FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution

Devore MC, Lam C, Xiao E, Devore J, McCain KRC, Wiley G, Park CC, Lynch DR, Bidichandani SI. FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution. Hum Mol Genet. 2026 Jun 9;35(11):ddag046. doi: 10.1093/hmg/ddag046. PMID: 42262226; PMCID: PMC13248553. 

 These data indicate that FXN protomutations serve as a reservoir for the generation of premutation and E alleles, and for millennia have sustained the geographically-defined population distribution of FRDA.

Integration of Evolutionary Analysis With RFdiffusion for De Novo Design of Aggregation-Resistant Frataxin

Kırboğa KK, Küçüksille EU. Integration of Evolutionary Analysis With RFdiffusion for De Novo Design of Aggregation-Resistant Frataxin. Proteins. 2026 Jun;94(6):1225-1244. doi: 10.1002/prot.70114. Epub 2026 Jan 21. PMID: 41563298. 

 This work establishes a generalizable framework for therapeutic protein engineering where backbone redesign enables conformational ensemble modulation beyond the limitations of sequence optimization alone.

Nerve ultrasound as a biomarker in Friedreich’s ataxia

Giuseppe Di Pietro, Ettore Cioffi, Pietro Falco, Caterina Leone, Giulia Di Stefano, Eleonora Galosi, Gianfranco De Stefano, Valentina Martinez, Stefano Perotti, Carlo Casali, Andrea Truini,, PO 286 Nerve ultrasound as a biomarker in Friedreich’s ataxia, Clinical Neurophysiology, Volume 185, 2026, 2111295, ISSN 1388-2457, doi:10.1016/j.clinph.2025.2111295. 

 All patients exhibited severe sensory axonal neuropathy. HRUS showed significant CSA enlargement in the median and ulnar nerves at the axilla and upper arm. The number of affected nerve sites correlated directly with disability scores (SARA, FARS, mFARS, ADL 0-36, INCAT) and inversely with IADL.

Sex-based differences in the NRF2 oxidative stress response: Implications for precision therapeutics

Giusy Russomanno, Karolina Kwiatkowska, Ian M. Copple, Sex-based differences in the NRF2 oxidative stress response: Implications for precision therapeutics, Redox Biology, Volume 92, 2026, 104128, ISSN 2213-2317, doi:10.1016/j.redox.2026.104128. 

 Hormonal status, age, and tissue-specific receptor distribution further modulate these effects, suggesting that therapeutic responses to NRF2 activators are inherently sex-dependent. Pharmacokinetic and pharmacodynamic differences, including CYP3A-mediated metabolism and body composition, may additionally influence systemic exposure and safety profiles. Despite clinical use of NRF2 activators such as dimethyl fumarate and omaveloxolone, sex-stratified data on efficacy, dosing, and safety are scarce. This knowledge gap underscores the need for systematic evaluation of sex, hormonal milieu, and age in pharmacokinetic, pharmacodynamic, and clinical studies to ensure treatments are safe, effective, and equitable. Integrating these variables into research and clinical practice will optimise therapeutic benefits and minimise adverse events by accounting for patient-specific biology.

Nonclinical efficacy and safety evaluation of SGT-212, a novel investigational AAV FXN gene therapy for the treatment of Friedreich’s ataxia

Nonclinical efficacy and safety evaluation of SGT-212, a novel investigational AAV FXN gene therapy for the treatment of Friedreich’s ataxia, Brandon YH Chan, Jun Lee, Jamie Marshall, Matthew Harmelink, Gourav Roy Choudhury, Heather Born, Juliette Hordeaux, James M Wilson, Jessie Hanrahan, Gabriel Brooks, Nicolas Christoforou. Solid Biosciences, Charlestown, USA; University of Pennsylvania, Philadelphia, USA. doi:10.1016/j.nmd.2026.106596 

 These positive nonclinical data supported initiation of the Phase 1b FALCON trial (NCT07180355), an actively enrolling first-in-human study of SGT-212.

