Modelling Friedreich’s ataxia cardiomyopathy: current directions and translational objectives

Friedreich’s ataxia (FRDA) is an autosomal recessive disease primarily affecting the nervous and cardiovascular systems. Hypertrophic cardiomyopathy that progresses to heart failure is the main cause of death among FRDA patients. The molecular genetics underlying FRDA is an autosomal recessive trinucleotide repeat expansion disorder that causes reduced levels of frataxin (FXN), a protein essential for iron-sulfur clusters biogenesis in the mitochondria. Frataxin reduction directly affects mitochondrial function, since iron-sulfur clusters are key redox cofactors of the respiratory chain and of the Krebs cycle enzyme aconitase. In the past years, the main research efforts were directed towards rescuing the FRDA-mediated neurological phenotype and corresponding experimental models were developed to assess improvement of neurological physiology under therapeutics which counteract neurodegeneration. However, since pathological cardiac remodelling is the main cause of mortality, researchers are also exploiting FRDA animal and cellular models to address specific questions regarding mechanisms that lead to FRDA cardiomyopathy and explore the pharmacological intervention or gene therapy approaches in restoring cardiac function. In this review, we give a comprehensive overview of existing in vivo and in vitro models for studying FRDA cardiomyopathy, with a special focus on human induced pluripotent stem cell (hiPSC)-derived cardiac models. Lastly, we discuss possible treatment options and their clinical benefits.