New Funding Opportunities for Friedreich Ataxia Research from the DoD
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Friedreich Ataxia has been added to the list of topic areas eligible for $370M in funding by the Congressionally Directed Medical Research Programs (CDMRP), within the Peer-Reviewed Medical Research Programs (PRMRP). All organizations, including foreign organizations, foreign public entities, and international organizations, are eligible to apply. To see funding opportunities, click here.
For more information join us on Tuesday, April 5, 2022 at 2pm (ET) for an informational webinar with Cecilia Dupecher, Ph.D, Program Manager for PRMRP. Dr. Dupecher will review available funding opportunities, offer guidance on the application process, and answer questions. Register for the webinar here.
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The National Ataxia Foundation (NAF), the Friedreich’s Ataxia Research Alliance (FARA), and Ataxia UK are pleased to announce the rescheduled date for the inaugural International Congress for Ataxia Research (ICAR) to be held at Renaissance Dallas Addison Hotel in Dallas, Texas, USA. Please save the date for November 1-4, 2022.
Abstract submission and registration are now open here.
Abstract Submission Deadline: June 13th, 2022 (11:59pm ET)
Abstract Acceptance Announced: August 15th, 2022
For more information, click here.
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Stealth BioTherapeutics Receives Orphan Drug Designation from FDA for Elamipretide for the Treatment of Friedreich's Ataxia
Stealth BioTherapeutics Corp, a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, announced that the US FDA Office of Orphan Products Development has granted Orphan Drug Designation to elamipretide for the treatment of patients with Friedreich's ataxia. A phase 2a investigator-initiated trial evaluating elamipretide for the treatment of Friedreich's ataxia has been initiated at Children's Hospital of Philadelphia (CHOP) under the direction of Dr. David Lynch. The trial is evaluating two doses of elamipretide in patients with Friedreich's ataxia to assess safety, visual function, and cardiac function. Click here to read the full press release.
Design Therapeutics Completes Dosing in First Patient Cohort of Phase 1 Trial of DT-216 GeneTAC™ Molecule for the Treatment of Friedreich Ataxia
Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for degenerative genetic disorders, announced that it has completed dosing in the first single ascending dose (SAD) cohort of its Phase 1 clinical trial of DT-216 in patients with Friedreich ataxia (FA). DT-216 is a novel GeneTAC™ gene targeted chimera small molecule designed to specifically target the GAA repeat expansion mutation, the underlying cause of FA, and restore frataxin (FXN) gene expression. Additionally, Design announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to DT-216 for the treatment of patients with FA. Click here to read the full press release.
Reata Pharmaceuticals Completes Rolling Submission of New Drug Application for Omaveloxolone for the Treatment of Patients with Friedreich’s Ataxia
Reata Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, today announced the completion of the rolling submission of a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia. This NDA is supported by the efficacy and safety data from the MOXIe Part 1, Part 2, and MOXIe Extension studies. The FDA has granted Fast Track Designation and Orphan Drug Designation to omaveloxolone for the treatment of Friedreich’s ataxia. Click here to read the full press release.
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The FARA Ambassador Team hosts a weekly interview series called "Meet the Community." Each week they introduce a new member of the global FA community. This week, let's meet Jakub from the Czech Republic. Jakub is a researcher at a university who makes contributions to his team through his work on mathematics and programming. When he is not working, Jakub loves to spend time outdoors, fishing, and exercising.
Jakub's offers this advice to others, "Do not panic, FA is not the end of the world. Remember you are a free person. Freedom also means responsibility and you (and nobody else) are responsible for your life." Click here to read the full interview with Jakub.
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Recent FARA Funded FA Publications: |
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Selected Histone Deacetylase Inhibitors Reverse the Frataxin Transcriptional Defect in a Novel Friedreich's Ataxia Induced Pluripotent Stem Cell-Derived Neuronal Reporter System.
Schreiber AM, Li Y, Chen YH, Napierala JS, Napierala M.
