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).

A Patient-Reported Outcome Measure of Communication Difficulties in Friedreich Ataxia: COMATAX

Buchholz M, Monier V, Ewenczyk C, Heinzmann A, Pierron L, Sayah S, Hilab R, Atencio M, Petit E, Bertrand F, Vallancien A, Diot C, Rouillon S, Nadke A, Feldmann K, Maas V, Faber J, Sarwinska D, Boesch SM, Indelicato E, Bischoff AT, Klopstock T, Schulz JB, Reetz K, Fleszar Z, Iskandar A, Klockgether T, Grobe-Einsler M, Xie F, Humphries B, Michalowsky B, Durr A, Borel S. A Patient-Reported Outcome Measure of Communication Difficulties in Friedreich Ataxia: COMATAX. Cerebellum. 2026 May 23;25(4):85. doi: 10.1007/s12311-026-02020-3. PMID: 42174309; PMCID: PMC13197451. 

 Background and Objectives: Friedreich ataxia (FA) causes progressive impairment of communication due to gradual deterioration of speech, associated with impaired hearing, socio-cognitive and language skills. There is an urgent need to investigate the impact of this multiparametric alteration on patients’ lives. Therefore, the COMunication and ATAXia measure (COMATAX) was developed and validated in French and German.

Friedreich's ataxia: pathology, symptoms and treatment

Friedreich's ataxia: pathology, symptoms and treatment. RUTVI JAIN B.A., Boston University, 2025. Boston University Theses & Dissertations. Submitted in partial fulfillment of the requirements for the degree of Master of Science 2026.

Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers

Hao Y and Hao X (2026) Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers. Front. Neurol. 17:1921210. doi: 10.3389/fneur.2026.1921210 

This review synthesizes evidence across five complementary biomarker domains, clinical, imaging, fluid, genetic, and digital, and judges their readiness for forecasting onset and progression. Clinical scales such as SARA capture genotype-specific trajectories but lose sensitivity at the extremes of the disease course. Volumetric, microstructural, and spectroscopic MRI and blood neurofilament light chain change before ataxia onset and predict subsequent decline, whereas repeat length and genetic modifiers set prior risk. Wearable-sensor gait and balance metrics detect change earlier than clinical scales and sharply reduce required sample sizes. We argue that no single modality satisfies every context of use, and that stage-specific, multimodal composites, integrated through harmonized international cohorts and machine learning, offer the most credible path to prognostic enrichment and to shorter, adequately powered, and preventive trials.

Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis

Garah B, Aljabri H, Aljohani A, Alnuzha E, Maihoub A, Almuzaini R, Aljohani L, Alshamani L, Alluqmani M. Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis. J Clin Med. 2026 Jul 21;15(14):5707. doi: 10.3390/jcm15145707. PMID: 42513621; PMCID: PMC13413417. 

 Friedreich’s ataxia (FRDA) is a challenging neurodegenerative disorder with limited pharmacologic treatment options. Among the therapies reviewed, omaveloxolone was the only agent to demonstrate a statistically significant improvement in neurological outcomes; however, this finding is based on very low-certainty evidence. Consequently, omaveloxolone may be the most promising current pharmacologic option, but its true efficacy remains uncertain and should be confirmed in larger, longer, and well-designed randomized controlled trials. Other pharmacologic agents showed no consistent evidence of benefit. Safety outcomes were broadly comparable between intervention and control groups; however, available safety evidence remains limited by imprecision, small sample sizes, and relatively short follow-up periods. Although no substantial increase in adverse events was observed, confidence in the safety estimates remains limited.

Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis−generating candidate for nephrolithiasis

Wu Y, Ye S, Li P, Wu Z, Guo Z, Bian J, Sheng M and Lai D (2026) Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis−generating candidate for nephrolithiasis. Front. Immunol. 17:1876576. doi: 10.3389/fimmu.2026.1876576 

This multi-omics MR study links mitochondrial genes, particularly FXN, to urolithiasis risk. Although colocalization evidence was weak (PP.H4 = 0.0239) and replication in independent cohorts was not statistically significant, the multi−omics consistency across methylation, expression, and protein levels prioritizes FXN as a hypothesis−generating candidate for further investigation. Because all QTL data are blood− or plasma−derived, this study provides blood/plasma QTL−based genetic prioritization rather than kidney−specific causal inference.

Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress

A. Terenzi, M.A. Pagani, M.V. Busi, D.F. Gomez-Casati, Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress, Plant Physiology and Biochemistry, Volume 238, 2026, 111687, ISSN 0981-9428, doi: 10.1016/j.plaphy.2026.111687.

Frataxin plays a crucial role in iron homeostasis, Fe-S cluster, and heme biogenesis. This study investigated the impact of constitutive AtFH overexpression in Arabidopsis thaliana. The results demonstrated significant alterations in Fe-S protein activity, iron distribution, and the expression of genes associated with iron transport, Fe-S cluster assembly, and iron storage. Notably, AtFH-overexpressing plants displayed enhanced growth, with increased rosette area and improved root development, under both iron-deficient and iron-excess conditions. While these findings provide valuable insights into the regulatory potential of frataxin in optimizing plant iron homeostasis, they also highlight the need for tissue-specific and stress-inducible approaches to fully evaluate its application in crop resilience.