Domain Adaptation for IMU Data to Enhance Objective Assessment of Friedreich Ataxia

Tran, M., Ranaweera, K., Ngo, T., Pathirana, P., Milne, S., Horne, M., Delatycki, M., & Corben, L. (2026). Domain Adaptation for IMU Data to Enhance Objective Assessment of Friedreich Ataxia. IEEE Journal of Biomedical and Health Informatics, PP. doi:10.1109/JBHI.2026.3702417 

 Our approach leverages a convolutional neural network (CNN) architecture to automatically learn high-level representations from raw IMU signals, minimizing reliance on manual feature engineering. Central to our method is a two-stage training strategy that incorporates domain adversarial learning, enabling knowledge transfer between two IMU-based assessment tools: the Ataxia Instrumented Measures cup (AIM-C) and spoon (AIM-S). This strategy enhances learning from each device by exploiting shared underlying representations.

Epigenetic reactivation in Friedreich’s ataxia from benzamides to gene‑targeted chimeras

Ansari, F. U., Rojsajjakul, T., Liu, J., Nageshwaran, S. K., & Blair, I. A. (2026). Epigenetic reactivation in Friedreich’s ataxia from benzamides to gene‑targeted chimeras. Expert Opinion on Drug Discovery, 21(7), 779–791. doi:10.1080/17460441.2026.2689723 

 This review summarizes the evolution of FXN protein‑reactivating approaches from first‑generation systemic epigenetic therapies, including class I‑selective benzamide histone deacetylase inhibitors and high‑dose nicotinamide, to emerging locus‑targeted platforms such as anti‑gene oligonucleotides and gene‑targeted chimera small molecules. The authors also examine splice‑modulating strategies aimed at increasing the extra‑mitochondrial FXN‑E isoform, discuss delivery and safety challenges across modalities, and highlight biomarker frameworks integrating isoform‑resolved FXN protein measurements and chromatin readouts.

Advances in Gene and Cellular Therapy in Friedreich Ataxia

Lazaropoulos MP, Lynch DR. Advances in Gene and Cellular Therapy in Friedreich Ataxia. Mol Diagn Ther. 2026 Jun 29. doi: 10.1007/s40291-026-00854-5. Epub ahead of print. PMID: 42373844. 

 Multiple investigational techniques and strategies seek to permanently alter the disease course in patients with Friedreich ataxia, although no product has established definitive benefit. This review catalogs both the history and ongoing efforts of genetic and cellular therapies applied to Friedreich ataxia and its disease models, including therapeutic efficacy and adverse effects. We list the key limitations and cautions of such therapies, chiefly those of potential FXN overexpression toxicity, critical therapeutic windows, and adverse effects of these therapies applicable to any disease target. As gene and cellular therapy continue to diversify in design and strategy, Friedreich ataxia patients will likely have multiple therapeutic options in the future from both investigational therapies described here and future ones yet to be optimized.

Frataxin attenuates endothelial inflammation triggered by engulfment of senescent erythrocytes

Xingyi Cheng, Yi Cheng, Chenglin Huang, Tong Wei, Yuetong Guo, Jing Gao, Weili Shen, Frataxin attenuates endothelial inflammation triggered by engulfment of senescent erythrocytes, Free Radical Biology and Medicine, 2026,ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2026.07.006. 

Hypertension is linked to a shortened erythrocyte lifespan, with endothelial cells acting as non-professional phagocytes to clear senescent erythrocytes. However, whether increased erythrophagocytosis contributes to endothelial inflammation remains unclear. Frataxin (FXN) plays a crucial role in controlling iron balance and metabolism. This study investigated the role of FXN-mediated iron engulfment in regulating endothelial pro-inflammatory phenotype.

Key Interventions in Friedreich's Ataxia and Their Impact on Patient Outcomes: A Systematic Review

Sarwinska D, Buchholz M, Iskandar A, Grobe-Einsler M, Klockgether T, Faber J, Michalowsky B. Key Interventions in Friedreich's Ataxia and Their Impact on Patient Outcomes: A Systematic Review. Mov Disord. 2026 Jul 6. doi: 10.1002/mds.70423. Epub ahead of print. PMID: 42410955. 

Friedreich's ataxia (FA) is a rare neurodegenerative disease with multisystemic symptoms that requires multidisciplinary care. This systematic review summarizes available pharmacological and nonpharmacological interventions, their outcomes, and alignment with patient-centered care domains, as well as their impact on these domains.

