Friedreich's ataxia—a rare multisystem disease

Friedreich's ataxia—a rare multisystem disease, Reetz, KathrinCosta, Ana Sofia et al., The Lancet Neurology, Volume 24, Issue 7, 614 - 624 

Friedreich's ataxia is a rare autosomal recessive neurodegenerative disease. Most patients have a homozygous GAA repeat expansion in the FXN gene, resulting in a deficiency of the mitochondrial protein frataxin. Disease onset occurs typically in adolescence but can vary widely, ranging from early childhood to late adulthood. Friedreich's ataxia is increasingly recognised as a multisystem disorder, affecting not only the nervous system, but also the heart and musculoskeletal system, and metabolism. Common extraneural manifestations include cardiomyopathy, which is the most common cause of mortality, and also scoliosis and diabetes.

Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons

Yang W, Thompson B, Miellet S, Maddock M, Napierala M, Dottori M, Kwa F. Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons. Antioxid Redox Signal. 2025 May 23. doi: 10.1089/ars.2024.0756. Epub ahead of print. PMID: 40406806. 

We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant in vitro FRDA model. Conclusion: SF offers a multipronged approach to alleviating the different cellular events underlying FRDA.

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy Lili Salinas BA , Francisco Figueroa BS , Claire B. Montgomery BS , Phung N. Thai PhD , Nipavan Chiamvimonvat MD , Gino Cortopassi PhD , and Elena N. Dedkova DVM, The Journal of the American Heart Association (JAHA): Cardiovascular and Cerebrovascular Disease doi:10.1161/JAHA.124.038505 

 In conclusion, we determined that omaveloxolone was much more effective in recovering cardiac contractile dysfunction in FXN‐cKO mice as compared with DMF. However, neither of the drugs improved structural derangements, fibrosis, hypertrophy, or improved survival rates. These data suggest that omaveloxolone, but not DMF, could improve cardiac contractile performance and potentially enhance the quality of life in FA patients with a late‐stage cardiomyopathy. Importantly, we noticed that cardiac function was impaired significantly more in FXN‐cKO males versus females; however, omaveloxolone‐treated FXN‐cKO females started dying sooner as compared with vehicle‐treated animals. This observation is highly important and suggests that women living with FA may experience negative side effects of Skyclarys and therefore, may require dose adjustment. It is possible that omaveloxolone overstimulating Nrf2 signaling in FXN‐cKO female mice led to a shift in redox potential into a too reduced state

Cerebellar transcranial direct current stimulation in Friedreich ataxia: anatomy matters

Roderick P.P.W.M. Maas, Dennis J.L.G. Schutter, Cerebellar transcranial direct current stimulation in Friedreich ataxia: anatomy matters, Clinical Neurophysiology, 2025, 2110784, ISSN 1388-2457, doi:10.1016/j.clinph.2025.2110784. 

In this issue of Clinical Neurophysiology, Naeije and colleague demonstrate, for the first time, an association between improvements in motor and non-motor symptoms following cerebellar tDCS and ataxia patients’ anatomical characteristics. patients with larger anterior and posterior lobe GM volumes were more likely to experience favorable effects on motor and non-motor symptoms, respectively, as compared to individuals with smaller volumes. Skin-cerebellum distance was not found to be correlated with tDCS-induced clinical changes. both in FA and in ataxia types with more marked cerebellar atrophy, the preliminary work by Naeije and colleagues marks an important first step towards developing individually tailored cerebellar tDCS interventions for patients with ataxia.

Design Therapeutics Announces Start of Friedreich Ataxia Patient Dosing Ex-U.S. in its RESTORE-FA Phase 1/2 Multiple-Ascending Dose Trial of DT-216P2

CARLSBAD, Calif., June 04, 2025 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. today announced that the first Friedreich ataxia (FA) patient has been dosed via intravenous (IV) infusion in its RESTORE-FA (Reactivating Expression Suppressed Through Overcoming Repeat Expansion for FA) open-label Phase 1/2 multiple-ascending dose (MAD) clinical trial of DT-216P2. 

