Treatment with ROS detoxifying gold clusters alleviates the progressive functional decline in a mouse model of Friedreich’s Ataxia

Friedreich's ataxia (FRDA) is caused by the reduced expression of the mitochondrial protein frataxin (FXN) due to an intronic GAA trinucleotide repeat expansion in the FXN gene. Although FRDA has no cure and few treatment options, there is research dedicated to finding an agent that can curb disease progression and address symptoms as neurobehavioral deficits, muscle endurance and heart contractile dysfunctions. Since oxidative stress and mitochondrial dysfunction are implicated in FRDA, we demonstrated the systemic delivery of catalysts activity of gold cluster superstructures (Au8-pXs) to improve cell response to mitochondrial reactive oxygen species (ROS) and thereby alleviate FRDA-related pathology in mesenchymal stem cells of FRDA patients. We also found that systemic delivery of Au8-pXs induced significant amelioration of motor function and cardiac contractility of YG8sR mouse model that recapitulates the FRDA phenotypes. These effects were linked to long-term improvement of mitochondrial functions and antioxidant cell responses. We coupled these events with increased expression of frataxin, which is sustained by reduced autophagy. Overall, these results suggest a cascade of Au8-pXs-related signals that encourage further optimization of the use of Au8-pXs in experimental clinical strategies for the treatment of FRDA.