Emerging therapeutics for the treatment of Friedreich's ataxia

Introduction: Friedreich ataxia (FRDA) is an autosomal recessive disorder which manifests with progressive instability, leading ultimately to loss of independent gait, dysarthria, skeletal abnormalities and cardiomyopathy. FRDA is caused in 96% of cases by a GAA repeat expansion in the first intron of FXN gene. Pathologic GAA expansions hinder transcriptional activity and result in a reduced expression of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency is accompanied by impaired oxidative phosphorylation, mitochondrial biogenesis and abnormal iron trafficking. From the discovery of disease causing mutation in 1996, combined efforts in basic and clinical research led to the investigation of several potential therapeutic compounds which intervene in different steps of the pathogenetic cascade. Areas covered: In the present review we aimed to critically reappraise current findings from clinical trials in FRDA, including an overview on trial design and preliminary data from ongoing studies. Expert opinion: Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.