Defining donor-host interactions to improve photoreceptor replacement therapy

定义供体-宿主相互作用以改善光感受器替代疗法

• 批准号: 399422891
• 负责人: Professor Dr. Marius Ader
• 金额: --
• 依托单位: Zentrum für Regenerative Therapien Dresden - CRTD
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/399422891?language=en
• 关键词: Defining; donor; host; interactions; improve

The loss of light-sensing photoreceptors represents the main cause for visual impairment and blindness in industrialized societies with no curative therapy established clinically. Transplantation of donor photoreceptors is discussed as a general treatment option aiming to replace degenerated photoreceptors. Indeed, recent technology progress allows the generation of human photoreceptors within pluripotent stem cell-derived retinal organoids in sufficient amounts in vitro. First pre-clinical studies in vivo provide evidence for some functional improvements after transplantation into animal models of retinal degeneration. However, the cellular and molecular requirements and mechanisms that allow successful structural and functional integration including connectivity with cells of the recipient retina are currently unknown. Additionally, while complete photoreceptor loss is the final stage of retinal degenerative diseases, the underlying causes and the dynamics of disease progression are highly diverse resulting in very heterogenous recipient environments. Therefore, based on our established pre-clinical transplantation pipeline using human induced pluripotent stem cell-derived photoreceptors, integration kinetics of transplants, transcriptome and proteome changes of endogenous retinal cells, as well as different degeneration stages of recipient mice will be assessed to identify cellular and molecular needs for successful photoreceptor replacement. Acquired knowledge will be of utmost importance for defining prerequisites as well as potential targets for modification of the recipient environment to optimize graft integration, organization and maturation with the ultimate goal to significantly improve visual perception within different retinal pathologies.

光感受器的丧失是工业化社会中视觉障碍和失明的主要原因，临床上没有建立治愈性治疗。供体光感受器的移植被讨论为旨在替换退化的光感受器的一般治疗选择。事实上，最近的技术进步允许在体外以足够的量在多能干细胞衍生的视网膜类器官内产生人光感受器。第一个临床前体内研究提供了移植到视网膜变性动物模型后某些功能改善的证据。然而，允许成功的结构和功能整合（包括与受体视网膜细胞的连接）的细胞和分子要求和机制目前是未知的。此外，虽然完全光感受器丧失是视网膜退行性疾病的最后阶段，但疾病进展的根本原因和动力学是高度多样的，导致非常异质的受体环境。因此，基于我们建立的使用人诱导多能干细胞衍生的光感受器的临床前移植管道，将评估移植物的整合动力学、内源性视网膜细胞的转录组和蛋白质组变化以及受体小鼠的不同变性阶段，以确定成功的光感受器替代的细胞和分子需求。获得的知识对于定义先决条件以及用于修改受体环境的潜在目标以优化移植物整合、组织和成熟具有至关重要的意义，最终目标是显著改善不同视网膜病变内的视觉感知。