Abstract
Purpose :
X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not yet fully understood. Animal models of XLRS have limitations in the study of XLRS. Here, we used induced pluripotent stem cell-derived retinal organoids (ROs) to investigate the potential disease mechanisms and treatment for XLRS.
Methods :
Human induced pluripotent stem cells (hiPSCs) reprogramming from peripheral blood mononuclear cells (PBMCs) of two RS1 mutation (E72K) XLRS patients were used to differentiate into ROs. The ROs were used to explore whether RS1 mutation affected patient RO development, and the effectiveness of RS1 gene augmentation therapy was evaluated.
Results :
The RO derived by RS1 (E72K) mutation hiPSCs exhibited a developmental delay in photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity by the assays of immunofluorescence staining and microelectrode array (MEA) recording when compared to control ROs. Moreover, these photoreceptor development delays are related to rod-specific precursor markers NRL and photoreceptor-specific marker recoverin (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor development delay of the RS1 (E72K) mutation ROs.
Conclusions :
The ROs derived from RS1 mutation hiPSCs are a suitable model for studying XLRS. The RS1 (E72K) mutation results in photoreceptor development delay in ROs and can be rescued by the RS1 gene augmentation therapy. Our findings suggest that the timing of XLRS therapy is essential.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.