Human pluripotent stem cell models of Friedreich’s ataxia: innovations, considerations, and future perspectives

Friedreich's ataxia (FRDA) is an inherited, autosomal recessive, multisystem disorder that primarily manifests in children and affects the nervous system and the heart. FRDA is caused by an expansion of GAA repeats in the first intron of the frataxin (FXN) gene. The expansion disrupts transcription of FXN, resulting in significantly decreased FXN expression in FRDA patients' tissues. Frataxin is involved in biosynthesis of iron-sulfur (Fe-S) clusters, which are critical for the function of the electron transport chain and many metabolic enzymes. Frataxin deficiency leads to reduced energy production and accumulation of iron in mitochondria that exacerbates oxidative stress. Despite significant advancements in the field, FXN cellular functions and underlying pathological mechanisms of FXN deficiency in cell-type specific contexts remain to be elucidated. Inaccessibility to the most vulnerable cell types in FRDA patients, including neurons, cardiomyocytes, and β-cells, largely accounts for these limitations. Significant progress in recent years regarding the derivation and differentiation of human pluripotent stem cells (hPSCs), along with breakthroughs in gene editing technologies, enables the generation of patient-derived and isogenic control disease-relevant cell types and organoid-like structures as platforms for studying disease mechanisms and for drug discovery. Herein, we first provide an overview of hPSC derivation and intrinsic properties of these cells. We then discuss current advances and limitations of hiPSC-based cell models for FRDA. We also highlight the need to further refine and develop these in vitro cell models for pre-clinical advancement of therapeutic approaches for FRDA.