Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy

Mutations in the GUCY2D gene coding for retinal membrane guanylyl cyclase 1 (RetGC1, or GC-E) can deregulate cGMP synthesis in photoreceptors by guanylyl cyclase-activating proteins (GCAPs) via negative Ca²⁺ feedback and elevate cGMP production in the dark, thus causing autosomal-dominant cone-rod dystrophy (GUCY2D adCORD). We expressed an engineered protein inhibitor of retinal guanylyl cyclase (PIGCY) in transgenic mice of either sex harboring the GUCY2D adCORD RetGC1 mutant Arg838Ser (R838S^{T g}) in order to suppress aberrant production of cGMP in their rods and prevent their fast degeneration. PIGCY did not return the abnormal Ca²⁺ sensitivity of cGMP synthesis in PIGCY^TgR838S^Tg retinas to the normal physiological range, but it reduced the overall rate of cGMP production. Decelerated cGMP production strongly suppressed degeneration of functional rods. By the age of 6 months, 70% of photoreceptor nuclei remained in PIGCY^TgR838S^Tg versus 20% in R838S^Tg Retinal response to light detected by electroretinography was preserved in PIGCY^TgR838S^Tg mice significantly better than that in R838S^Tg. The remaining altered calcium feedback affected the shape of PIGCY^TgR838S^Tg rod photoresponses, but overall light sensitivity was not drastically different from normal. Single photon response amplitude and time-to-peak in PIGCY^TgR838S^Tg rods were increased and more variable, but were similar to wild type in fractional light sensitivity and half-saturating light intensity. Consistent with the still abnormal calcium feedback, desensitization under background light in PIGCY^TgR838S^Tg rods was increased, and their noise was elevated under moderate background illumination as compared with wild type. In summary, PIGCY effectively rescued degenerating GUCY2D adCORD rods while maintaining their functional light sensitivity.