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.

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.

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).

Lexeo Therapeutics Reports First Quarter 2025 Financial Results and Operational Highlights

NEW YORK, May 12, 2025 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. today provided business updates across its portfolio and reported first quarter 2025 financial results.

LX2006 for the Treatment of FA Cardiomyopathy: In April 2025, Lexeo announced positive interim data of LX2006 across both the Lexeo-sponsored SUNRISE-FA Phase 1/2 clinical trial (NCT05445323) and the Weill Cornell Medicine investigator-initiated Phase 1A trial (NCT05302271). 

Efficacy: Clinically meaningful improvements were observed across cardiac biomarkers and functional measures in the majority of participants across both studies. Participants with abnormal left ventricular mass index (LVMI) at baseline achieved 25% mean reduction in LVMI by 12 months or sooner, exceeding the 10% target reduction in LVMI by 12 months aligned with the U.S. Food and Drug Administration (FDA) for the planned registrational study. 

Protein Expression: Increases in cardiac frataxin expression were observed in all SUNRISE-FA participants at 3-months post treatment, with an average increase of 115% over baseline observed in the high-dose cohort. 

Safety: LX2006 continues to be generally well tolerated with no new treatment-related serious adverse events to report. 

Regulatory Plans: Lexeo expects final alignment with FDA on the LX2006 planned pivotal study protocol and statistical analysis plan in 2025. Lexeo previously aligned with FDA on co-primary endpoints for the study and measurement thresholds: greater than 10% reduction in LVMI as measured by cardiac MRI, and any increase from baseline cardiac frataxin expression as measured by liquid chromatography mass spectrometry (LCMS). 

Next Steps: In Q2 2025, Lexeo expects to begin enrollment in a prospective natural history study serving as a concurrent external control arm for the registrational study. The Company expects to initiate a registrational study by early 2026 with a potential efficacy readout in 2027.

PTC Therapeutics (PTCT) Q1 2025 Earnings Call

May 6, 2025. Vatiquinone (Friedreich's Ataxia): FDA review proceeding without AdCom; confirmatory evidence from long-term data compared to FA-COMS natural history registry showing a reported 50% slowing in disease progression over three years.

Omaveloxolone for treating Friedreich’s ataxia in people 16 years and over (terminated appraisal)

National Institute for Health and Care Excellence (NICE). 06 May 2025. 

NICE is unable to make a recommendation on omaveloxolone (Skyclarys) for treating Friedreich’s ataxia in people 16 years and over. This is because Biogen withdrew its evidence submission.

Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression

Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S.J. Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S. Napierala, Pontus Blomberg, Per T. Jørgensen, Tanel Punga, C. I. Edvard Smith, Jesper Wengel, Rula Zain, Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression, Molecular Therapy Nucleic Acids, 2025, 102541, doi:10.1016/j.omtn.2025.102541. 

Friedreich’s ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA•TTC triplet-repeats in the first intron of the frataxin gene. GAA•TTC repeat expansion results in the formation of a non-B DNA intramolecular triplex as well as changes in the epigenetic landscape at the frataxin locus. Expansion of intronic GAA•TTC repeats is associated with reduced levels of frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA•TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in frataxin mRNA and protein levels in cells derived from Friedreich’s ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA•TTC DNA repeats to upregulate frataxin gene expression.

Hepatic Manifestations Following Gene Therapy

Akash Roy, Shalini Bansal, Anand Kulkarni, K. Rajender Reddy, Hepatic Manifestations Following Gene Therapy, Gastro Hep Advances, 2025, 100681, ISSN 2772-5723, doi:10.1016/j.gastha.2025.100681.

