Redox homeostasis and Inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk

Andrea Quatrana, Sara Petrillo Sara Petrillo, Caterina Torda Caterina Torda, Eleonora De Santis, Enrico Bertini Enrico Bertini, Fiorella Piemonte. Front. Mol. Neurosci., Sec. Molecular Signalling and Pathways, Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1571402.

We found a significant activation of the TLR4/NF-kB/IL-1β axis in patients, associated to a consistent increase of the redox enzymes thioredoxin 1 (TRX1) and glutaredoxin 1 (GLRX1), which are essential to activate NF-kB under oxidative stress conditions. Furthermore, we investigated the role of 4-HNE, a by-product of lipid peroxidation, as a potential mediator between ferroptosis and inflammation in FRDA.

Systemic AAV Gene Therapy with Next Generation Engineered Capsids for Treatment of CNS and Cardiac Symptoms in Friedreich’s Ataxia

MDA Conference 2025. Ryan Kast, PhD, Capsida Biotherapeutics, Celeste Stephany, PhD, Capsida Biotherapeutics, Miguel Chuapoco, PhD, Capsida Biotherapeutics, Xiaojing Shi, PhD, Capsida Biotherapeutics, Assaf Beck, PhD, Capsida Biotherapeutics, Austin Kidder, Capsida Biotherapeutics, Yixi Wang, Capsida Biotherapeutics, Kevin Lam, Capsida Biotherapeutics, Nicholas Flytzanis, PhD, Capsida Biotherapeutics, Nick Goeden, PhD, Capsida Biotherapeutics. The engineered capsid delivering human FXN transduced more than 80% of cerebellar Purkinje cells, dentate nucleus neurons, motor neurons in the cortex and spinal cord, and nearly 30% of cardiac tissue area. FXN protein levels in treated NHPs were 8.2x higher than endogenous levels in the motor cortex and 1.7x in the heart as measured by ELISA. Moreover, substantial FXN RNA expression was detected in the retina (~1E6 copies/ug RNA) suggesting potential benefit for sensory vision loss experienced by FA patients. Significant de-targeting of the liver and other non-target tissues contributed to the favorable safety profile characterized by no adverse immunogenicity, clinical pathology, and histopathology findings.

LEXEO THERAPEUTICS REPORTS FOURTH QUARTER AND FULL YEAR 2024 FINANCIAL RESULTS AND OPERATIONAL HIGHLIGHTS

NEW YORK, March 24, 2025 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. . 

Mid-Year Clinical Update Expected to Include: 

Safety and tolerability data for all participants dosed across both the SUNRISE-FA and Weill Cornell clinical trials (at least 16 participants, including 6 participants with abnormal LVMI at baseline) 

Pre- and post-treatment cardiac frataxin protein expression measured via LCMS for all four participants at the highest dose (1.2x1012 vg/kg, Cohort 3) 

Clinical biomarker data, including left ventricular mass index (LVMI), left ventricular wall thickness and high-sensitivity troponin I, for participants with >6-months of follow up 

Functional and patient-reported outcome data for participants with >6-months of follow up 

Safety: LX2006 continues to be generally well tolerated with no new treatment-related serious adverse events to report

Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study

Georgiou-Karistianis, N., Corben, L.A., Lock, E.F., Bujalka, H., Adanyeguh, I., Corti, M., Deelchand, D.K., Delatycki, M.B., Dogan, I., Farmer, J., França, M.C., Jr., Gabay, A.S., Gaetz, W., Harding, I.H., Joers, J., Lax, M.A., Li, J., Lynch, D.R., Mareci, T.H., Martinez, A.R.M., Pandolfo, M., Papoutsi, M., Parker, R.G., Reetz, K., Rezende, T.J.R., Roberts, T.P., Romanzetti, S., Rudko, D.A., Saha, S., Schulz, J.B., Subramony, S.H., Supramaniam, V.G., Lenglet, C. and Henry, P.-G. (2025), Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study. Ann Neurol. doi: 10.1002/ana.27237

 Our findings provide strong imaging evidence of impaired development of spinal cord and superior cerebellar peduncles during childhood in Friedreich ataxia and open the way for the use of neuroimaging biomarkers in clinical trials.

Debates over orphan drug pricing: a meta-narrative literature review

Hanchard, M.S. Debates over orphan drug pricing: a meta-narrative literature review. Orphanet J Rare Dis 20, 107 (2025). doi:10.1186/s13023-025-03634-2 

The review finds a sustained call for reform, centred on welfare economics and resource allocation, where current incentives and regulations are held to be insufficient. Overall, the article recommends that regulators look to alternative models of innovation steeped in social science thinking to modify reviewing appraisal, coverage, and reimbursement processes for orphan drugs. Also, that greater patient inclusion and transparency would help include a wider range of intangible social factors that rare disease patients face in accessing high priced orphan drugs.

