Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: studies using Mössbauer spectroscopy and mathematical modeling

Fernandez, Salvador et al., Journal of Biological Chemistry, Volume 0, Issue 0, 101921, doi:10.1016/j.jbc.2022.101921

 Simulations suggested partially independent regulation in which cellular iron import is regulated by ISC activity in mitochondria, mitochondrial iron import is regulated by a mitochondrial FeII pool, and vacuolar iron import is regulated by cytosolic FeII and mitochondrial ISC activity.

Serum glial fibrillary acidic protein is a body fluid biomarker: A valuable prognostic for neurological disease – A systematic review

Luana Heimfarth, Fabiolla Rocha Santos Passos, Brenda Souza Monteiro, Adriano Antunes de Souza Araújo, Lucindo José Quintans Júnior, Jullyana de Souza Siqueira Quintans, International Immunopharmacology, Volume 107, 2022, 108624, ISSN 1567-5769, doi:10.1016/j.intimp.2022.108624. 

Astrocytes are the most abundant cell type in the human central nervous system, and they play an important role in the regulation of neuronal physiology. In neurological disorders, astrocyte disintegration leads to the release of glial fibrillary acidic protein (GFAP) from tissue into the bloodstream. Elevated serum levels of GFAP can serve as blood biomarkers, and a useful prognostic tool to facilitate the early diagnosis of several neurological diseases ranging from stroke to neurodegenerative disorders. This systematic review synthesizes studies published between January 2012 and September 2021 that used GFAP as a potential blood biomarker to detect neurological disorders. The following electronic databases were accessed: MEDLINE, Scopus, and Web of Science. In all the databases, the following search strategy was used: ¨GFAP¨ OR ¨glial fibrillary acidic protein¨ AND ¨neurological¨ OR ¨neurodegenerative¨ AND ¨plasma¨ OR ¨serum¨. The initial search identified 1152 articles. After the exclusion criteria were applied, 48 publications that reported GFAP levels in neurological disorders were identified. A total of16 different neurological disorders that have plasmatic GFAP levels as a possible biomarker for the disease were described in the articles, being: multiple sclerosis, frontotemporal lobar degeneration, Alzheimer’s disease, Parkinson disease, COVID-19, epileptic seizures, Wilson Disease, diabetic ketoacidosis, schizophrenia, autism spectrum disorders, major depressive disorder, glioblastoma, spinal cord injury, asthma, neuromyelitis optica spectrum disorder and Friedreich’s ataxia. Our review shows an association between GFAP levels and the disease being studied, suggesting that elevated GFAP levels are a potentially valuable diagnostic biomarker in the evaluation of different neurological diseases.

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E

Layne N. Rodden, Kaitlyn M. Gilliam, Christina Lam, Teerapat Rojsajjakul, Clementina Mesaros, Chiara Dionisi, Mark Pook, Massimo Pandolfo, David R. Lynch, Ian A. Blair & Sanjay I. Bidichandani. Sci Rep 12, 5031 (2022). https://doi.org/10.1038/s41598-022-09002-5 

A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E 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. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.

Design Therapeutics Completes Dosing in First Patient Cohort of Phase 1 Trial of DT-216 GeneTAC™ Molecule for the Treatment of Friedreich Ataxia

CARLSBAD, Calif., March 30, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for degenerative genetic disorders, today 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.

Reata Pharmaceuticals Completes Rolling Submission of New Drug Application for Omaveloxolone for the Treatment of Patients with Friedreich’s Ataxia

PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA), (“Reata,” the “Company,” “our,” “us,” or “we”), 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.

Stealth Bio's Elamipretide Gets Orphan Drug Designation From FDA For Friedreich's Ataxia

BOSTON, March 28, 2022 /PRNewswire/ -- Stealth BioTherapeutics Corp (Nasdaq:MITO), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, announced today that the US Food and Drug Administration (FDA) Office of Orphan Products Development has granted Orphan Drug Designation to elamipretide for the treatment of patients with Friedreich's ataxia. 

ELVIS-FA , 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. 

ClinicalTrials.gov Identifier: NCT05168774. Phase 1, Phase 2. Drug: Elamipretide. Elamipretide is a tetra peptide with limited blood brain barrier penetration being developed for use in a variety of mitochondrial disorders, including FRDA, mitochondrial myopathy and Barth Syndrome.Other Names: MTP-131, SS-31

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Mercado-Ayón E, Warren N, Halawani S, Rodden LN, Ngaba L, Dong YN, Chang JC, Fonck C, Mavilio F, Lynch DR and Lin H (2022). Front. Neurosci. 16:819569. doi: 10.3389/fnins.2022.819569 

Taken together, our findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function.

The U.S. Food and Drug Administration granted orphan drug designation to elamipretide to treat Friedreich’s ataxia (FRDA).

 U.S. Food and Drug Administration, 03/22/2022

Generic Name:	elamipretide
Date Designated:	03/22/2022
Orphan Designation:	Treatment of Friedreich’s ataxia (FRDA)
Orphan Designation Status:	Designated
FDA Orphan Approval Status:	Not FDA Approved for Orphan Indication
Sponsor:	Stealth BioTherapeutics 275 Grove Street, Suite 3-107 Newton, Massachusetts 02466 United States The sponsor address listed is the last reported by the sponsor to OOPD.

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.; Brain Commun. 2022 Jan 13;4(1):fcab306. doi: 10.1093/braincomms/fcab306. PMID: 35291442; PMCID: PMC8914888. 

 Findings in FRDA were compared with findings in the most common forms of dominantly inherited ataxias [spinocerebellar ataxia types 1, 2, 3 and 6 (SCA1,2,3,6)] and a common form of non-hereditary degenerative ataxia [multiple system atrophy, cerebellar type (MSA-C)]. QSM revealed different patterns of abnormalities in the dentate nuclei. Abnormalities in susceptibility were most pronounced in SCA1, MSA-C and SCA6 patients. While susceptibility was significantly higher in SCA1 and MSA-C, it was significantly lower in SCA6 compared with healthy controls. Smaller changes in susceptibility were found in the dentate nuclei in FRDA and SCA2 and no change in SCA3 patients. Our data suggest that changes in iron concentration may contribute to the pathogenesis of a subset of cerebellar ataxias or at least be a result or indicator of the underlying pathology.

Study to Evaluate DT-216 in Adult Patients With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05285540. First Posted : March 17, 2022 

The purpose of this study Phase 1 is to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects of intravenous DT-216 in adult patients with Friedreich Ataxia. This single ascending dose study is randomized, double-blind, placebo-controlled.