In this study the investigators created a novel reporter cell line containing an FXN-Nanoluciferase (FXN-NLuc) fusion in induced pluripotent stem cells (iPSCs) reprogrammed from the fibroblasts of patients with FRDA, thus allowing quantification of endogenous FXN expression. A commercially available library of compounds consisting of molecules targeting various enzymes and pathways critical for silencing or activation of gene expression was screened in neural progenitor cells derived from the FXN-NLuc line. Only selected histone deacetylase inhibitors were capable of partial reactivation of FXN expression.
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Friedreich's Ataxia Related Diabetes: Epidemiology and Management Practices.
Tamaroff J, DeDio A, Wade K, Wells M, Park C, Leavens K, Rummey C, Kelly A, Lynch DR, McCormack SE.
The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related diabetes mellitus (DM). The authors performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk.
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Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice.
Kilikevicius A, Wang J, Shen X, Rigo F, Prakash TP, Napierala M, Corey DR.
This study investigates the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. After confirming successful in vivo delivery of oligonucleotides using a benchmark gapmer targeting the nuclear noncoding RNA Malat1, the authors tested anti-FXN oligonucleotides designed to function by various mechanisms. None of these strategies yielded enhanced expression of FXN in the model mice.
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Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich's Ataxia.
Monfort B, Want K, Gervason S, D'Autréaux B.
The authors review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.
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DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.
Rodden LN, Gilliam KM, Lam C, Rojsajjakul T, Mesaros C, Dionisi C, Pook M, Pandolfo M, Lynch DR, Blair IA, Bidichandani SI.
In this study, the authors show that frataxin-E, a lesser known extramitochondrial isoform of frataxin detected in erythrocytes, is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E.
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Serum glial fibrillary acidic protein is a body fluid biomarker: A valuable prognostic for neurological disease - A systematic review.
Heimfarth L, Passos FRS, Monteiro BS, Araújo AAS, Quintans Júnior LJ, Quintans JSS.
This systematic review analyzed studies published between January 2012 and September 2021 that used glial fibrillary acidic protein (GFAP) as a potential blood biomarker to detect neurological disorders. This review suggests that elevated GFAP level is a potentially valuable diagnostic biomarker in the evaluation of different neurological diseases.
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In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.
Huichalaf C, Perfitt TL, Kuperman A, Gooch R, Kovi RC, Brenneman KA, Chen X, Hirenallur-Shanthappa D, Ma T, Assaf BT, Pardo I, Franks T, Monarski L, Cheng TW, Le K, Su C, Somanathan S, Whiteley LO, Bulawa C, Pregel MJ, Martelli A.
In this study the authors, while evaluating an AAV9-based frataxin gene therapy using a chicken β-actin promoter, showed that toxic overexpression of frataxin could be reached in mouse liver and heart with doses between 1 × 1013 and 1 × 1014 vg/kg. In a mouse model of cardiac disease, these doses only corrected cardiac dysfunction partially and transiently and led to adverse findings associated with iron-sulfur cluster deficiency in liver.
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Downregulation of Three Immune-Specific Core Genes and the Regulatory Pathways in Children and Adult Friedreich's Ataxia: A Comprehensive Analysis Based on Microarray.
Liu L, Lai Y, Zhan Z, Fu Q, Jiang Y.
This study identified the up-regulated and down-regulated differentially expressed genes (DEGs) in children and adult FRDA from the GSE11204 dataset and intersected them to determine the co-expressed DEGs (co-DEGs). Enrichment analysis suggested that these co-DEGs were primarily enriched in immune response, inflammatory reaction, and necroptosis.
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Heat and cold denaturation of Yeast frataxin: the effect of pressure.
Puglisi R, Cioni P, Gabellieri E, Presciuttini G, Pastore A, Temussi PA.
Here, the authors present the phase diagram of Yfh1 unfolding as a function of pressure (0.1 - 500 MPa) and temperature 278 - 313 K (5 - 40 °C) both in the absence and in the presence of stabilizers using Trp fluorescence as a monitor. The protein showed a remarkable sensitivity to pressure.
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Cur@SF NPs alleviate Friedreich's ataxia in a mouse model through synergistic iron chelation and antioxidation.