Brain microvascular endothelial cells differentiated from a Friedreich's Ataxia patient iPSC are deficient in tight junction protein expression and paracellularly permeable

Brain microvascular endothelial cells differentiated from a Friedreich's Ataxia patient iPSC are deficient in tight junction protein expression and paracellularly permeable. Front. Mol. Neurosci. Sec. Brain Disease Mechanisms, Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1511388 

These data show that decreased barrier integrity is a pathophysiologic phenotype of FA brain microvascular endothelial cells. Clinically, this may be a targetable pathway to abrogate brain iron accumulation, neuroinflammation, and neurodegeneration profiles of FA. Additionally, investigation into other barrier systems, such as the blood-nerve barrier, blood-CSF barrier, or cardiac vasculature may inform on extra-neural symptoms experienced by the FA patient.

SKYCLARYS™ (omaveloxolone) Approval by Health Canada Ushers in a New Era for Friedreich’s Ataxia Treatment in Canada

TORONTO, March 17, 2025 /CNW/ - Biogen Canada Inc. is pleased to announce that Health Canada has approved SKYCLARYS™ (omaveloxolone) for the treatment of Friedreich’s ataxia (FA) in patients 16 years of age and older.2 This approval – granted under Health Canada’s Priority Review process – marks an important milestone making SKYCLARYS the only treatment in Canada to specifically target the underlying mechanisms of this rare, progressive neurodegenerative disease.

P732: Identification of pathogenic expansions within FXN in individuals with suspected Friedreich ataxia diagnoses

P732: Identification of pathogenic expansions within FXN in individuals with suspected Friedreich ataxia diagnoses, Bohm, Kaitlynne et al., Genetics in Medicine Open, Volume 3, 103101 doi:10.1016/j.gimo.2025.103101 

Our PCR and NGS-based test designed to detect pathogenic GAA repeat expansions and sequence variants within the FXN gene was successful in providing 18 positive test results to individuals known to have, or suspected of having, Friedreich Ataxia. The FA Identified sponsored testing program has presented a unique opportunity to understand the milieu of clinical characteristics of individuals with a positive FA diagnosis, and the health care providers seeking such testing for their patients.

P356: Prediction of tissue frataxin levels with long term administration of nomlabofusp in adults with Friedreich’s ataxia using modeling and simulations

P356: Prediction of tissue frataxin levels with long term administration of nomlabofusp in adults with Friedreich’s ataxia using modeling and simulations, Clayton, Russell et al., Genetics in Medicine Open, Volume 3, 102321. doi: 10.1016/j.gimo.2025.102321 

Modeling and simulations using PK and PD data from short term studies can be used to predict a potential long term therapeutic dose. In the majority of patients with FRDA, daily administration of 50 mg nomlabofusp is predicted to result in skin frataxin concentrations that are ≥ 50% of concentrations observed in healthy controls.

P289: Disease characteristics and tissue frataxin concentrations in adults with Friedreich’s ataxia participating in nomlabofusp interventional studies

Russell Clayton, Mohamed Hamdani, Noreen Scherer,, P289: Disease characteristics and tissue frataxin concentrations in adults with Friedreich’s ataxia participating in nomlabofusp interventional studies, Genetics in Medicine Open, Volume 3, Supplement 2, 2025, 102254, ISSN 2949-7744, doi10.1016/j.gimo.2025.102254. 

Tissue frataxin concentration data from these studies are consistent with prior studies demonstrating that lower frataxin concentrations are associated with earlier onset of disease. The range of characteristics observed in the population of patients with FRDA participating in the nomlabofusp interventional studies is representative of the general FRDA adult population. Buccal and skin cell frataxin levels correlate with each other.

A Study to Learn More About the Long-Term Safety of BIIB141 (Omaveloxolone) in Participants With Friedreich's Ataxia Who Are Prescribed it for the First Time

ClinicalTrials.gov ID NCT06623890.  Last Update Posted 2025-03-04

In this study, researchers will learn more about the safety of BIIB141, also known as omaveloxolone or SKYCLARYS®. This is a drug available for doctors to prescribe for people with Friedreich's Ataxia, also known as FA. This is known as an "observational" study, which collects health information about study participants without changing their medical care. Participants for this study will be found using a group called the Friedreich's Ataxia Global Clinical Consortium (FA GCC). This is a group of study research centers that help provide clinical care for people with FA.

The primary objective of this study is to assess the long-term safety of omaveloxolone as prescribed to participants with FA in the real-world setting, including characterization of all drug-induced liver injury (DILI) and congestive heart failure (CHF) AEs. The secondary objective of this study is to capture the reasons and timing of omaveloxolone treatment interruptions, discontinuations, and drug overdose.

Design Therapeutics Highlights Progress Across Lead GeneTAC® Programs and Reports Fourth Quarter and Full Year 2024 Financial Results

CARLSBAD, Calif., March 10, 2025 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc.. Friedreich Ataxia (FA) Design has initiated dosing in a Phase 1 clinical trial in healthy volunteers in Australia to evaluate the safety and pharmacokinetics (PK) of single ascending doses of DT-216P2 via multiple routes of administration (intravenous infusion, subcutaneous infusion and subcutaneous injection). A Phase 1/2 multiple ascending dose (MAD) clinical trial to assess safety, PK and pharmacodynamics (PD) in FA patients is anticipated to begin in mid-2025. Data based on twelve weeks of DT-216P2 dosing in patients is anticipated in 2026.

