Deciphering the missing links between Friedreich ataxia and multiple sclerosis for targeted drug development

Kwa FAA, Anjomani-Virmouni S, Ramchunder Z, Kendal E, Xiao J. Deciphering the missing links between Friedreich ataxia and multiple sclerosis for targeted drug development. Drug Discov Today. 2026 Mar 16;31(3):104644. doi: 10.1016/j.drudis.2026.104644. Epub ahead of print. PMID: 41850598. 

 FA and MS appear to share some overlapping molecular mechanisms, including iron and lipid dysregulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Recent research, including comparative transcriptomic analyses, offers valuable insights into shared disease pathways, with implications for potential biomarkers and therapeutic targets. In this review, we explore the shared pathological features and disease mechanisms in FA and MS, highlighting how delineating these shared pathways could inform early diagnostic strategies and support the development of targeted, mechanism-based interventions, including opportunities for drug repurposing.

Advancing a novel ASO therapy for Friedreich ataxia cardiomyopathy using a pre-clinical human vascularised cardiac organoid model

Jarmon G. Lees, Li Li, Haoxiang Zhang, Anne M. Kong, Andrew Treller, Geraldine M. Mitchell, Mirella Dottori, Alice Pebay, Stephen Wilcox, Mark Chong, Roger Peverill, Martin Delatyki, Jeffrey M. Pullin, Davis McCarthy, Jill S. Napierala, Marek Napierala, Shiang Y. Lim, Advancing a novel ASO therapy for Friedreich ataxia cardiomyopathy using a pre-clinical human vascularised cardiac organoid model, Journal of Molecular and Cellular Cardiology Plus, Volume 15, Supplement, 2026, 100527, ISSN 2772-9761, doi:10.1016/j.jmccpl.2025.100527. 

ASO-mediated knockdown of MEG3 reversed EC angiogenic dysfunction, limited SMC migration, reversed mitochondrial dysfunction, and prevented cardiac injury in a human vascularized cardiac organoid model. These findings suggest that MEG3 may be a promising novel therapy for treating cardiovascular disease in FA.

Fronto-Cerebellar Connectivity Disruptions and Functional Reorganization in Friedreich’s Ataxia: A Structural and Resting-State fMRI Study

Ravi Dadsena, Sandro Romanzetti, Stella Andrea Lischewski, Yingua Jing, Dagmar Timmann, Jennifer Faber, Jörg B. Schulz, Kathrin Reetz, Imis Dogan, Fronto-Cerebellar Connectivity Disruptions and Functional Reorganization in Friedreich’s Ataxia: A Structural and Resting-State fMRI Study, NeuroImage, 2026, 121872, ISSN 1053-8119, doi:10.1016/j.neuroimage.2026.121872.

While regional atrophy is known to be associated with symptoms, functional network alterations may represent a critical pathological mechanism; however, their specific contribution to motor and cognitive impairment remains unclear.

Advanced Heart Failure in Friedreich's Ataxia: A Story of Challenges, Opportunities, and Hope

Advanced Heart Failure in Friedreich's Ataxia: A Story of Challenges, Opportunities, and Hope. Satoshi Miyashita, Anthony Zaki, Kaitlin Schlabach, Gabriel Kim, Juliane K. Vierecke, David Lynch, Carmela Tan, Eileen Hsich, and Paulino Alvarez; JACC: Case Reports, 2026, 107391, ISSN 2666-0849, doi:10.1016/j.jaccas.2026.107391.

Heart failure is the leading cause of death in patients with FRDA. For those with high-risk features for adverse cardiovascular outcomes, careful monitoring of disease progression and early evaluation for advanced heart failure therapies are warranted.

Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia

Rummey C, Blair IA, Mesaros C, Rojsajjakul T, Dong Y, Wilmot G, et al. Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia. BMJ Neurology Open. 2026;8:e001561. doi:10.1136/bmjno-2026-001561 

 The present study demonstrates that frataxin levels directly correlate with all major clinical outcomes in FRDA, including not only cross-sectional markers such as AOO and disease severity, but also LoA as a disease milestone and long-term progression slopes of mFARS and USS. The associations were observed consistently across two independent cohorts and two distinct assay platforms, providing robust support for peripheral frataxin level as a clinically meaningful biomarker in both natural history studies and interventional trials.

