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.

Goldenrod Therapeutics: brain-penetrant PDE4 inhibitor from UNMC

Goldenrod Therapeutics is developing 11h, a brain-penetrant inhibitor of the inflammatory enzyme PDE4, for neurological diseases driven by brain inflammation, with Friedreich's ataxia as an initial target. Existing PDE4 drugs are limited by nausea and poor uptake into the central nervous system, which 11h was designed to overcome. 

The molecule was created by chemist Corey Hopkins, PhD, at the University of Nebraska Medical Center College of Pharmacy. UNeMed, UNMC's technology transfer office, helped establish Goldenrod in 2023 and put the licence in place. In June 2026 the company closed a $6.5M seed round led by Ataxia Ventures and an affiliate of Fannin Partners to complete the studies needed for clinical trials planned for 2027.

Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions

M. P. Lazaropoulos, M. C. Devore, C. Lam, C. Park, S. Bidichandani, and D. R. Lynch, “ Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions,” Annals of Clinical and Translational Neurology 13, no. 10 (2026): 2134–2137, doi:10.1002/acn3.70408. 

 We present Friedreich ataxia patients with frataxin gene deletions. Data and records were collected at the Children's Hospital of Philadelphia from patients enrolled in the FACOMS natural history study.

TwinPE delivered as RNA or VLP enables precise deletion of GAA repeats in the FXN gene

Xuntao Zhou, Thomas C. Todeschini, Tianxiong Yu, Runyuan Wang, Bin Liu, Annie Collins, Whitney Welch, Aditya Valji Ansodaria, Zhiping Weng, Scot A. Wolfe, Jonathan K. Watts, Erik J. Sontheimer, Wen Xue, TwinPE delivered as RNA or VLP enables precise deletion of GAA repeats in the FXN gene, Cell Insight, 2026, 100368, ISSN 2772-8927, doi:10.1016/j.cellin.2026.100368. 

Abstract: Friedreich’s ataxia (FRDA or FA) is a rare autosomal recessive neurodegenerative disorder caused by guanine-adenine-adenine (GAA) repeat expansions in the first intron of the frataxin (FXN) gene. To address this underlying genetic cause, we developed paired prime editors (twinPE) to precisely delete GAA repeats. Using a 38-bp attachment site of bacteria (attB) sequence as the reverse transcription template (RTT), we achieved a precise 1.2-kb deletion with attB insertion in HEK293T cells with a 48.0% editing efficiency. We further delivered two synthetic pegRNAs and PE6 mRNA into GM03816 FRDA fibroblasts and GM23404, as well as GM23913 patient-derived induced pluripotent stem cells (iPSCs) via electroporation, achieving average editing rates of 13.3%, 40.6%, and 25.0%, respectively. In both patient-derived iPSCs, twinPE successfully restored FXN expression, resulting in a ∼2-fold increase in mRNA levels, relative to non-treated controls, demonstrating a promising functional correction of gene expression. Importantly, NGS analysis revealed that >95% of all edits were precise, with minimal indels across all tested cell types. We directly delivered twinPE to iPSC-derived motor neurons (iMNs) using virus-like particles (VLPs), achieving 12.6% editing. In summary, our results demonstrate that twinPE enables efficient and precise deletion of GAA repeats across multiple cell types, including iMNs. The restoration of FXN mRNA in iPSCs represents a promising functional recovery, establishing a foundation for twinPE-mediated genome editing as a potential therapeutic strategy for FRDA.

Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts

Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts Anna Stepanova, Hibiki Kawamata, Giovanni Manfredi bioRxiv 2026.09.21.753166; doi: doi:10.64898/2026.09.21.753166 

Our study suggests that cytosolic Ca regulation modifies profibrotic stimulation in FA. We propose the following mechanism for intrinsic profibrotic bias in human FA fibroblasts: NCX1 downregulation contributes to slower cytosolic Ca clearance, thereby sustaining Ca-dependent signaling and consequently increased expression of CCN2 and other profibrotic factors. If validated in FA heart, our findings would identify NCX1-mediated Ca extrusion in fibroblasts as a potential therapeutic target to mitigate fibrosis that contributes to lethal cardiomyopathy in FA patients.

Long-Term Experience in the Molecular Genetic Diagnosis of Friedreich Ataxia in the Russian Federation

Ismagilova, O.; Adyan, T.; Galeeva, N.; Zabnenkova, V.; Shatokhina, O.; Kazaryan, M.; Rudenskaya, G.; Dadali, E.; Saifullina, E.; Polyakov, A. Long-Term Experience in the Molecular Genetic Diagnosis of Friedreich Ataxia in the Russian Federation. Genes 2026, 17, 1169. doi:10.3390/genes17101169  

Friedreich’s ataxia in considered the most common form of autosomal recessive ataxia; however, it’s prevalence in the Russian Federation remains poorly studied. 

This paper presents the results of a long-term study on the molecular genetic causes of FRDA in Russian Federation, yielding an estimated frequency of 1:102,000 individuals for the disease associated with GAA repeat expansion.

Lexeo Therapeutics Enters Into Agreement to Acquire Mantle Therapeutics and Announces Multiple New Strategic Collaborations to Expand Leadership in Friedreich Ataxia

NEW YORK, Sept. 22, 2026 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. today announced a series of strategic transactions to expand its presence in Friedreich ataxia (FA), including the signing of a definitive agreement to acquire Mantle Therapeutics Inc. and three new research collaborations supporting cerebellar-targeted development opportunities for frataxin gene therapy. Together, these transactions will simultaneously expand Lexeo's vision and capabilities beyond gene therapy, deepen the company’s focus on the multisystem burden of FA, and add multiple therapeutic approaches designed to increase or restore frataxin in the brain. These transactions are being pursued within Lexeo's existing balance sheet capacity, with cash runway guidance unchanged into 2028 and future investment decisions guided by predefined milestones to identify and prioritize the most compelling central nervous system (CNS) opportunities. 

The acquired portfolio will include: LX3010 (MTL-104), LX3030 (MTL-707), LX3050 (MTL-501) y LX3070 (MTL-801).