Ppcd1 corneal dystrophy phenotypes are rescued by Ovol2 disruption and modified by genetic background in a mouse...

Posterior polymorphous corneal dystrophy (PPCD) is a rare ocular disorder characterized by both genetic (PPCD1-4) and phenotypic heterogeneity. Genetic mapping and in vitro experiments provide evidence that OVOL2 promoter mutations are associated with human PPCD1, possibly through OVOL2 overexpression. A recent effort to engineer point mutations orthologous to those that induce human disease reported limited phenotypic effects, suggesting that current murine models may be of limited use in developing therapeutic approaches. Here, we provide evidence that, by manipulating the genetic background, a murine model can serve as a robust platform for studying gene-editing therapies for this disease. To support our idea, we employed a mouse model that exhibits PPCD-like phenotypes resulting from a chromosomal rearrangement in a region syntenic to the human PPCD1 locus. Observing that disease presentation is dependent upon a sensitive murine genetic background (DBA/2J), we then demonstrated that genetic disruption of Ovol2 rescues PPCD phenotypes, including corneal endothelial metaplasia, iridocorneal angle occlusion, elevated intraocular pressure, and retinal degeneration. These results support the model that Ovol2 upregulation drives PPCD1 in both humans and the mouse model. Moreover, studies on the genetic background provide opportunities to test novel therapeutic intervention strategies and provide evidence to support investigations into modifiers of human disease and their treatment.