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.

No abstrac provided

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.