The impact of network remodelling on outcomes for regenerative medicine in the retina - defining the therapeutic window

遗传性视网膜疾病是失明的主要原因，影响着全世界数百万人。这些情况通常会导致眼睛的专门感光细胞的丧失，进而导致视力丧失并最终失明。目前在人类临床试验中有许多有希望的再生方法来治疗这些疾病，提高了许多人类患者恢复视力的可能性。在这些情况下，视力丧失通常是一个缓慢的渐进过程，但目前的临床试验仅限于那些视力完全丧失的患者。这些疾病涉及视觉组织的复杂缓慢变化，有理由相信再生干预的时机可能是决定治疗最终成功的关键。在这里，我们设计了一个实验程序，使用一个建立的人类条件的动物模型来确定干预时间对视觉恢复水平的影响。我们将使用一种有前途的当前光遗传学方法来再生治疗遗传性人类失明的小鼠模型。治疗将在疾病的不同阶段进行，并评估其恢复视力的能力。为了理解细胞水平的过程，我们将使用最先进的方法测量视网膜和大脑神经元中视觉系统的详细反应。这些发现将影响为患有视网膜疾病和视力丧失的患者开发新的改进治疗方案。

Inherited retinal diseases are a leading cause of blindness, affecting millions of people worldwide. These conditions typically lead to a loss of the specialised light sensing cells of the eye progressing to a loss of vision and ultimately blindness. There are a number of promising regenerative approaches to treating these conditions currently in human clinical trials, raising the possibility of restoring vision to many human patients. Visual loss in these conditions is generally a slow, progressive process, yet the current clinical trials are confined to those patients in which all vision has been lost. The diseases involve complex slow changes to the visual tissues and there is reason to believe that the timing of regenerative interventions may be critical in determining the ultimate success of therapy. Here we have devised a program of experiments that determine the impact of the time of intervention upon the level of visual restoration using an established animal model of the human condition. We will use one of the promising current optogenetic approaches to regenerative therapy delivered to a mouse model of hereditary human blindness. The treatment will be delivered at different stages of the disease and its ability to restore vision will be assessed. In order to understand the process at the cellular level we will measure the detailed responses of the visual system in neurons in the retina and brain using state of the art approaches. These findings will influence the development of new improved treatment options for patients suffering from retinal disease and loss of vision.