Human stem cell-based retina on chip as new translational model for validation of AAV retinal gene therapy vectors

Summary Gene therapies using adeno-associated viruses (AAVs) are among the most promising strategies to treat or even cure hereditary and acquired retinal diseases. However, the development of new efficient AAV vectors is slow and costly, largely because of the lack of suitable non-clinical models. By faithfully recreating structure and function of human tissues, human induced pluripotent stem cell (iPSC)-derived retinal organoids could become an essential part of the test cascade addressing translational aspects. Organ-on-chip (OoC) technology further provides the capability to recapitulate microphysiological tissue environments as well as a precise control over structural and temporal parameters. By employing our recently developed retina on chip that merges organoid and OoC technology, we analyzed the efficacy, kinetics, and cell tropism of seven first- and second-generation AAV vectors. The presented data demonstrate the potential of iPSC-based OoC models as the next generation of screening platforms for future gene therapeutic studies.
Highlights • The retina on chip (RoC) combines iPSC-organoid and organ-on-chip technology • We characterized seven adeno-associated viruses (AAVs) in terms of transduction efficacy and cell tropism • The RoC is a novel translational tool for AAV vector characterization • The presented workflow could be a blueprint for future drug development
Loskill and colleagues demonstrate that the retina on chip combining hiPSC-organoid and organ-on-chip technologies can serve as a novel translational tool for characterization and validation of AAV vectors by mimicking clinically relevant application routes. Seven AAVs were characterized in terms of transduction efficacy, cell tropism, and pharmacokinetics, showcasing a workflow that could serve as blueprint for future drug and gene therapy development.