From Genetic Mutation to Therapy in Friedreich Ataxia: Molecular Mechanisms, Therapeutic Advances, and Translational Challenges

Friedreich ataxia (FRDA) is a rare, autosomal recessive, progressive neurodegenerative disorder characterized by multisystem involvement, including gait and limb ataxia, cardiomyopathy, skeletal deformities, and metabolic dysfunction. Most patients harbor biallelic GAA trinucleotide repeat expansions in intron 1 of FXN, whereas others are compound heterozygotes with a GAA expansion on one allele and a pathogenic FXN variant on the other. FXN encodes frataxin, a nuclear-encoded mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis and mitochondrial energy production. Frataxin deficiency disrupts mitochondrial metabolism, promotes iron dysregulation and oxidative stress, and leads to progressive cellular injury, particularly in high-energy tissues such as the nervous system and myocardium. Despite substantial advances in understanding FRDA pathogenesis, no curative therapy is currently available. In 2023, omaveloxolone (Skyclarys) became the first approved treatment for FRDA, marking a significant therapeutic milestone. Concurrently, disease-directed strategies have expanded rapidly, including small-molecule modulators, adeno-associated virus (AAV)-mediated gene replacement, and transcriptional or epigenetic approaches aimed at restoring endogenous FXN expression. In addition, antisense oligonucleotide-based therapies and emerging CRISPR-mediated gene editing platforms are advancing through preclinical and early clinical development. This review provides a comprehensive overview of the evolving therapeutic landscape in FRDA, highlighting mechanistic rationales, preclinical progress, clinical trial outcomes, and the key translational challenges that must be addressed to achieve durable disease modification.