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis Marnie L Maddock, Sara Miellet, Anjila Dongol, Amy J Hulme, Chloe K Kennedy, Louise A Corben, Rocio K Finol-Urdaneta, Alberto Nettel-Aguirre, Chiara Dionsi, Martin B Delatycki, Joel M Gottesfeld, Massimo Pandolfo, Elisabetta Soragni, Sanjay I Bidichandani, Jarmon G Lees, Shiang Y Lim, Jill S Napierala, Marek Napierala, Mirella Dottori bioRxiv 2026.03.18.712785; doi: 10.64898/2026.03.18.712785 

Together, these findings implicate cell type specific transcriptional programs as potential drivers of selective vulnerability and establish a framework for prioritising biomarkers in FRDA.

The multifaceted nature of Friedreich ataxia: strategies for comprehensive patient care.

Raza, M. L., Rawalia, M. A., Fatima, Z., & Zehra, H. (2026). The multifaceted nature of Friedreich ataxia: strategies for comprehensive patient care. Neurodegenerative Disease Management, 1–9. doi:10.1080/17582024.2026.2645501

Design Therapeutics Maps H2 Data Readouts for RESTORE-FA

MarketBeat. Sun, March 15, 2026. RESTORE-FA targets a demonstrable increase in endogenous frataxin (measured in mRNA and protein, including muscle biopsy) after 12 weeks of dosing, with topline data expected in the second half of the year. According to Shah, achieving that type of increase would be notable because it has “never been achieved before.” He said the company is measuring both frataxin mRNA and frataxin protein, describing mRNA as “completely endogenous” and specifying that the assay looks at “normal processed mRNA.” Measurements will be taken in whole blood cells and also in affected tissue via muscle biopsy, though he noted biopsy sampling is limited and would generally be conducted before and after dosing, with a possible third sample.

On the question of GeneTAC selectivity, Shah pointed to preclinical work across multiple FA patient-derived cell types. He said GeneTAC molecules increased endogenous frataxin RNA and led to downstream effects including normalization of protein levels and improvements in functions such as cis-aconitate and cellular respiration. He added that exposure of wild-type genotype cells to an FA GeneTAC molecule had no impact because the repeat number in the wild-type allele is short and therefore does not produce a functional consequence when treated.

Patient population and endpoints in the FA study Shah described RESTORE-FA enrollment criteria as “pretty permissive” beyond genetic confirmation of FA, including ambulatory and wheelchair-bound patients. He said the current study explores both IV and subcutaneous (sub-Q) administration to help determine dose route, dosing interval, and the frataxin response to inform future clinical investigation. While functional assessments are customary in FA trials and are being performed, he said the primary goal of the study is to look for a frataxin response.

Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review

Baris S, Dogan M, Terali K, Gezdirici A, Eroz R, Yucel PP, Kilic H, Yavas C, Yildirim G, Baris I. Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review. Int J Mol Sci. 2026 Jan 6;27(2):575. doi: 10.3390/ijms27020575. PMID: 41596228; PMCID: PMC12841059.

The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.

Hereditary Ataxias: From Pathogenesis and Clinical Features to Neuroimaging, Fluid, and Digital Biomarkers-A Scoping Review

Bernardi E, López-Lombardía Ó, Olmedo-Saura G, Pagonabarraga J, Kulisevsky J, Pérez-Pérez J. Hereditary Ataxias: From Pathogenesis and Clinical Features to Neuroimaging, Fluid, and Digital Biomarkers-A Scoping Review. Int J Mol Sci. 2026 Jan 15;27(2):881. doi: 10.3390/ijms27020881. PMID: 41596528; PMCID: PMC12841259.

We conducted a scoping review of PubMed and complementary sources (2010-2025) to map and describe the current landscape of genetic, imaging, fluid, electrophysiological, and digital biomarkers across the most prevalent hereditary ataxias, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, SCA27B, dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia (FRDA), RFC1-related ataxia (CANVAS), SPG7, and fragile X-associated tremor/ataxia syndrome (FXTAS). 

 Mapping current approaches also reveals substantial variability and gaps across diseases and modalities, underscoring the need for harmonized validation in international multicenter cohorts and systematic integration into future clinical trials to advance precision medicine in hereditary ataxias.