Autosomal Recessive Ataxias in Northeast Brazil: A Regional Multicenter Case Series

Camelo-Filho, A.E., da Rosa, R.F., Lima, P.L.G.S.B. et al. Autosomal Recessive Ataxias in Northeast Brazil: A Regional Multicenter Case Series. Cerebellum 24, 59 (2025). Doi:10.1007/s12311-025-01814-1

Patients underwent clinical evaluations, including neurological examinations and functional assessments. Results: Friedreich’s ataxia (FRDA) was the most prevalent diagnosis, accounting for 12 cases (21%), followed by Ataxia-Telangiectasia (A-T) with (N = 9; 15.8%) and Niemann-Pick Disease Type C (NPC) (N = 9; 15.8%). Metabolic disorders, including Cerebrotendinous Xanthomatosis (N = 6;10.5%) were also common causes.

Design Therapeutics Highlights Progress Across Lead GeneTAC® Programs

CARLSBAD, Calif., March 10, 2025 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. today announced progress across its portfolio of GeneTAC® candidates and reported fourth quarter and full year 2024 financial results.

Friedreich Ataxia (FA) Design has initiated dosing in a Phase 1 clinical trial in healthy volunteers in Australia to evaluate the safety and pharmacokinetics (PK) of single ascending doses of DT-216P2 via multiple routes of administration (intravenous infusion, subcutaneous infusion and subcutaneous injection). A Phase 1/2 multiple ascending dose (MAD) clinical trial to assess safety, PK and pharmacodynamics (PD) in FA patients is anticipated to begin in mid-2025. Data based on twelve weeks of DT-216P2 dosing in patients is anticipated in 2026.

FDA Action Update, February 2025: Approvals, Designations, and Acceptances

NeurologyLive. March 9, 2025. The FDA was busy in March 2025, making a number of decisions on potential new therapeutic agents including granting approvals, acceptances, and designations.

- Solid Biosciences' SGT-212 gene therapy for Friedreich ataxia received FDA clearance, targeting neurologic and systemic manifestations via dual administration routes. 

-On the same day, February 19, the FDA accepted PTC Therapeutics’ new drug application (NDA) for its investigational agent vatiquinone as a treatment for patients with Friedreich ataxia (FA)

Robust behavioral assessment of the inducible Friedreich's ataxia mouse does not show improvement with NRF2 induction

Claire B. Montgomery, Lili Salinas, Garrett P. Cox, Lauren E. Adcock, Tiffany Chang, Francisco Figueroa, Gino Cortopassi, Elena N. Dedkova; Robust behavioral assessment of the inducible Friedreich's ataxia mouse does not show improvement with NRF2 induction. Dis Model Mech 2025; dmm.052128. doi: https://doi.org/10.1242/dmm.052128

 We developed a novel Salinas-Montgomery Ataxia Scale (SMAS) which allows for more comprehensive assessment versus a 4-part cerebellar ataxia scale. Despite validating multiple sensitive techniques, we did not see any benefits of NRF2-inducing therapies in any tests. This was exacerbated by the discovery of a sexual dimorphism in FXNKD mice, in which males show a more significant decline and better responsiveness to NRF2-inducing therapeutics.

Solid Biosciences Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Updates

CHARLESTOWN, Mass., March 06, 2025 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. SGT-212 for Friedreich’s ataxia (FA) As announced on January 7, 2025, the FDA has cleared the IND for SGT-212 for the treatment of FA. SGT-212 is the first gene therapy candidate to utilize a dual route of administration to treat FA. The Company expects to initiate a first-in-human, open-label, Phase 1b clinical trial of SGT-212 in the second half of 2025. The trial is expected to enroll non-ambulatory and ambulatory adult participants living with FA across up to three cohorts and is designed to evaluate the safety and tolerability of concurrent systemic and bilateral IDN administration of SGT-212.

Gait Characteristics in People with Friedreich Ataxia: Daily Life versus Clinic Measures

Hannah L. Casey • Vrutangkumar V. Shah • Daniel Muzyka • James McNames • Mahmoud El-Gohary • Kristen Sowalsky • Delaram Safarpour • Patricia (Patty) Carlson-Kuhta • Christian Rummey • Fay B. Horak • Christopher M. Gomez, Front. Neurol. Sec. Movement Disorders, Volume 16 - 2025 | doi: 10.3389/fneur.2025.1544453 

Digital gait characteristics from inertial sensors are sensitive and specific for FRDA in both environments. However, different gait measures were more sensitive and specific during free-living versus prescribed gait, suggesting that in-clinic gait does not reflect daily life gait.

A global perspective on research advances and future challenges in Friedreich ataxia

Indelicato, E., Delatycki, M.B., Farmer, J. et al. A global perspective on research advances and future challenges in Friedreich ataxia. Nat Rev Neurol (2025). doi:10.1038/s41582-025-01065-y