Optimisation of human ESC-derived photoreceptor cell differentiation

视网膜变性，其中眼睛的感光细胞丢失，是英国无法治愈的失明的主要原因。遗传性视力丧失影响3,000人中的1人，年龄相关性黄斑变性（AMD）影响60岁以上的10人中的1人。目前没有可以恢复视力的治疗方法，因此需要开发新的治疗方法。由于大多数神经连接在视网膜疾病后仍然存在，因此新的光感受器只需要与剩余的视网膜细胞进行短而单一的连接就可以促进视力。因此，通过将新的光感受器移植到患病的视网膜来进行视网膜修复是最可行的CNS修复类型之一。我们先前在视网膜修复的细胞移植疗法方面取得了重要突破。在具有里程碑意义的研究中，我们已经证明，感光细胞可以移植到成人视网膜中，并在视网膜变性的动物模型中恢复视力，前提是感光细胞处于正确的发育阶段。基于从人类胎儿中获得感光细胞来开发治疗方法是不切实际的，因此我们需要在实验室中从人类胚胎干细胞中产生感光细胞。继其他小组发现胚胎干细胞可以自发地自我组织并发育成视网膜，如果放置在三维培养系统中的正确条件下，我们已经表明，我们可以从培养皿中生长的小鼠胚胎干细胞中产生适合移植的光感受器。在本项目中，我们提出了一种方法来产生，纯化和存储人类感光细胞前体细胞，适用于临床级的人类胚胎干细胞移植，以确定最佳的细胞系和临床应用的协议。该项目将为未来临床试验的发展和将我们的干细胞治疗计划转化为临床提供必要的基础。

Retinal degenerations, in which the light-sensing photoreceptor cells of the eye are lost, are a major cause of untreatable blindness in the UK. Inherited sight loss affects 1 in 3,000 of the population, and age-related macular degeneration (AMD) affects 1 in 10 people over 60 yrs. Currently there are no treatments that can restore sight and thus there is a need to develop new therapeutic approaches. As the majority of the neural connections remain following retinal disease, new photoreceptors need only make short, single connections to the remaining retinal cells to contribute to vision. Therefore, retinal repair by the transplantation of new photoreceptors to the diseased retina represents one of the most feasible types of CNS repair.We have previously made important breakthroughs regarding cell transplantation therapy for retinal repair. In landmark studies, we have demonstrated that photoreceptor cells can be transplanted into an adult retina and restore vision in animal models of retinal degeneration, provided the photoreceptor cells are at the correct stage of development. It is not practical to develop treatments based on obtaining photoreceptor cells from human fetuses and we therefore need to generate photoreceptor cells in the laboratory from human embryonic stem cells. Following the discovery by other groups that embryonic stem cells can spontaneously self-organise and develop into a retina if placed in the right conditions in a three-dimensional culture system, we have shown that we can produce photoreceptors that are suitable for transplantation from mouse embryonic stem cells grown in a dish. In this project we propose to develop a methods to generate, purify and store human photoreceptor precursors that are suitable for transplantation from clinical-grade human embryonic stem cells in order to determine the best cell lines and protocols for clinical application. This project will provide essential underpinning for the development of future clinical trials and the translation of our stem cell therapy programme into the clinic.