Barber, AC; (2013) Photoreceptor transplantation in the degenerating retina. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Retinal degenerative disorders are the leading cause of blindness in the developed world, resulting in loss of the photoreceptor cells and vision. Few treatments are available and none can reverse the loss of sight. Photoreceptor transplantation offers the potential to restore vision by replacing cells lost in disease. Previous work has demonstrated that, following transplantation, rod-precursor cells can migrate into the retina, differentiate into mature phenotypes and confer increased sensitivity to light in the rod range. However, rigorous assessment of whether transplanted photoreceptors can actually restore vision is required. In order to do this, we first optimized rod photoreceptor transplantation. To test the functionality of the transplanted rod photoreceptors, we selected a model in which improvements could be assessed unambiguously. The Gnat1-/- mouse, a model of stationary night-blindness, lacks rod a-transducin and thus has no rod function. We demonstrate that transplanted cells robustly integrate forming synaptic connections with the recipient. Integrated cells form inner/outer segments that appropriately expressed phototransduction proteins. Single cell recordings demonstrate that integrated cells are light responsive and intrinsic imaging of the visual cortex shows that visual signals generated by transplanted rods project to higher visual areas. These cells are also capable of restoring optokinetic head-tracking and visually-guided behavior in response to scotopic visual stimuli. A major question remains as to how amenable the heterogeneous diseases encompassed within retinal degenerative disorders will be to photoreceptor replacement and if treatment of late-stage disease is feasible. We performed a comprehensive assessment of photoreceptor transplantation in 6 murine models of inherited retinal degeneration encompassing different types and stages of degeneration. Transplantation is feasible in all models examined but disease type has a major impact on outcome, as assessed both by the morphology and number of integrated rod-photoreceptors. Integration can increase, decrease or remain constant with disease progression, depending upon the gene defect, with no correlation with disease severity. Robust integration into late-stage disease is possible in some disease types. We assessed features of the recipient microenvironment known to change during degeneration, namely gliosis, outer nuclear layer cyto-architecture and outer limiting membrane (OLM) integrity. Disruption of glial scarring and OLM integrity significantly increased integration to levels sufficient to restore optokinetic head-tracking responses in a model with an otherwise poor transplantation outcome. Together, these findings demonstrate the feasibility of photoreceptor transplantation as a strategy for the restoration of vision in retinal disease.

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