RFP Pharmacodynamic Biomarker Development: LOI submission deadline is December 1, 2021
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FARA is issuing a request for proposal (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.
FARA will consider proof of concept and high-risk proposals.
You can access the full RFP here.
Please submit a Letter of Intent here.
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ICAR2022: Abstract submission deadline has been extended to December 1, 2021
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The inaugural International Congress for Ataxia Research (ICAR) will be held at the Caribe Royale resort in Orlando, Florida, USA. Please save the date for March 15th – 18th, 2022.
You can submit your abstract and register here.
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In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.
Schur GM, Dunn J, Nguyen S, Dedio A, Wade K, Tamaroff J, Mitta N, Wilson N, Reddy R, Lynch DR, McCormack SE.
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. 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. 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.
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Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18 F]-FEMPA PET Study
Khan W, Corben LA, Bilal H, Vivash L, Delatycki MB, Egan GF, Harding IH.
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. [18 F]-FEMPA binding was significantly increased in the dentate nuclei, superior cerebellar peduncles, and midbrain, alongside increased plasma interleukin-6 (IL-6), 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 and in the pons and anterior lobe with shorter disease duration.
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Targeting 3' and 5' untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression.
Li Y, Li J, Wang J, Lynch DR, Shen X, R Corey D, Parekh D, Bhat B, Woo C, Cherry JJ, Napierala JS, Napierala M.
This work pursued a novel approach based on oligonucleotide-mediated targeting of FXN mRNA ends to extend its half-life and availability as a template for translation. This group demonstrated that oligonucleotides designed to bind to FXN 5' or 3' noncoding regions can increase FXN mRNA and protein levels. Simultaneous delivery of oligonucleotides targeting both ends increases efficacy of the treatment. Mechanistically, a significant elongation of the FXN mRNA half-life without any changes in chromatin status at the FXN gene was observed upon treatment with end-targeting oligonucleotides.
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Other FA Research Publications, October 2021 |
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Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study.
Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V, Stuart G, Uzun O, McLeod KA, Ilina M, Adwani S, Daubeney P, Delle Donne G, Linter K, Jones CB, Bharucha T, Cervi E, Kaski JP.
This study aimed to describe the clinical characteristics of children with Friedreich's ataxia hypertrophic cardiomyopathy (FA-HCM). This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.
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Designing phase II clinical trials in Friedreich ataxia.
Rodden LN, Lynch DR.
In this review, the authors summarize data from major phase II clinical trials in FRDA published between 2015 and 2020 which includes A0001/EPI743, Omaveloxolone, RT001, and Actimmune. The authors outline critical lessons that have been learned and that should be incorporated into future trial design to ultimately optimize drug development in FRDA.
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Construction of DNA/RNA Triplex Helices Based on GAA/TTC Trinucleotide Repeats.
Zhang J, Fakharzadeh A, Pan F, Roland C, Sagui C.
This work focuses on the construction of DNA triplexes and RNA/DNA hybrids formed from GAA/TTC trinucleotide repeats. In this protocol, the authors illustrate how to build up more generalized DNA triplexes and DNA/RNA mixed hybrids by making use of both the Discovery Studio Visualizer and the AMBER simulation package to construct the initial triplexes.
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Mitochondrial Iron-Sulfur Cluster Biogenesis and Neurological Disorders.
Selvanathan A, Parayil Sankaran B.
This review focuses on the disorders of iron-sulfur clusters (ISCs) biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features are discussed, providing a reference point for clinicians diagnosing and managing these patients.
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Longitudinal investigation of brain activation during motor tasks in Friedreich ataxia: 24-month data from IMAGE-FRDA.
Shishegar R, Harding IH, Selvadurai LP, Corben LA, Delatycki MB, Egan GF, Georgiou-Karistianis N.
In this study, the authors investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. This study demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus.
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Tract-Specific Spinal Cord Diffusion Tensor Imaging in Friedreich's Ataxia.
