Abstract
BackgroundLeber congenital amaurosis (LCA) is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans.Methods and FindingsA lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration.ConclusionsBlindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness.
Highlights
Vertebrate vision begins with absorption of light by visual pigments in retinal rod and cone photoreceptors
Blindness associated with loss of function of retinal guanylate cyclase–1 (retGC1) in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer
Mutations in the gene encoding retGC1 that disrupt synthesis of cGMP lead to a loss of photoreceptor function that presents as blindness or severely compromised vision at birth followed by photoreceptor degeneration in chicken [11,12] and human [13,14,15]
Summary
Vertebrate vision begins with absorption of light by visual pigments in retinal rod and cone photoreceptors. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. About 20% of children with LCA have the most common type, called LCA1, which is caused by defects in a gene called retinal guanylate cyclase (GUCY2D) that is found on Chromosome 17 It is one of a group of genes that produce proteins that are important in determining how rods and cones—specialized light receptor cells at the back of the eye—respond to light, in particular, how they can return to the resting state after being stimulated by light. Gene therapy works by replacing a defective gene with a normal functional one, usually by packaging the normal gene into a harmless virus and injecting it into the affected tissue, in this case the eye
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