Restoration of photopic vision by cell transplantation

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The prime reason for disability in industrialized countries is vision impairment and blindness caused by degeneration of the main light sensing cells of the retina - the photoreceptors. Whereas rod photoreceptors contribute to vision in dim light conditions (scotopic vision), cone photoreceptors are only active in day-light conditions (photopic vision). Specifically the loss of cone photoreceptors as in age related macular degeneration (AMD) or cone-rod dystrophies leads to impaired focused day-light vision and color discrimination. Replacement of lost photoreceptors by cell transplantation represents a promising treatment option. Indeed, recent pre-clinical studies demonstrated that immature rod photoreceptors have the potential to correctly integrate following transplantation into the adult, non-neurogenic mouse retina and form fully mature and functional photoreceptors. However, currently most studies focused on rod photoreceptors as donor cells due to the accessibility of sufficient donor material from the rod-dominated mouse retina, leaving transplantation of cones not well studied. Therefore we propose to investigate the probability of cone photoreceptors for the restoration of photopic vision in pre-clinical mouse models of cone function loss. To decipher the cellular and molecular requirements for successful cone transplantation we will take advantage of cone-specific reporter mice and will establish an alternative source of cone-like photoreceptors for transplantation studies. The retinas of neural retina leucine zipper (Nrl) deficient mice are characterized by the absence of rod photoreceptors and instead consist solely of cone and cone-like photoreceptors. Therefore, sufficient amounts of cone-like photoreceptors can be isolated from Nrl-deficient retinas allowing to systematically evaluate their migration, integration and maturation following transplantation into the adult mouse retina. Furthermore, we will investigate the functional integration of cone and cone-like photoreceptors into the neuronal circuitry of mouse models of achromatopsia that are characterized by loss of cone photoreceptors. Due to the importance of photopic vision for humans, the proposed proof-of-principle study assessing the restoration of cone-mediated light detection will be an essential prerequisite to pave the way towards the clinical application of cell-based methods for the treatment of up to date incurable retinal diseases.