Fig. 3

An ideal paradigm of drug discovery utilising patient iPSC-derived models. Following drug discovery and screening, potential FRDA therapeutic compounds undergo in vitro testing in reporter cell lines and patient cell lines before traditionally progressing to in vivo mouse and human clinical trials. We propose the additional testing of compounds in patient iPSC-derived models (e.g., cardiomyocytes and neurons), before in vivo and clinical studies. The addition of this step allows the assessment of drugs in a phenotypically relevant and human-specific model of FRDA, screening out drugs which may fail to show therapeutic benefit in expensive and time-consuming human clinical trials. An alternative to disease phenotype-driven drug screening may involve high-throughput screening of drugs directly in iPSC-derived cells with FXN levels as the read-out, such as by using iPSC-derived FRDA lines or iPSC FXN-GAA reporter models. Figure created with BioRender.com