Clinical Evidence for Variegated Silencing in Patients With Friedreich Ataxia

Layne N. Rodden, Christian Rummey, Yi Na Dong, David R. Lynch; Neurol Genet Jun 2022, 8 (3) e683; DOI: 10.1212/NXG.0000000000000683

In the variegated silencing model in PBMCs, the proportion of spared cells decreases with increasing GAA-TR length until it plateaus at 500 triplets, at which the maximum of both number of silenced cells and severity of FXN deficiency has been reached. If such an effect occurs in affected tissues in patients, there should be a similar ceiling effect of GAA-TR length on clinical severity. Patients with GAA-TR levels greater than this ceiling would constitute a subpopulation with relatively similar frataxin levels and potentially more homogeneous clinical features when controlling for disease duration and age. Based on the variegated silencing model described in PBMCs, we aimed to determine whether the clinical features of FRDA reach a similar ceiling in which severity of symptoms reaches a maximum and worsens minimally past a certain GAA-TR length.

Anaesthesia for a patient with Friedreich’s ataxia undergoing emergency tibia interlocking nail insertion

Ahmed Abd Elmohsen Bedewy (2022), Egyptian Journal of Anaesthesia, 38:1, 324-325, DOI: 10.1080/11101849.2022.2082789

Friedreich’s ataxia has many effects on various systems of the body especially the nervous system and the heart that makes delivery of anaesthesia such a critical situation that should be dealt with caution.

Lexeo to start phase I/II clinical trial for patients with Friedreich’s ataxia cardiomyopathy

May 26, 2022 -- Gene therapy company Lexeo Therapeutics in 2022 plans to launch a phase I/II clinical trial of its adeno-associated virus-based therapy designed to intravenously deliver a functional frataxin gene for the treatment of Friedreich’s ataxia (FA) cardiomyopathy. CEO Nolan Townsend told ScienceBoard.net at the American Society of Gene & Cell Therapy (ASGCT) 2022 annual meeting in Washington, DC that LX2006, whose investigational new drug application was recently cleared by the U.S. Food and Drug Administration, is the first disease-modifying, clinical-stage gene therapy treatment for Friedreich's ataxia and the first clinical-stage program from the company's cardiovascular gene therapy pipeline.

Reata Pharmaceuticals Announces FDA Filing Acceptance and Priority Review Designation for the NDA for Omaveloxolone for the Treatment of Patients with Friedreich’s Ataxia

May 26, 2022. PLANO, Texas--(BUSINESS WIRE)-Today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing and granted Priority Review of its New Drug Application (“NDA”) for omaveloxolone for the treatment of patients with Friedreich’s ataxia. The FDA indicated that at this time it has not identified any potential review issues. The NDA is supported by the efficacy and safety data from the MOXIe Part 2 trial and additional supporting data from the MOXIe Part 1 and MOXIe Extension trials. Omaveloxolone received Fast Track Designation in November 2021 and Rare Pediatric Disease Designation in May 2022. The FDA grants Priority Review to medicines that may offer significant improvements in the treatment, diagnosis, or prevention of a serious condition. This Designation shortens the FDA’s review of the NDA to eight months from the time of submission, versus a standard review timeline of 12 months. The FDA has assigned a Prescription Drug User Fee Act (“PDUFA”) target action date of November 30, 2022. The FDA indicated it is currently planning to hold an advisory committee meeting to discuss the application. “We are pleased with the FDA’s decision to grant Priority Review to our NDA for omaveloxolone for the treatment of patients with Friedreich’s ataxia in the United States,” said Warren Huff, Reata’s Chief Executive Officer. “With the FDA’s acceptance of our NDA for filing, omaveloxolone is now one step closer to potentially providing a treatment option for patients with Friedreich’s ataxia, a rare, genetic, debilitating, and degenerative neuromuscular disorder with no approved therapies. We look forward to working with the FDA during the review process, and if approved, we are looking forward to a commercial launch in early 2023.”

