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.

Modelling Protein Plasticity: The Example of Frataxin and Its Variants

Botticelli, S.; La Penna, G.; Nobili, G.; Rossi, G.; Stellato, F.; Morante, S.; Molecules 2022, 27, 1955. doi:10.3390/molecules27061955 

Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the FXN gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich’s ataxia) and several types of cancer. By using altruistic metadynamics in conjunction with the maximal constrained entropy principle, we estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants. The sampled configurations highlight differences between the wild-type and mutated sequences in the stability of the folded state. In partial agreement with thermodynamic experiments, where most of the analyzed variants are characterized by lower thermal stability compared to wild type, the D104G variant is found with a stability comparable to the wild-type sequence and a lower water-accessible surface area. These observations, obtained with the new approach we propose in our work, point to a functional switch, affected by single-point mutations, of frataxin from iron storage to iron release. The method is suitable to investigate wide structural changes in proteins in general, after a proper tuning of the chosen collective variable used to perform the transition.

Control of arm movements in Friedreich's ataxia patients: role of sensory feedback

Zhang L, Straube A, Eggert T. ; Exp Brain Res. 2022 Mar 14. doi: 10.1007/s00221-022-06343-5. Epub ahead of print. PMID: 35286422. 

The model simulations revealed that the feedback delay, but not the feedback gain was affected in FA patients. They also showed that the descending control signal was scaled in time and amplitude and co-contraction was smaller in FA patients. Thus, our study explains how the motor deficits of FA patients result from pathological alterations of both top-down and feedback control.