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