A comprehensive Triple Repeat Primed PCR (TR-PCR) and a Long-Range PCR (LR-PCR) agarose-based assay for improved genotyping of GAA repeats in Friedreich’s Ataxia

Mohamed Jama, Rebecca L. Margraf, Ping Yu, N. Scott Reading, Pinar Bayrak-Toydemir; The Journal of Molecular Diagnostics, 2022, doi:10.1016/j.jmoldx.2022.04.008. 

A two-tier genotyping assay with an improved triple-repeat primed PCR (TR-PCR) for alleles < 200 GAA repeats (± 1-5 repeats), and an agarose gel-based, long-range PCR (LR-PCR) assay to genotype expanded alleles > 200 GAA repeats (± 50 repeats) is described. Of the 1236 DNA samples tested using TR-PCR, 31 were identified to have expanded alleles >200 repeats and were reflexed to the LR-PCR procedure for confirmation and quantification. The TR-PCR assay described here, is a diagnostic genotyping assay which reduces the need for further testing. The LR-PCR component is a confirmatory test for true homozygous and heterozygous samples with normal and expanded alleles as indicated by the TR-PCR assay. The use of this two-tier methodology offers a comprehensive evaluation to detect and genotype the smallest and largest number of GAA repeats, improving the classification of FXN alleles as normal, mutable normal, borderline and expanded alleles.

A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models

Abeti R, Jasoliya M, Al-Mahdawi S, Pook M, Gonzalez-Robles C, Hui CK, Cortopassi G and Giunti P (2022). Front. Mol. Biosci. 9:830650. doi: 10.3389/fmolb.2022.830650 

Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.

Towards a metabolomic approach to investigate iron-sulfur cluster biogenesis

Marengo M, Fissore A, Oliaro-Bosso S, Adinolfi S, Pastore A.; IUBMB Life. 2022 Apr 27. doi: 10.1002/iub.2618. Epub ahead of print. PMID: 35474632. 

Our data prove that this ex vivo approach closely reproduces the in vitro results while retaining the full complexity of the system. We demonstrate that co-presence of bacterial frataxin and iron is necessary to observe an inhibitory effect of the enzymatic activity of bacterial frataxin. Our approach provides a new powerful tool for the study of iron-sulfur cluster biogenesis.

Novel Regulatory Role of SIRT3 on Cardiomyocyte Mitochondrial Frataxin and Ferroptosis

Cantrell A, Su H, Zeng H, Chen JX.; FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R2008. PMID: 35557151. 

We have demonstrated that cardiomyocyte SIRT3 deficiency causes mitochondrion-specific acetylation and impairment of frataxin and ferroportin potentially via downregulation of HIF-2α. Our results suggest that the SIRT3-ferroptosis pathway may be a novel target for the mitochondrial cardiomyopathy of FRDA.

Reata plan to submit an MAA to the EMA in the fourth quarter of 2022.

PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, today announced financial results for the first quarter of 2022 and provided an update on the Company’s business operations and clinical development programs.-- The FDA has granted Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation to omaveloxolone for the treatment of Friedreich’s ataxia. In March 2022, we completed the rolling submission of an NDA to the 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 2 trial and additional supporting data from the MOXIe Part 1 and MOXIe Extension trials.-- We have secured an agreement on our Pediatric Investigation Plan with the European Medicines Agency (“EMA”) Pediatric Committee, and we are continuing to complete the regulatory procedures and submissions required prior to filing a Marketing Authorization Application (“MAA”) in Europe for approval of omaveloxolone for the treatment of patients with Friedreich’s ataxia. We plan to submit an MAA to the EMA in the fourth quarter of 2022.