Nrf2 modulates cytosolic and mitochondrial calcium signal

Alessandra Preziuso, Artyom Y. Baev, Fozila R. Rustamova, Sharadha Dayalan Naidu, Lauren Millichap, Plamena R. Angelova, Vincenzo Lariccia, Albena T. Dinkova-Kostova, Andrey Y. Abramov, Nrf2 modulates cytosolic and mitochondrial calcium signal, Redox Biology, Volume 94, 2026, 104213, ISSN 2213-2317, doi:10.1016/j.redox.2026.104213.

Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.

The importance of this research lies in providing a key scientific foundation, demonstrating that omaveloxolone not only reduces oxidative stress but also directly protects neurons by correcting mitochondrial calcium defects—a critical process that is impaired in patients with Friedreich's Ataxia.

LEXEO THERAPEUTICS ANNOUNCES REGULATORY UPDATE AND REGISTRATIONAL TRIAL DESIGN FOR LX2006 GENE THERAPY IN FRIEDREICH ATAXIA

NEW YORK, June 15, 2026 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, today announced that the Company has finalized the SUNRISE-FA 2 pivotal trial protocol and statistical analysis plan (SAP) intended to provide clinical evidence to support the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for gene therapy candidate LX2006 under the accelerated approval pathway in 2028.

Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions

Cravin G, Cozza G. Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions. Ferroptosis Oxid Stress. 2026;2:202618. doi:10.70401/fos.2026.0032 

 In the present review, we explore how FXN loss undermines cellular defenses against oxidative damage, placing a specific focus on the regulation of the lipid redox landscape. We detail the breakdown of glutathione (GSH)-dependent mechanisms, specifically highlighting the blunted Nrf2 antioxidant response and the subsequent reduced capacity of glutathione peroxidase 4. Alongside these deficits, we investigate the compensatory roles of GSH-independent rescue networks, namely ferroptosis suppressor protein 1 and mitochondrial dihydroorotate dehydrogenase. Looking toward clinical translation, we critically assess emerging pharmacological interventions designed to target these ferroptotic nodes. The potential of mitochondria-targeted iron chelators, lipoxygenase inhibitors, lipophilic radical-trapping antioxidants, and novel Nrf2 activators is evaluated to determine whether inhibiting ferroptosis can serve as a viable disease-modifying strategy. Moving forward, combinatorial “protect and restore” approaches will likely prove essential for maximizing therapeutic efficacy in FRDA.

Transitional Life Events in Friedreich Ataxia: Differential Age at Onset Perspectives

Iskandar, A., Buchholz, M., Sarwinska, D. et al. Transitional Life Events in Friedreich Ataxia: Differential Age at Onset Perspectives. Cerebellum 25, 96 (2026). doi:10.1007/s12311-026-02038-7 

 The results underscore the importance of incorporating onset-specific considerations into clinical care and support strategies. Future studies should aim to gain a deeper understanding of the psychosocial burden of FA across the lifespan. By considering the unique pathways of patients in different life stages, researchers can tailor interventions to address differing illness perceptions across various age at onset. Comparative studies across different hereditary ataxias, such as spinocerebellar ataxias, could clarify whether the onset-dependent patterns we observed are specific to FA or represent broader features of progressive ataxic disorders. Moreover, qualitative approaches should complement quantitative measures to deepen insight into patients’ lived experiences, particularly regarding interpersonal challenges and the use of assistive devices. Finally, future intervention studies should include targeted psychosocial support, counselling, or stigma-reduction strategies can mitigate the adverse impact of relationship-related life events and improve mental wellbeing in FA, especially for those with pediatric onset.

AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial

Crystal RG, Weinsaft JW, Kaminsky SM, et al. AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial. JAMA Cardiol. Published online June 17, 2026. doi:10.1001/jamacardio.2026.1699 

In an open-label, dose-ranging, nonrandomized clinical trial of 17 patients, intravenous administration of AAVrh.10hFXN was associated with minimal toxic effects, reduced cardiac magnetic resonance imaging assessment of left ventricular mass index, and reduced serum high-sensitivity troponin I level.

Seventeen patients with FA cardiomyopathy (mean [SD] age, 25 [6] years; 11 [65%] female) were followed up for a mean (SD) of 20 (8) months. There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Other adverse events were transient, nonserious, or not treatment related. In all 8 patients with cardiac biopsy 3 months after therapy, there were higher levels of cardiac FXN (dose cohort 1, 20%; cohort 2, 81%; cohort 3, 123%). After therapy, LVMI was lower by at least 10% in 9 patients and stabilized in 8 patients. Excluding the patient with myocarditis, posttherapy values of serum hs troponin I were lower by at least 10% in 15 patients and higher by at least 10% in 2 patients.