Hernandez ALCC, Rezende TJR, Martinez ARM, de Brito MR, França MC Jr.
This cross-sectional study evaluates microstructural integrity in spinal cord (SC) white matter (WM) tracts of FRDA patients using diffusion tensor imaging (DTI) with an automated analysis pipeline. DTI uncovered abnormalities in SC WM tracts, which correlated with clinical features in FRDA. SC WM microstructure is a potential neuroimaging biomarker to be explored in the disease.
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The FARA Forum is a monthly webinar featuring investigators who have been awarded FARA grants. The webinar is open to FARA grant awardees, and it is held on the second Tuesday of every month. Upcoming Dates:
December 14, 2021
12:00 PM ET Vania Broccoli, San Raffaele Scientific Institute and CNR Institute of Neuroscience, Milan
12:45 PM ET Katia Aquilano, University of Rome Tor Vergata
January 11, 2022
5:00 PM ET Elena Dedkova, University of California, Davis
5:45 PM ET Jarmon Lees, St Vincent's Institute of Medical Research, Melbourne
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FARA Newly Awarded Research Grants |
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Kyle Bryant Translational Research Award:
Arturo Sala, PhD – Brunel University, London
Therapeutic activity of a haemotopoietic stem cell delivered tissue penetrating peptide in a Friedreich's ataxia mouse model
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Meetings of Interest to the FA Community |
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Neuroscience 2021, November 13-17, 2021 - McCormick Place Convention Center, Chicago.
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FARA research grants: RFP – Pharmacodynamic biomarker development –LOI deadline is December 1, 2021; See FARA grant program priorities here.
CIRM - Various grant opportunities for stem cell-related projects in California.
- Discovery Awards - November 11, 2021
- Career Development Awards - November 16, 2021
- Early-Career Awards - February 15, 2022
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Post-doctoral fellow position – Mouro Pinto Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School
The Mouro Pinto Laboratory in the Center for Genomic Medicine at Massachusetts General Hospital and Harvard Medical School is seeking a highly motivated post-doctoral fellow candidate. The Lab is interested in repeat expansion disorders, such as Friedreich Ataxia and Huntington’s disease, with a major focus on the mechanisms responsible for repeat instability as potential therapeutic targets. The Lab uses both mouse and patient-derived cellular models, in combination with genome engineering tools, viral-based delivery techniques, and next-generation sequencing methods to identify genetic disease modifiers and develop novel methods for unbiased quantification of long somatic repeat expansions.
The major goal of this project is to determine the role of somatic FXN GAA repeat expansions in Friedreich ataxia-related phenotypes and testing of candidate therapeutics targeting this pathway. The ideal candidate would have significant expertise in various molecular biology techniques, animal handling, and mammalian cell culturing. Desirable skills also include gene expression analysis (RT-qPCR and RNAseq), differentiation of iPS cells, immunohistochemistry, CRISPR/Cas9-based genome editing, and bioinformatics analysis.
We offer competitive pay at NIH recommended level and assistance with visa application for international candidates. Interested applicants should contact Dr. Mouro Pinto (rmouropinto@mgh.harvard.edu) directly with their CV, a summary of their research accomplishments, and a brief description of research interests and career goals.
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Multiple positions – Napierala Laboratory, Peter O’Donnell Jr Brain Institute, UT Southwestern Medical Center
The Napierala laboratory now located at UT Southwestern’s Peter O’Donnell Jr Brain Institute has various job openings. The research is focused on Friedreich’s ataxia, specifically on the use of cell culture models, including induced pluripotent stem cells, and mouse models to study molecular mechanisms underlying the pathology of the disease. The primary aspects of the research include transcriptional regulation, mitochondria dysfunction and protein structure/function analyses and the use of multiple -omics approaches to identify new targets for therapeutic intervention.
The laboratory is also looking for postdocs and any interested candidate is welcome to send an email directly to Dr. Marek Napierala (mnapiera@uab.edu) or Dr. Jill Napierala (jsbutler@uab.edu) to inquire.
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