Antioxidantes en el tratamiento de la ataxia de Friedreich. Ensayo in vitro de la eficacia del aceite esencial de clavo

García Vivancos, Marta; Repositorio Institucional Universitat de les Illes Balears, URI: http://hdl.handle.net/11201/157022, Fecha: 2021, Fecha de depósito: 2022-01-27 

En este trabajo se realizó un análisis bibliográfico sobre el estado actual del tratamiento de la ataxia de Friedreich, y también una parte experimental que consistió en un ensayo in vitro para valorar la eficacia antioxidante del aceite esencial de clavo utilizando fibroblastos derivados de un paciente y un sujeto sano. Entre los principales resultados experimentales destaca la capacidad antioxidante del aceite esencial de clavo, y su capacidad para inducir la expresión de algunos enzimas antioxidantes. No obstante, no se observó que el tratamiento con este aceite mejorase la supervivencia de las células expuestas a peróxido de hidrógeno. Los resultados de este trabajo sugieren que el aceite esencial de clavo tiene propiedades antioxidantes, pero serán necesarios un mayor número de experimentos en modelos de ataxia para determinar si estas propiedades pueden tener efectos terapéuticos.

In this work, a bibliographic analysis was carried out on the current status of Friedreich's ataxia treatment, and also an experimental part that consisted of an in vitro test to assess the antioxidant efficacy of clove essential oil using fibroblasts derived from a patient and a healthy subject. Among the main experimental results, the antioxidant capacity of clove essential oil and its capacity to induce the expression of some antioxidant enzymes stand out. However, treatment with this oil was not found to improve the survival of cells exposed to hydrogen peroxide. The results of this work suggest that clove essential oil has antioxidant properties, but a greater number of experiments in ataxia models will be necessary to determine if these properties can have therapeutic effects.

EU/3/21/2456: Orphan designation for the treatment of Friedreich's ataxia. Withdrawn

Sponsor: Novartis Gene Therapies EU Limited The designation was withdrawn from the Union Register of orphan medicinal products in March 2022 upon request of the sponsor.

Neurological Recovery with Interferon-gamma Treatment in Friedreich's Ataxia

Tekin HG, Levent E.; J Coll Physicians Surg Pak. 2022 May;32(5):671-673. doi: 10.29271/jcpsp.2022.05.671. PMID: 35546709. 

The treatment was evaluated by physical examination and side effects assessment. Friedreich Ataxia Rating Scale (FARS), 9-hole peg test (9HPT), and time of 25-foot walk (T25FW) were measured. Ataxia and cerebellar findings improved within 9 months. Although clinical neurological improvement was achieved, there was no improvement in cardiomyopathy. Key Words: Interferon-gamma, Friedreich ataxia, FARS, Children, Cardiomyopathy.

Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle

César Vásquez-Trincado, Julia Dunn, Ji In Han, Briyanna Hymms, Jaclyn Tamaroff, Monika Patel, Sara Nguyen, Anna Dedio, Kristin Wade, Chinazo Enigwe, Zuzana Nichtova, David R. Lynch, Gyorgy Csordas, Shana E. McCormack, Erin L. Seifert. Published May 9, 2022 JCI Insight. 2022;7(9):e155201. doi:10.1172/jci.insight.155201. 

Friedreich’s ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, we show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, we used a transgenic mouse model of whole-body inducible and progressive FXN depletion. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.

Identification of the Minimum Therapeutic Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia

Presenter: Carlos Munoz Zuluaga, M.D., Weill Cornell Medicine Date/Time: Wednesday, May 18, 2022 at 5:30 PM ET Session Title: AAV Vectors – Preclinical and Proof-of-concept Studies III Abstract Number: 936

 Abstract highlights: This preclinical study identified a therapeutically effective dose of AAVrh10 expressing human FXN (AAVrh.10hFXN) that has the potential to be clinically relevant for the treatment of the cardiac manifestations of FA. Assessment by echocardiography demonstrated that a dose of 1.8x1012 gc/kg (qPCR determined) led to a beneficial outcome with significant improvement in ejection fraction and fractional shortening compared to untreated mice. This dose mediated a 21.5 % improvement in mortality. In nonhuman primates, the levels in the heart were comparable to levels in the range estimated necessary to convert the FA homozygote to an FA heterozygote, which based on prior research, present no clinical manifestations of FA.

 Friedreich’s ataxia (FA) cardiomyopathy program will be presented at the 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), which is being held live in Washington, D.C. and virtually from May 16-19, 2022.