Xu L, Sun Z, Xing Z, Liu Y, Zhao H, Tang Z, Luo Y, Hao S, Li K.
Here, the authors synthesized slow-release nanoparticles (NPs) by loading curcumin (Cur) into silk fibroin (SF) to form NPs with an average size of 150 nm (Cur@SF NPs), which exhibited satisfactory therapeutic effects on the improvement of FRDA phenotypes in lymphoblasts (1 μM) derived from FRDA patients and in YG8R mice (150 mg/kg/5 days).
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Gene therapy for Friedreich ataxia: Too much, too little, or just right?
Payne RM.
This is an editorial commenting on the article by Huichalaf et al. “In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.” published in Molecular Therapy: Methods & Clinical Development.
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The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis.
Naeije G, Schulz JB, Corben LA.
This study analyzes the cognitive profile of individuals with Friedreich ataxia and seeks evidence for correlations between clinical, genetic and imaging characteristics and neuropsychological impairments.
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Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias.
Deistung A, Jäschke D, Draganova R, Pfaffenrot V, Hulst T, Steiner KM, Thieme A, Giordano IA, Klockgether T, Tunc S, Münchau A, Minnerop M, Göricke SL, Reichenbach JR, Timmann D.
In this exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias.
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Control of arm movements in Friedreich's ataxia patients: role of sensory feedback.
Zhang L, Straube A, Eggert T.
Here, the authors investigated single-joint movements of the upper limb in FA patients. This study explains how the motor deficits of FA patients result from pathological alterations of both top-down and feedback control.
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Modelling Protein Plasticity: The Example of Frataxin and Its Variants.
Botticelli S, La Penna G, Nobili G, Rossi G, Stellato F, Morante S.
This study used altruistic metadynamics in conjunction with the maximal constrained entropy principle to estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants.
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Recessive cerebellar and afferent ataxias - clinical challenges and future directions.
Beaudin M, Manto M, Schmahmann JD, Pandolfo M, Dupre N.
In this review, the authors discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype-phenotype correlations.
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Should Advanced Friedreich's Ataxia Be a Contraindication for Heart Transplantation? A Case Report of a Successful Procedure in a 58-Year-Old Patient.
Valero MJ, Muñoz-Blanco JL, Sanchez AG, Cuerpo G, Castrodeza J, Navas P, Sousa I, Villa A, Fernández-Avilés F, Martínez-Sellés M.
Here the authors present the case of a 58-year-old patient with advanced FA, admitted for a refractory arrhythmic storm, who underwent heart transplantation.
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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. Here are the next dates:
April 12, 2022
12:00 PM ET Masimo Pandolfo, McGill University
May 10, 2022
6:00 PM ET Christina Cortez-Jugo, University of Melbourne
There will be no forum in June.
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FARA Newly Awarded Research Grants
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General research grant
Mark Payne, MD & Thomas O’Connell, PhD - Indiana University School of Medicine
Diagnostic and Mechanistic Validation of a Metabolic Biomarker Panel to Guide Therapeutic Interventions in Friedreich’s Ataxia
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Meetings of Interest to the FA Community |
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The Ataxia Global Initiative (AGI) is holding a webinar series called Young Investigator Initiative (YII). The next webinar “Standard clinical assessment in ataxia” will be held on Tuesday May 17, 2022 at 5pm CEST. You can register and find more information on upcoming webinars here.
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General Research Grants – next LOI deadline is August 15, 2022. See FARA grant program priorities here.
The Chan Zuckerberg Initiative invites applications from collaborative teams bringing together patient-led rare disease organizations and research teams for 4-year research projects aimed at advancing our understanding of the fundamental science of rare diseases.
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RFA for Patient-Partnered Collaborations for Single-Cell Analysis of Rare Inflammatory Pediatric Disease – application deadline is May 24, 2022.
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RFA for Patient-Partnered Collaborations for Rare Neurodegenerative Disease – application deadline is May 24, 2022.
CIRM - Various grant opportunities for stem cell-related projects in California.
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