Abstract
Vertebrate species possess two retinal guanylate cyclases (retGC1 and retGC2) and at least two guanylate cyclase activating proteins (GCAPs), GCAP1 and GCAP2. GCAPs function as Ca2+ sensors that regulate the activity of guanylate cyclases. Together, these proteins regulate cGMP and Ca2+ levels within the outer segments of rod and cone photoreceptors. Mutations in GUCY2D, the gene that encodes retGC1, are a leading cause of the most severe form of early onset retinal dystrophy, Leber congenital amaurosis (LCA1). These mutations, which reduce or abolish the ability of retGC1 to replenish cGMP in photoreceptors, are thought to lead to the biochemical equivalent of chronic light exposure in these cells. In spite of this, the majority of LCA1 patients retain normal photoreceptor laminar architecture aside from foveal cone outer segment abnormalities, suggesting they may be good candidates for gene replacement therapy. Work began in the 1980s to characterize multiple animal models of retGC1 deficiency. 34 years later, all models have been used in proof of concept gene replacement studies toward the goal of developing a therapy to treat GUCY2D-LCA1. Here we use the results of these studies as well as those of recent clinical studies to address specific questions relating to clinical application of a gene therapy for treatment of LCA1.
Highlights
The ability to process light into an electrochemical signal depends on the precise regulation of levels of cGMP and Ca2+ within the outer segments of rod and cone photoreceptor cells
Some studies show that GCAP1 and GCAP2 can activate both retGCs, albeit with slightly different affinities and sensitivity to Ca2+ (Hwang et al, 2003; Peshenko and Dizhoor, 2004; Peshenko et al, 2011) while another shows that GCAP1 cannot activate retGC2 (Haeseleer et al, 1999)
This study showed for the first time that, along with the rescue effects seen on cones, associated virus (AAV)-mediated retGC1 expression can restore rod photoreceptor function and rod-mediated visual behavior and preserve rod structure over the long term in an animal model of Leber congenital amaurosis-1 (LCA1)
Summary
The ability to process light into an electrochemical signal depends on the precise regulation of levels of cGMP and Ca2+ within the outer segments of rod and cone photoreceptor cells. As a consequence of retGC1 deficiency, photoreceptors of post-hatch day 1 (P1) GUCY1∗B chickens have only 10–20% cGMP relative to that found in age-matched, wild type controls and affected chickens are blind at hatch They have unrecordable ERGs and lack optokinetic and volitional visual behavior (Ulshafer et al, 1984; Williams et al, 2006). At 1 month post-hatch, ERG testing under both dark and light-adapted conditions revealed that LV-EF1α-bGC1 treatment produced modest increases in photoreceptor-mediated awave amplitudes in treated chickens (∼6% of wild type). These results were the first demonstration that retGC1 gene replacement could restore retinal function. ERG improvements were associated with a restoration of visually guided behavior, as assessed by
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