Genetic prevalence of repeat expansion and other rare neurological disorders in the Quebec population

De Mori A, Labrecque M, Triassi V, Audet S, Pelletier J, Lai A, La Piana R, Duquette A, Bhérer C and Tetreault M (2026) Genetic prevalence of repeat expansion and other rare neurological disorders in the Quebec population. Front. Genet. 17:1964104. doi: 10.3389/fgene.2026.1964104 

Among the diseases expected to be enriched in the CaG cohort given their established association with the French-Canadian founder effect, FXN and DMPK variants were identified at elevated frequencies, as anticipated. The high CF of FXN variants is consistent with the autosomal recessive nature of FRDA, in which carriers are unaffected and therefore not excluded during recruitment of CaG participants. The recent approval of omaveloxolone as a therapy for FRDA further increases the clinical value of identifying expansion carriers early in the Quebec population

Cells heal themselves: gene-edited hematopoietic stem cells restore frataxin deficiency in multiple organs

Lucy R. Osborne. Cells heal themselves: gene-edited hematopoietic stem cells restore frataxin deficiency in multiple organs. J Clin Invest. 2026;136(20):e211630. doi:10.1172/JCI211630. 

 There is undoubtedly a lot of work to be done optimizing the editing efficiency of the repeat expansion, cell engraftment, and the timing of delivery, but the results reported by Sivakumar et al. are very encouraging and demonstrate that even with relatively limited editing and chimerism, there were concrete improvements in neurological, pancreatic, and cardiac function in the humanized mouse model of FRDA.

Recent developments in Friedreich's ataxia: a state-of-the-art review

Chapman LR, Mortiboys H, Shaw PJ. Recent developments in Friedreich's ataxia: a state-of-the-art review. Brain Commun. 2026 Apr 20;8(3):fcag143. doi: 10.1093/braincomms/fcag143. PMID: 42158846; PMCID: PMC13180647. 

We have conducted a critical review of all the studies published between 1999 and December 2024. The free text search terms were ((Friedreich's Ataxia) OR (FRDA) OR (FRDA) OR (inherited ataxias)) AND ((recent developments) OR (new developments) OR (new treatments) OR (phenotype)).

Metabolic dysfunction in Friedreich ataxia

David Lynch, Clementina Mesaros, Elizabeth Mercado Ayon, Yi Na Dong; Metabolic dysfunction in Friedreich ataxia. Open Biol. 1 November 2026; 16 (11): 260221. doi:10.1098/rsob.260221 

This review traces that logic from the cell to the organ to the whole body. The same map defines a compact panel of blood-based biomarkers, anchored on frataxin protein itself and extended by chain-resolved ceramides and by the succinate : fumarate, BHB : acetoacetate, NAD+ : NADH and GSH : GSSG ratios. It also nominates targets that do not require restoration of frataxin, including NRF2 activation, ferroptosis inhibition, NAD+ and sirtuin repletion, PPARgamma agonism, anaplerosis and ketone-based therapy. Reframing FRDA as a disorder of fuel logistics, rather than of fuel combustion alone, explains why a globally reduced protein produces a selective yet multisystem disease.

Larimar Therapeutics Completes Rolling BLA Submission Seeking Accelerated Approval of Nomlabofusp for Friedreich’s Ataxia

BALA CYNWYD, Pa., Nov. 09, 2026 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. today announced completion of its rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) seeking accelerated approval of nomlabofusp for the treatment of patients with Friedreich’s ataxia (FA). Completion of the submission follows previously disclosed FDA feedback on key elements of the BLA and represents a significant milestone for Larimar. Larimar is currently enrolling patients in FORWARD-FA, its global confirmatory Phase 3 study, a double-blind, placebo-controlled study that will evaluate daily subcutaneous use of nomlabofusp over 18 months in ambulatory participants ages 2 to 40 who are new to the drug. Approximately two thirds of the participants will be under the age of 21.

Submission Highlights: Data Package Supporting Submission and Review: FDA reviewed OL study data submitted in a briefing package and confirmed in minutes from the multidisciplinary Type B pre-BLA meeting that the existing data package appears capable of supporting submission and review of a BLA seeking accelerated approval of nomlabofusp as a treatment for patients with FA. Approval will be a matter of review. 

FXN as a Potential Surrogate Endpoint: In those previously disclosed interactions, FDA reaffirmed its willingness to consider FXN as a novel surrogate endpoint and indicated that Larimar’s exposure-response analysis linking nomlabofusp exposure to clinical outcomes is the type of analysis that could support the BLA submission. 

Additional Biological Evidence: FDA previously noted that prospectively collected exploratory gene expression and lipid pharmacodynamic markers data may help further characterize the biological activity of nomlabofusp beyond tissue FXN concentrations. 

Potential Upcoming Milestones BLA Submission Acceptance: Early 2027 Open Label Study Safety Update: Q1 2027 U.S. Approval: Mid-2027 Obtaining & Monetizing the Rare Pediatric Disease Priority Review Voucher: Mid-2027, if approved U.S. Launch: Targeting Q3 2027 launch, if approved.