Phosphodiesterase 5 expression in photoreceptors rescues retinal degeneration induced by deregulation of membrane guanylyl cyclase.

Mutations in retinal membrane guanylyl cyclase 1 (RetGC1) and its calcium-sensor protein (guanylyl cyclase activating protein 1, GCAP1) cause congenital dominant retinopathies by elevation of cGMP synthesis in photoreceptors in the dark. We explored counteracting the elevated cGMP synthesis causing photoreceptor degeneration using ectopic expression of a nonphotoreceptor cGMP phosphodiesterase (PDE) isozyme PDE5. PDE5 primary structure was modified to direct the delivery of the recombinant PDE5 (PDE5r) to rod outer segments, by placing a C-terminal fragment derived from a cone-specific alpha-subunit of PDE6C at the C terminus of the PDE5, which allowed PDE5r expressed under control of mouse rod opsin promoter to accumulate in rod outer segments.