Emerging antioxidant therapies in Friedreich’s ataxia

Friedreich’s ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in
50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA
repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of
the mitochondrial protein frataxin. The disease is characterised by progressive
neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and
musculoskeletal deformities. The reduced expression of frataxin has been
suggested to result in the downregulation of endogenous antioxidant defence
mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial
iron accumulation thereby leading to oxidative stress. The confirmation of
oxidative stress as one of the pathological signatures of FRDA led to the
search for antioxidants which can be used as therapeutic modality. Based on
this observation, antioxidants with different mechanisms of action have been
explored for FRDA therapy since the last two decades. In this review, we bring
forth all antioxidants which have been investigated for FRDA therapy and have
been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.