DeFend - De-ironing Friedreich’s Ataxia with innovative mitochondria-targeted chelators

Friedreich's ataxia (FRDA; ORPHA:95) is the most common autosomal recessive ataxia and is characterized by progressive cardio- and neurodegenerative effects. The cause for this rare disease is a trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene. This expansion impairs the production of FXN, a mitochondrial matrix protein involved in mitochondrial iron homeostasis that mediates the assembly of iron-sulfur clusters (ISCs). The pathophysiological consequences of FXN deficiency include severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron deregulation, an increased sensitivity to oxidative stress (OS) and mitochondrial dysfunction. Moreover, some of the molecular mechanisms of FRDA overlap those of oxytosis/ferroptosis, a form of iron-induced cell death characterized by iron-induced oxidative stress, impairment of antioxidant defenses and accumulation of lipid peroxides. Despite massive eorts, there is no current approved drug to prevent or delay the progression of FRDA. Thus, finding a therapy for FRDA is a major unmet medical need. DFP, an iron chelator approved to treat thalassemia, presents beneficial effects in the treatment of FRDA when used alone or combined with other molecules. DFP can cross the BBB and shuttle iron between cellular organelles. However, the lack of mitochondria specificity limits its therapeutic use for FRDA. Over the last decades, medicinal chemists have been developing innovative mitochondria-targeted antioxidants (MTAs) with therapeutic potential for diseases associated with mitochondrial dysfunction. In fact, our team developed AntiOxCIN4, a safe caffeic acid-based MTA able to prevent mitochondrial dysfunction and OS in in vitro cellular models. Recent studies also showed that MitoQ10, a MTA based on coenzyme Q10, presents protective effects on cellular models of FRDA. However, the therapeutic potential of MitoQ10 on FR.