Improving functional connectivity following transplantation of cone photoreceptors

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Hereditary retinal disease and age-related macular degeneration (AMD) are major causes of irreversible blindness in the UK. Inherited retinal dystrophies affect 1 in 2,500, usually during childhood or early adulthood, while AMD affects 1:3 over the age of 75. The number of number of people in the UK affected by sight loss is set to double, to 4 million, by 2050 and sight loss is estimated to cost the UK economy £28bn a year, directly and indirectly. At present, we lack effective treatments for these conditions and there is an urgent requirement to develop new therapies. Both conditions involve the loss of the light sensitive cone and rod photoreceptor cells in the retina. Photoreceptor replacement aims to restore vision by the transplantation of healthy cells, ideally derived from a renewable source. Once transplanted these cells must form new connections (synapses) with their target cells, called bipolar cells, within the host retina. Restoring functional connectivity following transplantation is an ambitious goal for CNS repair. Nonetheless, the macula, which is crucial for high acuity daylight vision occupies a small area and relatively few functional photoreceptor cells may be required to achieve useful vision, so even low efficiency cone photoreceptor transplantation may result in clinical benefit. Stem cell biology has seen extraordinary progress in the past decade and we, and others, now have the ability to generate of large numbers of transplantable photoreceptors from a variety of stem cell sources. While there are some reported indications of new connections being formed between transplanted photoreceptors and host bipolar cells, achieving robust functional synaptic connectivity remains a significant challenge, particularly in advanced retinal disease, where the retina can undergo many, often inhibitory, changes. We have new and exciting data that demonstrates the feasibility of rescuing visual function (mouse models of) advanced retinal disease by transplantation of human stem cell-derived photoreceptors. Most importantly, this rescue does indeed appear to be mediated by the formation of new synaptic connections between the donor and host neurons. In this project, we will establish the full extent of synaptic connections following transplantation of stem cell-derived cone photoreceptors that can be achieved used current methods. We then seek to develop new methods to further improve functional connectivity in order to restore daylight vision in animal models of advanced degenerative retinal disease. We will conduct the following investigations to achieve this goal. We will (i) perform experiments to establish the extent of functional connectivity between transplanted cells and the host eye using current reported protocols, (ii) identify important interactions that may limit the number of new functional connections made after transplantation and develop strategies to improve connectivity and restore vision. Together, these experiments using both murine and human embryonic stem cell-derived donor cells and rodent models of advanced retinal disease will provide the framework for us to move to developing similar approaches to treat human disease.