Frataxin: from the sequence to the biological role

Pignataro MF, Noguera ME, Herrera MG, Roman EA, Santos J. Frataxin: from the sequence to the biological role. Biophys Rev. 2025 Apr 3;17(2):449-465. doi: 10.1007/s12551-025-01311-z. PMID: 40376404; PMCID: PMC12075029. 

In this review, we focused on different aspects concerning the biophysics and the biochemistry of frataxin and its partners, as well as on the current knowledge regarding proteostasis and post-translational modifications. The involvement of frataxin and its partners in diseases will also be addressed, including the current therapeutic approaches. Finally, a section is dedicated to understanding the phylogenetic distribution of frataxin.

Cerebellar grey matter volume predicts cerebellar tDCS efficacy in individuals with Friedreich ataxia

Gilles Naeije, Christian Georgiev, Pierre Cabaraux, Mathieu Bourguignon; Cerebellar grey matter volume predicts cerebellar tDCS efficacy in individuals with Friedreich ataxia, Clinical Neurophysiology, 2025, 2110744, ISSN 1388-2457, doi:10.1016/j.clinph.2025.2110744. 

FA patients exhibited significantly reduced cerebellar gray matter volume compared to controls (p = 0.024) after intracranial volume correction, skin-to-cerebellum distance did not differ between groups (p = 0.11). Stepwise linear regression analysis disclosed that the anterior cerebellar gray matter volume was a significant predictor of SARA improvement (β = −0.18, p < 0.001) and the posterior cerebellar gray matter volume of CCAS-S improvement (β = −0.13, p 0.023). Neither SCP diameter nor skin-to-cerebellum distance significantly impacted ctDCS efficacy. Cerebellar gray matter volume is associated to ctDCS-induced symptoms improvements in FA.

Predictive machine learning and multimodal data to develop highly sensitive, composite biomarkers of disease progression in Friedreich ataxia

Saha, S., Corben, L.A., Selvadurai, L.P. et al. Predictive machine learning and multimodal data to develop highly sensitive, composite biomarkers of disease progression in Friedreich ataxia. Sci Rep 15, 17629 (2025). doi:10.1038/s41598-025-01047-6 

 This study pioneers the development of clinically relevant, multidomain, fully objective composite biomarkers of disease severity and progression, using multimodal neuroimaging and background data (i.e., demographic, disease history, genetics). Data from 31 individuals with FRDA and 31 controls from a longitudinal multimodal natural history study IMAGE-FRDA, were included.

Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich’s Ataxia-GAA Repeats

Park, Joohyun, Claudia Dufke, Zofia Fleszar, Michael Schlotterbek, Elena Buena-Atienza, Lara G. Stühn, Caspar Gross, Marc Sturm, Stephan Ossowski, Ludger Schöls, and et al. 2025. "Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich’s Ataxia-GAA Repeats" International Journal of Molecular Sciences 26, no. 11: 4969. doi:10.3390/ijms26114969 

 Genetic testing included fragment analysis, gene panel analysis and exome sequencing, which only detected one pathogenic heterozygous missense variant (c.389 G>T,p.Gly130Val) in FXN. Although conventional repeat analyses failed to detect GAA expansions in our patient, subsequent short-read genome sequencing (GS) indicated a potential GAA repeat expansion. This finding was confirmed by long-read GS, which in addition revealed a complex pattern of interruptions. Both large and small GAA expansions with divergent interruptions containing G, A, GA, GAG and/or GAAG sequences were present within one allele, indicating mosaic sequence variations. Our findings underscore the complexity of repeat expansions which can exhibit both interruptions and somatic instability. We also highlight the utility of long-read GS in unraveling intricate genetic profiles, ultimately contributing to more accurate diagnoses in clinical practice.

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia. Minggang Fang, Shahid Banday, Sara K. Deibler, Tessa M. Simone, Madison Coleman, Emerald O’Connor, Rui Li, Lihua Julie Zhu, Michael R. Green, Journal of Neuroscience 22 May 2025, e2307242025; DOI: 10.1523/JNEUROSCI.2307-24.2025 

 Through an RNA interference screen, we identified ROCK1 and ROCK2 kinases as critical repressors of FXN expression, making them promising therapeutic targets for upregulating FXN in patient-derived cells. Treatment with small-molecule ROCK inhibitors, including the FDA-approved drug belumosudil and clinically advanced fasudil, restores frataxin levels, alleviates mitochondrial defects, and improves disease phenotypes in cells and animal models. These findings establish ROCK kinases as targets for Friedreich ataxia therapy and open new avenues for repurposing existing ROCK inhibitors, warranting clinical exploration.

