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.

使用腺相关病毒（AAV）的基因疗法是治疗甚至治愈遗传性和获得性视网膜疾病最有前途的策略之一。然而，新的高效 AAV 载体的开发缓慢且成本高昂，很大程度上是因为缺乏合适的非临床模型。通过忠实地重建人体组织的结构和功能，人类诱导多能干细胞（iPSC）衍生的视网膜类器官可能成为解决转化方面的测试级联的重要组成部分。器官芯片（OoC）技术进一步提供了重现微生理组织环境以及对结构和时间参数的精确控制的能力。通过采用我们最近开发的融合类器官和 OoC 技术的视网膜芯片，我们分析了七个第一代和第二代 AAV 载体的功效、动力学和细胞向性。所提供的数据证明了基于 iPSC 的 OoC 模型作为未来基因治疗研究的下一代筛选平台的潜力。