title: Lentiviral expression of retinal guanylate cyclase-1 (RetGC1) restores vision in an avian model of childhood blindness.
abstract: BACKGROUND
  Leber 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.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  Blindness 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.
authors.affiliation: Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville, Florida, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Williams
authors.forename: Jason E
authors.initials: JE
authors.lastname: Coleman
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Haire
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Izabel
authors.initials: I
authors.lastname: Sokal
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Semple-Rowland
mesh_terms: D000818:Animals; D001766:Blindness / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002642:Chick Embryo; D002645:Chickens; D004195:Disease Models, Animal; D004596:Electroretinography; D005133:Eye Movements; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006162:Guanylate Cyclase / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology; D011956:Receptors, Cell Surface / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000201:enzymology / Q000473:pathology; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014796:Visual Perception
chemical_list: D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C110715:guanylate cyclase 1; D049452:Green Fluorescent Proteins; D006162:Guanylate Cyclase