Development of stem cell therapy to restore photopic vision

Hereditary retinal disease and age related macular degeneration (AMD) are major causes of irreversible blindness in Europe and involve the loss of the light sensitive cone and rod photoreceptor cells in the retina. Inherited retinal dystrophies affect 1 in 3,000, and age related macular degeneration (AMD) affects 1 in 10 people over the age of 60. 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 demonstrated that transplantation of immature photoreceptor cells (precursors) from the developing retina into mouse models of retinal disease results in the integration of new rod photoreceptors that restore low light vision in mice with a non progressive form of inherited blindness. As human vision is dependent upon cone photoreceptors, which provide high acuity daylight and colour vision, as well as rod photoreceptors, which provide low light vision, cone transplantation is likely to be essential for clinical application. In late stage retinitis pigmentosa, despite loss of most rods, patients have useful vision until the last remaining cones degenerate. Furthermore, cone transplantation is critical for optimal retinal repair in patients with AMD as this condition involves degeneration only of the cone-rich macula region of the retina. Since the retina consists of only 5% cones we might be able to restore significant function with the replacement of relatively few cones. In certain instances patients with macular degeneration can fixate and create new pseudo-fovea following training and this might be enhanced if, by transplantation, cone density could be increased outside the degenerate macula. In this project we will determine the conditions for effective transplantation of cone photoreceptors and the restoration of daylight vision in animal models of degenerative retinal disease, in order to provide the framework for developing similar approaches to treat human disease. We will conduct the following investigations to achieve this goal. (i) We will perform experiments to identify important interactions that may limit the number of new photoreceptors connecting after transplantation and will modify conditions to improve transplantation into the degenerating retina. We will study rod transplantation in order to develop improved protocols for transplanting cones (ii) We will identify and manipulate the genetic controls that may limit cone integration and use our acquired knowledge of how to effectively isolate and transplant rod precursors in order to achieve optimal integration of new functional cone cells. (iii) We will determine the synaptic connectivity of new cone and rod cells as, in order to restore vision, it is necessary for transplanted photoreceptors to form connections with cells of the inner retina (bipolar cells) and we need to know whether this occurs in the degenerating environment. (iv) We will transplant photoreceptor precursors generated from stem cell lines (embryonic stem cell lines) and examine whether these are as good as the cells isolated from the developing retina, which we use in our proof of principle experiments. This is essential as to translate our findings in mice to humans we need to show that photoreceptor precursors from a renewable source, such as embryonic stem cells can effectively restore vision. We will progress from studies involving transplantation of photoreceptor precursors derived from developing mouse retinae, to studies involving transplantation of human stem cell-derived cone precursors that might be useful for clinical application. Each programme component will inform the next step, providing the best opportunity to develop a successful long-term strategy for clinical application.