FA hiPSCs in Translational Drug Development

Friedreich’s ataxia (FA) is a progressive, multisystem disorder characterized by neurodegeneration, cardiomyopathy, and metabolic dysfunction, with limited disease-modifying treatment options. In a recent review published in Stem Cell Research & Therapy (January 2026), Nguyen et al. highlight advances in human induced pluripotent stem cell (hiPSC) models of FA. This review focuses on the clinical applications of FA hiPSC-derived cellular models for drug discovery and therapeutic development, emphasizing their translational relevance and future potential.

FA hiPSC-derived models have emerged as powerful platforms for evaluating therapeutic strategies aimed at restoring frataxin (FXN) expression and mitigating downstream cellular dysfunction. One major area of investigation involves transcriptional activation approaches, particularly histone deacetylase inhibitors (HDACis), which have demonstrated the ability to partially reverse FXN repression and improve cellular phenotypes in a cell type–dependent manner. Similarly, synthetic transcriptional activators such as Syn-TEF1 have shown promise in enhancing FXN expression by facilitating transcription across expanded GAA repeat regions, with early clinical translation underway.

Antisense oligonucleotide (ASO) therapies represent a complementary strategy. These approaches can increase FXN expression either by targeting expanded repeat regions or by stabilizing FXN mRNA, thereby improving protein levels without directly modifying chromatin. Importantly, FA fibroblasts and hiPSC-derived neural progenitors have enabled functional validation of these strategies in human disease-relevant contexts.

In parallel, small molecule therapies continue to be explored using hiPSC-derived models. Compounds targeting oxidative stress and mitochondrial dysfunction—central features of FA pathophysiology—have demonstrated variable efficacy depending on both mechanism and cell type. Notably, NRF2 pathway activators such as omaveloxolone have translated from preclinical models to clinical approval, underscoring the value of hiPSC platforms in identifying clinically actionable therapies. These findings highlight that therapeutic responses can differ across neuronal and cardiac cell types, reinforcing the need for diverse cellular models in drug development.

More recently, gene editing approaches aimed at removing expanded GAA repeats have shown the potential to restore FXN expression and partially rescue disease phenotypes in hiPSC-derived neurons and cardiomyocytes. While still at the preclinical stage, these strategies represent a promising avenue for therapeutic intervention.

Despite these advances, several understudied areas and unmet clinical needs remain. FA-associated diabetes, for example, reflects β-cell vulnerability that is not yet fully understood. HiPSC-derived β-cell models offer an opportunity to investigate disease mechanisms and therapeutic responses. Similarly, retinal involvement and vision loss, though less common, remain poorly characterized and may benefit from emerging retinal organoid systems. In the central nervous system, cerebellar degeneration and glial activation suggest that non-neuronal cells, including astrocytes and microglia, may play critical roles in disease progression.

To address these gaps, there is growing interest in next-generation in vitro systems, including co-culture models and three-dimensional organoids. These approaches better recapitulate cell–cell interactions and tissue architecture, enabling investigation of non-cell-autonomous mechanisms and supporting more accurate preclinical drug screening.

Ultimately, FA hiPSC-derived cellular models have become valuable tools for therapeutic development, offering preclinical platforms to evaluate diverse treatment strategies. Continued refinement of these models, particularly through incorporation of complex multicellular systems, will be essential to fully realize their potential in advancing therapeutic approaches for FA.

Reference:
Nguyen HT, Napierala M, Napierala JS. Human pluripotent stem cell models of Friedreich's ataxia: innovations, considerations, and future perspectives. Stem Cell Res Ther. 2026;17(1):84. Published 2026 Jan 9. doi:10.1186/s13287-025-04861-x