Correction of the retinal dystrophy phenotype of the RCS rat by viral genetransfer of Mertk

The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithel ium (RPE) to phagocytize shed photoreceptor outer segments leads to a progr essive loss of rod and cone photoreceptors. We recently used positional clo ning to demonstrate that the gene Mertk likely corresponds to the retinal d ystrophy (rdy) locus of the RCS rat. In the present study, we sought to det ermine whether gene transfer of Mertk to a RCS rat retina would result in c orrection of the RPE phagocytosis defect and preservation of photoreceptors . We used subretinal injection of a recombinant replication-deficient adeno virus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection reveale d an increased sensitivity of treated eyes to low-intensity light. Histolog ic and ultrastructural assessment demonstrated substantial sparing of photo receptors, preservation of outer segment structure, and correction of the R PE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retin al dystrophy phenotype, and that the phenotype can be corrected by treatmen t of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, toge ther with the recent discovery of MERTK mutations in individuals with retin itis pigmentosa, emphasize the importance of the RCS rat as a model for gen e therapy of diseases that arise from RPE dysfunction.