDA patients with an ASO <11 years presented altered temporal dynamics of those two HMM states compared with FRDA patients with an ASO >11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute-long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub-second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub-second network activity and functional brain integration over long timescales.

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Friedreich Ataxia: Multidisciplinary Clinical Care

Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000-100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.

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A Focus on "Bio" in Bio-Nanoscience: The Impact of Biological Factors on Nanomaterial Interactions

Bio-nanoscience research encompasses studies on the interactions of nanomaterials with biological structures or what is commonly referred to as the biointerface. Fundamental studies on the influence of nanomaterial properties, including size, shape, composition, and charge, on the interaction with the biointerface have been central in bio-nanoscience to assess nanomaterial efficacy and safety for a range of biomedical applications. However, the state of the cells, tissues, or biological models can also influence the behavior of nanomaterials at the biointerface and their intracellular processing. Focusing on the "bio" in bio-nano, this review discusses the impact of biological properties at the cellular, tissue, and whole organism level that influences nanomaterial behavior, including cell type, cell cycle, tumor physiology, and disease states. Understanding how the biological factors can be addressed or exploited to enhance nanomaterial accumulation and uptake can guide the design of better and suitable models to improve the outcomes of materials in nanomedicine.

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