Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Light-adapted retinas from Irish setters affected with inherited rod-cone dysplasia accumulate high concentrations of cyclic GMP in the outer plexiform layer (OPL). A 29-fold difference in OPL cGMP levels between affected and normal occurs at 19-20 days. However, the highest concentration, 550 mumol kg-1 (dry) wt, is reached at about 4 weeks of age, at which time OPL cyclic GMP is 20-fold higher than cGMP in the OPL of normal control retinas. Levels remain high in affected OPL until about 7 weeks of age; after this, the cyclic GMP level falls and the peak shifts to the outer nuclear layer (ONL). In the normal retina on the other hand, the highest cyclic GMP levels are in the outer segments (OS). The result is that cyclic GMP is highest at opposite ends of the photoreceptor neuron in normal and affected retinas during the first 7 weeks of development. These differing distributions are established as early as postnatal day 10, before signs of degeneration become evident, as determined by either ERG or morphological examination. Moreover, a 38-fold rise in cyclic GMP occurs in the ONL of affected retinas between 1 and 3 weeks of age significantly before the degeneration of nuclei begins at 4 to 5 weeks. The early differences in cyclic GMP distribution are probably not due to differences in guanylate cyclase activity since enzyme levels in normal and affected photoreceptor cells are virtually identical until about 4 weeks of age. Since cGMP has been observed to reach high levels in normal dark-adapted rabbit and frog OPL, the extraordinary OPL levels seen in affected setters may indicate the importance of cGMP in both normal synaptic function and in the disease process.
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PMID:Inherited rod-cone dysplasia: abnormal distribution of cyclic GMP in visual cells of affected Irish setters. 289 11

Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery from photoexcitation. Recent clinical data show that, despite a high degree of visual disturbance stemming from a loss of cone function, LCA1 patients retain normal photoreceptor architecture, except for foveal cone outer segment abnormalities and, in some patients, foveal cone loss. These results point to the cone-rich central retina as a target for GUCY2D replacement. LCA1 gene replacement studies thus far have been conducted in rod-dominant models (mouse) or with vectors and organisms lacking clinical translatability. Here we investigate gene replacement in the Nrl(-/-) Gucy2e(-/-) mouse, an all-cone model deficient in retGC1. We show that AAV-retGC1 treatment fully restores cone function, cone-mediated visual behavior, and guanylate cyclase activity, and preserves cones in treated Nrl(-/-) Gucy2e(-/-) mice over the long-term. A novel finding was that retinal function could be restored to levels above that in Nrl(-/-) controls, contrasting results in other models of retGC1 deficiency. We attribute this to increased cyclase activity in treated Nrl(-/-) Gucy2e(-/-) mice relative to Nrl(-/-) controls. Thus, Nrl(-/-) Gucy2e(-/-) mice possess an expanded dynamic range in ERG response to gene replacement relative to other models. Lastly, we show that a candidate clinical vector, AAV5-GRK1-GUCY2D, when delivered to adult Nrl(-/-) Gucy2e(-/-) mice, restores retinal function that persists for at least 6 months. Our results provide strong support for clinical application of a gene therapy targeted to the cone-rich, central retina of LCA1 patients.
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PMID:Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1. 2624 68