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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.

Request For Proposals: Pharmacodynamic Biomarker Development

 

Request For Proposals: Pharmacodynamic Biomarker Development

FARA is issuing a request for proposals (RFP) to support clinical drug development programs in Friedreich’s ataxia (FRDA) by promoting the discovery of technologies to measure frataxin or surrogates of frataxin in inaccessible and disease relevant tissues.

This RFP supports the discovery and validation of non-invasive and quantitative methodologies to measure the following in FRDA affected tissues (brain, spinal cord or heart):

  • Frataxin protein levels
  • Biochemical activities dependent on/downstream of frataxin function that can be surrogates of frataxin in inaccessible tissues

Allowed budget will depend on stage and scope of research.

FARA will consider proof of concept and high-risk proposals, without preliminary data, provided they show a strong rationale for the proposed use and development of such biomarkers.

Informal inquiries regarding study relevance and interest to FARA are welcome and should be directed to grants@curefa.org.

Read the Full RFP


Please click below to submit a Letter of Intent.The LOI submission deadline is December 1, 2021.

Submit a Letter of Intent


 

 

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia

The objective of this study was to assess skeletal muscle oxidative metabolism in vivo in adults with FRDA as compared to adults without FRDA using chemical exchange saturation transfer (CrCEST) MRI, which measures free creatine (Cr) over time following an in-magnet plantar flexion exercise. Participants included adults with FRDA (n = 11) and healthy adults (n = 25). All underwent 3-Tesla CrCEST MRI of the calf before and after in-scanner plantar flexion exercise. Participants also underwent whole-body dual-energy X-ray absorptiometry (DXA) scans to measure body composition and completed questionnaires to assess physical activity. In adults with FRDA (vs. healthy adults), prolonged post-exercise exponential decline in CrCEST (τCr) in the lateral gastrocnemius (LG, 274 s vs. 138 s, p = 0.01) was observed, likely reflecting decreased OXPHOS capacity. Adults with FRDA (vs. healthy adults) also engaged different muscle groups during exercise, as indicated by muscle group-specific changes in creatine with exercise (∆CrCEST), possibly reflecting decreased coordination. Across all participants, increased adiposity and decreased usual physical activity were associated with smaller ∆CrCEST. In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

Read the Full article here
 

Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18 F]-FEMPA PET Study

Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. The purpose of this study was to examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. [18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all rpart < -0.6), and in the pons and anterior lobe with shorter disease duration (r = -0.66; -0.73). Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness.

Read the Full article here
 

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.

Read the Full article here
 

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.

Read the Full article here
 

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