Development of stem cell therapy for the treatment of retinal degneration

遗传性视网膜疾病和年龄相关性黄斑变性（AMD）是英国不可逆失明的主要原因，涉及视网膜中光敏感光细胞的丧失。这些疾病缺乏有效的治疗方法，这意味着需要开发新的治疗方法。通过细胞移植替代失去的光感受器是一种可能的方法，但移植的细胞需要与宿主视网膜建立功能连接。我们最近发现，将发育中的视网膜未成熟的光感受器细胞移植到视网膜变性的小鼠模型中，可以整合新的光感受器，形成与其他视网膜细胞的功能连接，并改善这些失明小鼠的视觉功能。在确定了对视网膜修复有效的细胞类型之后，我们现在需要增加整合到视网膜中的新细胞的数量，并找到在实验室中产生最佳类型的未成熟细胞的方法。成人视网膜含有视网膜干细胞，在细胞培养皿中具有产生新的光感受器的能力，这些细胞是用于移植的潜在细胞来源，可以避免外来组织排斥的问题。本提案的目的是制定策略，通过移植视网膜干细胞，在实验室中进行各种操作，以优化其发育，从而取代视网膜疾病小鼠模型中缺失的光感受器。我们将研究是否可以通过引入改变干细胞本身的基因来产生适合移植的细胞，以及在接受移植的视网膜中引入基因是否可以促进细胞整合水平的提高并增强视力的改善。通过确定使用来自成人眼睛的干细胞有效治疗动物模型的条件，我们的目标是为开发治疗人类疾病的类似方法提供基本框架。

Hereditary retinal disease and age related macular degeneration (AMD) are major causes of irreversible blindness in the UK and involve the loss of the light sensitive photoreceptor cells in the retina. The lack of effective treatments for these conditions means there is a requirement to develop new therapies. The replacement of lost photoreceptors by cell transplantation is one possible approach, but transplanted cells need to make functional connections with the host retina. We have recently discovered that transplantation of immature photoreceptor cells from the developing retina into mouse models of retinal degeneration results in the integration of new photoreceptors that form functional connections with other retinal cells and improve visual function in these blind mice. Having defined the type of cell that is effective for retinal repair we now need to increase the number of new cells that integrate into the retina and find ways of generating the optimal type of immature cell in the laboratory. The adult retina contains retinal stem cells with the capacity to give rise to new photoreceptors in a cell-culture dish and these are a potential source of cells for transplantation that would avoid problems of rejection of foreign tissue. The aim of this proposal is to develop strategies to replace missing photoreceptors in mouse models of retinal disease by transplanting retinal stem cells following various manipulations in the laboratory to optimise their development. We will investigate whether appropriate cells for transplantation can be generated by the introduction of genes that alter the stem cells themselves, and whether the introduction of genes into the retina receiving the transplant promotes increased levels of cell integration and enhances the improvement in vision. By determining the conditions for effective treatment of animal models using stem cells derived from the adult eye, we aim to provide the basic framework for developing similar approaches to treat human disease.