 Abstract: Gene therapy (GT) involves the introduction of genetic materials, most commonly using viral vectors, to alter gene expression to ameliorate or cure disease symptoms and with minimal adverse events. While interest in GT has been on the increase, concerns have arisen about the potential for hepatotoxicity, which arises from diverse mechanisms. While viral vectors can produce dose-dependent hepatotoxicity secondary to integration, immune responses appear to be the primary driving mechanism. A mild increase in aminotransferases is the most common hepatic manifestation, occurring variably in 20-80%, while there has been rare progress to acute liver failure. The occurrence of hepatotoxicity is unpredictable and can vary depending on patient comorbidities, vector dose, vector type, and degree of immune activation. Pre-treatment screening for underlying chronic liver disease and exclusion of advanced fibrosis or cirrhosis using non-invasive tests is essential. Literature on liver biopsy pre and post-therapy is limited, but small studies show safety in the long term. Immunosuppression, most commonly using corticosteroids, is the first-line modality in management. Approaches vary between prophylactic and reactive strategies, and there remains an absence of consensus on the most appropriate strategies. First-line therapy for a variable duration and dose settles most cases of hepatoxicity. In selected difficult-to-treat cases, second-line agents (sirolimus, mycophenolate mofetil, calcineurin inhibitors) are required, while there is no current consensus on the ideal second-line strategy. Intense short-term and extended long-term hepatic monitoring is recommended. Variabilities in presentation and challenges in management strategies mandate a multidisciplinary collaboration with the active involvement of hepatologists/gastroenterologists to optimize liver health 

Rgenta Therapeutics Announces Presentation of Preclinical Data from Proprietary RSwitch Technology

WOBURN, Mass., April 30, 2025 /PRNewswire/ -- Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA and RNA regulation for oncology and neurological disorders, announced today that preclinical data will be presented on its proprietary RSwitch technology, which enables the fine-tuning of transgene levels in gene and cell therapy applications, at the American Society of Gene And Cell Therapy (ASGCT) 28th Annual Meeting, which will be held from May 13 -17th, 2025, in New Orleans, LA. 

Title: RSwitch Enabled Gene Therapy to Fine Tune Frataxin Expression for the Treatment of Friedrich's Ataxia, Samuel A. Hasson, Jon Dempersmier, Mariam Elhawary, Diane Hamann, Ian McLachlan, Chris Yates, Travis Wager, and Simon Xi 

 RSwitch is a proprietary regulatable gene therapy system that enables oral, small molecule drug control of transgene levels in gene and cell therapy applications. RSwitch encodes a "dimmer" switch that makes the expression of transgene dependent on the administration of an oral small molecule drug that controls the system. Only when the drug is administered is the system activated. Furthermore, the level of gene expression is dependent on how much drug is administered. This precise gene control has the potential to enable fine control of the expression of a therapeutic protein.

Larimar Therapeutics Reports First Quarter 2025 Financial Results

BALA CYNWYD, Pa., April 30, 2025 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today reported its first quarter 2025 operating and financial results.

Completed Dosing of Adolescents in Pharmacokinetic (PK) Run-In Study.

Potential for Accelerated Approval Pathway Based on Skin FXN Concentrations. 

Planned Upcoming Regulatory Discussions. 

50 mg OLE Data Expected in September 2025. 

Planned Transition to Lyophilized Form of Nomlabofusp. 

BLA Submission and Initiation of Global Phase 3 Study on Track

Gene circuits enable more precise control of gene therapy

Anne Trafton | MIT News Publication Date:April 28, 2025 

Very few gene therapy treatments have been approved by the FDA. One of the challenges to developing these treatments has been achieving control over how much the new gene is expressed in cells — too little and it won’t succeed, too much and it could cause serious side effects. 

To demonstrate this system, the researchers designed ComMAND circuits that could deliver the gene FXN, which is mutated in Friedreich’s ataxia — a disorder that affects the heart and nervous system. They also delivered the gene Fmr1, whose dysfunction causes fragile X syndrome. In tests in human cells, they showed that they could tune gene expression levels to about eight times the levels normally seen in healthy cells. 

Without ComMAND, gene expression was more than 50 times the normal level, which could pose safety risks. Further tests in animal models would be needed to determine the optimal levels, the researchers say.

Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells

Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells. Love, Kasey S. et al., Cell Systems, Volume 0, Issue 0, 101269 DOI: 10.1016/j.cels.2025.101269

In a therapeutic context, supraphysiological expression of transgenes can compromise engineered phenotypes and lead to toxicity. To ensure a narrow range of transgene expression, we developed a single-transcript, microRNA-based incoherent feedforward loop called compact microRNA-mediated attenuator of noise and dosage (ComMAND).

ComMAND effectively sets levels of the clinically relevant transgenes frataxin (FXN) and fragile X messenger ribonucleoprotein 1 (Fmr1) within a narrow window.