LAY SUMMARY

Can we precisely control frataxin (FXN) expression for gene therapy?

A challenge facing FA gene replacement therapy is that frataxin overexpression is harmful in multiple tissues, necessitating careful control of FXN levels to achieve efficacy and safety. Fine control of transgene expression is difficult to achieve clinically with current-generation AAV-based gene therapies. Rgenta has developed a regulatable gene therapy system called RSwitch, that can fine-tune the transgene levels in gene therapy approaches. RSwitch is a genetic dimmer switch that makes the expression of the gene dependent on the administration of an oral small molecule drug that controls the system. Only when the drug is administered is the system activated. Furthermore, the level of FXN production is dependent on how much drug is administered, with a higher drug dose yielding increased FXN level and vice versa. This precise gene control has the potential to give patients the ability to achieve their optimum FXN levels. Rgenta has demonstrated the RSwitch system’s feasibility in vitro and in vivo, achieving dose-dependent expression of reporter transgenes following small molecule administration. With this grant, Rgenta is set to apply the RSwitch technology to control FXN expression. They will first design the most appropriate switch for FXN that allows for fine tuning in cell culture. Next, they will deliver the system to FA mice to demonstrate that RSwitch achieves safe and effective frataxin levels and improves FA mouse survival.