The RESTORE-FA trial is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of IV and subcutaneous administration of DT-216P2 in patients with FA. DT-216P2 has been administered in one patient to date with no adverse events reported, including no injection site thrombophlebitis. The trial is currently open for enrollment in Australia. Design anticipates reporting data from the MAD trial, including levels of frataxin (FXN) expression based on 12 weeks of dosing, in 2026.

Managing Aminotransferase Elevations in Patients with Friedreich Ataxia Treated with Omaveloxolone: A Review and Expert Opinion on Use Considerations

Authors: Susan Perlman, Mathieu Anheim, Sylvia Boesch, James H. Lewis, David R. Lynch. Published in: Neurology and Therapy. doi:10.1007/s40120-025-00752-8

Use considerations herein may inform decisions on monitoring and managing ALT and AST elevations, which potentially help to encourage the treatment adherence needed to achieve the slowing of FA progression seen in MOXIe.

EMA approved orphan medicines since the implementation of the orphan legislation

Hahl, E., Kurko, T., Koskinen, H. et al. EMA approved orphan medicines since the implementation of the orphan legislation. Orphanet J Rare Dis 20, 266 (2025).doi:10.1186/s13023-025-03756-7

The number of orphan medicines in EU has increased significantly since the introduction of the orphan legislation, i.e., from 2000 to 2022. The selection of orphan medicines tends to focus on medicines used for treating cancer and inborn errors of metabolism or immune system disorders. The coverage of orphan medicines is still minor compared to number of orphan diseases and it seems that the orphan medicines market is focused on rare conditions with highest prevalence. The development of orphan medicines for paediatric use has not been proportionate to the prevalence of rare diseases in children. Orphan medicines with marketing authorisation often target diseases or disease groups that already have available treatments, while several rare diseases remain without available treatment.

Safety Monitoring of Omaveloxolone in Friedreich Ataxia: Results from One Year of Clinical Treatment

Gunther, K., Profeta, V., Keita, M. et al. Safety Monitoring of Omaveloxolone in Friedreich Ataxia: Results from One Year of Clinical Treatment. Neurol Ther 14, 1105–1114 (2025). doi:10.1007/s40120-025-00749-3

 Most patients with FRDA eventually had access to omaveloxolone, and it was generally well tolerated. Side effects were modest, and, overall, most patients remained on the drug. Abnormalities in serum liver function tests were limited to transaminases, resolved with dose pausing or reduction, and diminished markedly over time. Thus, the safety features of omaveloxolone after administration largely resemble the favorable features noted during clinical trials.

Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice

Matuszek, Z., Arbab, M., Kesavan, M. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat Genet (2025). doi:10.1038/s41588-025-02172-8 

 In this study, we have begun the characterization of unintended targets of these repeat base editing strategies, and found that: (1) the level of off-target editing is inversely correlated with the number of mismatches between the repeat-targeting sgRNA and the sequence of the off-target locus, as expected70,71,72; (2) the vast majority of undesired editing occurs in noncoding or intergenic regions of the human genome; and (3) repeat-targeting base editing often leads to the induction of benign single-nucleotide variations that are observed in the general population and synonymous substitutions at protein-coding loci that preserve endogenous protein sequence. The alternative target and off-target sites of repeat-targeting in the human genome observed in this study warrant further comprehensive cell-type-specific longitudinal analyses to evaluate the regulatory risks of accumulated mutations in targeted tissues, to better assess the safety profile of our approaches and whether interrupting pathogenic repeats that underlie TNR diseases may be a viable therapeutic approach in the future. Nonetheless, the approaches and findings developed here should prove useful to elucidate the causality and biological consequences of uninterrupted and interrupted repeat tracts in cultured cells and animal models of TNR diseases.

Impaired DNA double-strand breaks repair in Friedreich’s Ataxia fibroblasts

Rafka Challita, Dana Tohme, Charbel Feghaly, Hanin Bou Hadir, Walaa Chebli, Elie Estephan, Rana El-Hassan, Sima Hussayni, Wassim Abou Kheir, Larry Bodgi, 2735 Impaired DNA double-strand breaks repair in Friedreich’s Ataxia fibroblasts, Radiotherapy and Oncology, Volume 206, Supplement 1, 2025, Pages S3933-S3935, ISSN 0167-8140, doi:10.1016/S0167-8140(25)01252-6.

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