Can we prevent vision loss in FA with gene therapy?

This proposal seeks to validate a new mouse model for the eye disease in FA and develop a gene therapy to prevent vision loss. The ocular symptoms of FA are underappreciated since they are not a major cause of mortality despite a large proportion of FA patients being affected. The retina is the part of the eye that is affected in FA. Photoreceptor cells in the retina capture incoming light and send signals to downstream cells and ultimately to the brain, where those signals are processed as vision. In FA, the cells responsible for sending that signal to the brain, retinal ganglion cells (RGCs), are dysfunctional and can degenerate over time. The goal of this proposal is to develop a new FA mouse model with the ultimate goal of developing a gene therapy to prevent vision loss. Complete knockout of frataxin (FXN) is embryonically lethal, and existing conditional knockout models do not focus on the retina. Dr. Boye, therefore, developed a novel, conditional knockout mouse model that lacks FXN expression exclusively in RGCs. Her group has already established that this mouse (“Pou4f2-FXN KO”) exhibits clear deficits in retinal structure and function. The plan now is to use those readouts to establish proof of concept that an intravitreally delivered AAV-based gene therapy can prevent vision loss in FA. Experiments are also proposed to optimize an AAV-FXN construct to allow for clinically relevant (safe and effective) levels of FXN in the target cells. To accomplish these goals, Dr. Boye will leverage her deep experience in developing AAV vectors for targeting therapies to the retina and her established track record of performing translational research.