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The recent emergence of three-dimensional organoids and their utilization as in vitro disease models confirmed the complexities behind organ-specific functions and unravelled the importance of establishing suitable human models for various applications. Also, in light of persistent challenges associated with their use, researchers have been striving to establish more advanced structures (i.e. assembloids) that can help address the limitations presented in the current organoids. In this review, we discuss the distinct organoid types that are available to date, with a special focus on retinal and brain organoids, and highlight their importance in disease modelling. We refer to published research to explore the extent to which retinal and brain organoids can serve as potential alternatives to organ/cell transplants and direct our attention to the topic of photostimulation in retinal organoids. Additionally, we discuss the advantages of incorporating microfluidics and organ-on-a-chip devices for boosting retinal organoid performance. The challenges of organoids leading to the subsequent development of assembloid fusion models are also presented. In conclusion, organoid technology has laid the foundation for generating upgraded models that not only better replicate in vivo systems but also allow for a deeper comprehension of disease pathophysiology.

Background 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 fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS. Methods hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy. Results ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation. Conclusions The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.