OR02

Stargardt disease (STGD1) is an autosomal recessive genetic disorder affecting the gene coding for the ABCA4 protein, leading to a juvenile form of severe macular dystrophy. Accounting for nearly 7% of retinopathies, STGD1 currently lacks any treatment. To address the limitations of existing STGD1 models, such as the lack of macula in rodents, the utilization of human induced pluripotent stem cells (hiPSCs) carrying the disease-associated mutations represents a promising technology. With the differentiating capabilities of hiPSCs, it is now possible to generate multi-layered 3D structures resembling optical vesicles, referred to as retinal organoids (ROs). This advancement allows for the in vitro recapitulation of the structure and physiology of the human retina.

The objective of our project is to model the visual cycle, a critical process for vision deregulated in STGD1, using hiPSCs and ROs from patients and healthy donors. In our initial experiments, we successfully developed ROs with visible photoreceptors (PRs) expressing ABCA4, together with a mature retinal pigmented epithelium (RPE) cell layer which shows a correct polarization and low expression of ABCA4.

Our next step involves recreating the visual cycle by coculturing ROs on a monolayer of RPE cells. Comparative analysis between patient-derived and healthy control models will contribute to a more comprehensive understanding of the cellular and molecular mechanisms underlying the observed retinal degeneration in patients with STGD1, and may be used to assess and optimize gene therapy strategies.