Multi-Omics Biomarker Discovery in Friedreich’s Ataxia Cardiomyopathy

F. Siddiqui, T. Keller, C. Koehring, G. Upadhyay, B. Higgins, T. Zesiewicz, K. Kim, G. Halade, A. Patel, T. Mcdonald. Multi-Omics Biomarker Discovery in Friedreich’s Ataxia Cardiomyopathy [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/multi-omics-biomarker-discovery-in-friedreichs-ataxia-cardiomyopathy/. Accessed October 19, 2026. 

Cytokine analyses demonstrated alterations in circulating inflammatory and remodeling markers; however, predictive modeling indicated that these alone had limited discriminatory performance. Model accuracy improved when variables were integrated with clinical and imaging metrics, suggesting a subset of circulating proteins contributes to disease pathways. Lipidomic profiling revealed distinct remodeling of inflammatory lipid mediator pathways, with clear separation between FA and control driven by coordinated pathway-level changes. Mass spec proteomics and early single-cell immune profiling further identified trends consistent with mitochondrial stress, immune activation, and fibro-inflammatory signaling.

Transcriptomic Profiling of Frataxin-Deficient Drosophila melanogaster to Identify Molecular Drivers and Pathway Disruptions in Friedreich’s Ataxia

V. Swarup, R. Yadav, A. Ahuja, P. Yadav, A. Srivastava, D. Garg. Transcriptomic Profiling of Frataxin-Deficient Drosophila melanogaster to Identify Molecular Drivers and Pathway Disruptions in Friedreich’s Ataxia [abstract]. Mov Disord. 2026; 41 (suppl 1).  October 19, 2026. 

Out of 2035 genes, 1260 were upregulated and 775 downregulated. FBgn0000261 (Catalase) and FBgn0024958 (Irp1A) were significantly down in fh-/- mutants, while FBgn0039561 (mitoferrin) was significantly up.GO enrichment highlighted proteolysis as the top biological process, followed by small molecule metabolism and transmembrane transport. KEGG and REACTOME analyses confirmed enrichment in oxidative phosphorylation, metabolic pathways, and immune processes (FDR<0.001). These defects reveal mitochondrial dysfunction and oxidative stress in the disease model.

Ethical considerations in the conduct of rare disease neuroscience clinical trials

Olugemo, K., Horrigan, J., Busner, J. et al. Ethical considerations in the conduct of rare disease neuroscience clinical trials. Orphanet J Rare Dis (2026). doi:10.1186/s13023-026-04635-5 

 In this position paper of the International Society of CNS Clinical Trials and Methodology (ISCTM), the Orphan Diseases Working Group examines key ethical considerations specific to rare disease neuroscience clinical trials. We address the challenges of maintaining clinical equipoise in small, often heterogenous populations; the justification and limitations of placebo-controlled designs; the ethical complexities introduced by gene therapies and other biologics, including consent, assent, and participation of vulnerable populations; the imperative for responsible data sharing and transparent communication with patient advocacy organizations; and best practices for compassionate use programs. Drawing on existing regulatory frameworks, published literature, and the collective experience of the working group, we offer recommendations intended to guide sponsors, investigators, regulators, and ethics committees in the ethical design and conduct of these critical trials.

1H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2

sabelle Iltis, Diane Hutter, Khalaf O. Bushara, H. Brent Clark, Myron Gross, Lynn E. Eberly, Christopher M. Gomez, Gülin Öz, 1H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2, Brain Research, Volume 1358, 2010, Pages 200-210, ISSN 0006-8993, doi:10.1016/j.brainres.2010.08.030. 

 Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p < 0.01).

Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich’s ataxia mice

Sivakumar, Anusha & Corl, Alexis & Muñoz, Keneth & Arumugam, Subhashini & Gunes, Betul & Solis, Angelyn & Murthy, Rishika & El-Hachem, Lilas & Pizzo, Donald & Blair, Ian & Rojsajjakul, Teerapat & Mesaros, Clementina & Wan, Xinlong & Rainaldi, Joseph & Badell-Grau, Rafael & Khare, Veenita & Thai, Kevin & Biederman, Kavya & Cherqui, Stephanie. (2026). Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich’s ataxia mice. Journal of Clinical Investigation. 136. DOI:10.1172/JCI209546. 

 Here, we demonstrate that ex vivo CRISPR/Cas9 excision of the GAA expansion in hematopoietic stem and progenitor cells (HSPCs) provides durable, systemic therapy for FRDA. A single infusion of gene-edited Sca1+ HSPCs, mPPL-001, into myeloablative, humanized YG8JR mice resulted in long-term engraftment of donor-derived cells across hematopoietic and FRDA-affected tissues. mPPL-001 increased FXN expression and corrected multiple key pathogenic drivers of FRDA, including mitochondrial stress, microglial and macrophage activation, and inflammatory signaling. These coordinated effects improved motor functions, preserved cerebellar architecture, mitigated cardiac pathology, and promoted survival of insulin-producing β cells in the pancreatic islets of Langerhans.

Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia

Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Israel Manjarres-Raza, Maria Pazos-Gil, Fabien Delaspre, Jordi Tamarit, Juan P. Bolaños, Joaquim Ros, Elisa Cabiscol, Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia, Redox Biology, Volume 98, 2026, 104437, ISSN 2213-2317, doi:10.1016/j.redox.2026.104437. 

Highlights: Glial dysfunction, not neuronal failure, is linked to regional degeneration in FA. Satellite glia and sensory neurons show early iron overload and oxidative stress. Astrocytic dysfunction precedes neuronal pathology in the cerebrum and cerebellum. Mitochondrial impairment and iron overload contribute to cell-specific ferroptosis. NRF2-GPX4 axis collapse is associated with disease progression in FA.

A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models

Hong Wang et al., A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2618654123

GBT601/PT2399 Halts Neurological Disease Phenotypes in Friedreich’s Ataxia Mouse Model. Here, we tested whether the GBT601/PT2399 combination could mimic the effects of inhalational hypoxia to similarly halt neurological symptoms in the shFxn mice once they began to exhibit signs of advanced debility. Hence, these studies indicate that initiating the combination treatment at 24 wk of age, can halt further progression of the ataxia phenotype, though in contrast to 11% FIO2 (13), is unable to reverse these motor phenotypes.

Reduction of interleukin-6 levels in patients with Friedreich's Ataxia treated with omaveloxolone

Di Stefano V, Lima S, Campo S ... Reduction of interleukin-6 levels in patients with Friedreich's Ataxia treated with omaveloxolone; Journal of the Neurological Sciences, 2026; 491. DOI:10.1016/j.jns.2026.126204 

 Omav confirmed a favorable safety and tolerability profile in adult patients with FRDA in a real-world setting after 48 weeks of treatment. The sustained reduction in IL-6 levels further supports a potential direct immunomodulatory effect of the drug, consistent with its proposed disease-modifying activity. However, further long-term studies are warranted to better define the efficacy of Omav in FRDA.

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model

Autonomic neurons are intrinsically hyperexcitable in a Friedreich ataxia iPSC model; Shiang L (Max), Jarmon Lees, Haoxiang Zhang, Li Li, Mirella Dottori, Alice Pebay, Louise Corben, Martin Delatycki, Stephen Wilcox, Jeffrey Pullin, Jarny Choi, Davis McCarthy, Jill Napierala, Marek Napierala. bioRxiv 2026.10.06.757136; doi:10.64898/2026.10.06.757136 

 Bulk RNA sequencing of all three isogenic pairs revealed loss of extracellular matrix programs and activation of stress response pathways. The top differentially expressed gene was MEG3, a maternally imprinted long noncoding RNA, which was consistently upregulated across all three isogenic pairs. MEG3 sits within the imprinted 14q32 DLK1-DIO3 locus, whose maternally expressed noncoding transcripts were co-ordinately de-repressed in FRDA autonomic neurons. Competitive gene-set testing of 43 imprinted genes across 20 domains showed this to be specific to 14q32: no other imprinted domain was co-ordinately altered. Together, these findings establish hyperexcitability of autonomic neurons as a cell autonomous consequence of frataxin deficiency, accompanied by mitochondrial dysfunction. This provides a cellular basis for the increased sympathetic tone observed in clinical studies.

Exploring the molecular landscape of Friedreich ataxia with long-read sequencing

Sebastien Audet, Marjorie Labrecque, Valerie Triassi, Carolane Charest, Adrien Rihoux, Laura Hamilton, Grace Yoon, Antoine Duquette, Martine Tetreault, 1.45P Exploring the molecular landscape of Friedreich ataxia with long-read sequencing, Neuromuscular Disorders, Volume 67, Supplement 1, 2026, 106600, ISSN 0960-8966, doi:10.1016/j.nmd.2026.106600. 

 Data integration utilized custom bioinformatics pipeline. Following the analysis, we observe 1) a repeat length quantification that broadly correlates clinical data but exhibiting events of somatic expansion and non-homogeneous repeat motifs. 2) We identify regions of differential methylation near promoters that correspond to 3) genes exhibiting significant changes in expression. We 4) evaluated LRS-enabled alternative splicing/poly-A tailing detection and 5) assessed if the levels of differential methylation/expression correlate to increased repeat length. This project should consolidate the potential of LRS in clinical genetics and functional studies. Regarding FRDA, results should provide new insights into pathogenic mechanisms and potentially identify molecular signatures of the disease, assisting in the search for new therapeutic targets.