Modeling Friedreich's ataxia with Bergmann glia-enriched human cerebellar organoids

Modeling Friedreich's ataxia with Bergmann glia-enriched human cerebellar organoids. Seungmi Ryu, Jason Inman, Hyenjong Hong, Vukasin M Jovanovic, Yeliz Gedik, Yogita Jethmalani, Inae Hur, Ty Voss, Justin Lack, Jack Collins, Pinar Ormanoglu, Anton Simeonov, Carlos A Tristan, Ilyas Singe"ç". bioRxiv 2025.05.16.654315; doi:10.1101/2025.05.16.654315 

 Despite the progress in generating neural tissues from human induced pluripotent stem cells (iPSCs), an organoid model that recapitulates the key features of cerebellar development has not been widely established. Here, we report the generation of a 60-day method for human cerebellar organoids (hCBOs) that is characterized by induction of rhombomere 1 (R1) cellular identity followed by derivation of neuronal and glial cell types of the cerebellum. In contrast to forebrain organoids with multiple neural rosettes and inside-out neuronal migration, hCBOs develop a SOX2+ cerebellar plate on the outermost surface of organoids with outside-in neuronal migration, which is a characteristic hallmark of cerebellar histogenesis.

Therapeutic combination of L-ascorbic acid, N-acetylcysteine, and dimethyl fumarate in Friedreich’s ataxia: insights from in vitro models

Edzeamey, F. J., Ramchunder, Z., Valle Gómez, A., Ge, H., Marobbio, C. M. T., Pourzand, C., & Virmouni, S. A. (2025). Therapeutic combination of L-ascorbic acid, N-acetylcysteine, and dimethyl fumarate in Friedreich’s ataxia: insights from in vitro models. Redox Report, 30(1). doi:10.1080/13510002.2025.2505303

Treatment with LAA, NAC, and DMF resulted in significant reductions in mitochondrial and cellular ROS, along with increased FXN and NRF2 expression, and enhanced NRF2 nuclear translocation. Furthermore, these compounds improved aconitase/citrate synthase activity, GSH/GSSG ratios, and mitochondrial membrane potential. Notably, the combination of LAA and NAC consistently alleviated multiple disease-associated defects in FRDA cells, suggesting its potential as a promising therapeutic approach.

Neuromagnetic Responses to Multimodal Stimuli in Friedreich’s Ataxia

Elisa Visani, Laura Canafoglia, Lorenzo Nanetti, Davide Rossi Sebastiano, Dunja Duran, Paola Anversa, Deborah Bonfoco, Sara Dotta, Davide Tabarelli, Anna Castaldo, Gloria Marchini, Alessia Mongelli, Caterina Mariotti, Neuromagnetic Responses to Multimodal Stimuli in Friedreich’s Ataxia, Clinical Neurophysiology, 2025, 2110738, doi:10.1016/j.clinph.2025.2110738. 

 Neuromagnetic responses were identifiable in more than 90% of cases. A significant response delay was observed in all tested modalities (auditory, somatosensory, tactile and visual responses). P300 responses were comparable in patients and healthy subjects. Latencies of visual and auditory responses correlated with SARA scores. Moreover, latencies of auditory responses correlated with disease onset age, whereas latencies of visual responses correlated with disease severity.

Solid Biosciences Reports First Quarter 2025 Financial Results and Provides Business Updates

GuruFocus News. 16/05/2025 

The U.S. FDA has granted IND clearance for SGT-212, intended for treating Friedreich's Ataxia, with first participant dosing anticipated in the second half of 2025.

Neurodegenerative and Metabolic Disease Challenges and Solutions at ASGCT 2025

2025-05-15. ASGCT 2025. Neurodegenerative diseases like ALS, frontotemporal dementia, and Friedreich’s ataxia pose significant challenges with limited treatment options. 

Rgenta’s RSwitch technology offers precise control over FXN expression for Friedreich’s ataxia. It minimizes risks like cardiotoxicity through adjustable dosing via oral RDrugs.

This means that instead of a one-time, permanent change to the gene, RSwitch enables doctors to adjust the therapy’s effects in response to the patient’s needs. The gene therapy approach aims to correct the FXN deficiency, but unregulated FXN overexpression can lead to harmful side effects, including cardiotoxicity (damage to the heart).