title: Adenovirus-mediated delivery of Factor H attenuates complement C3 induced pathology in the murine retina: a potential gene therapy for age-related macular degeneration.
abstract: BACKGROUND
  Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly, with no therapy available for 90% of patients. Recent genetic evidence implicates activation of complement in the pathogenesis of AMD. We have recently discovered that adenovirus (Ad)-mediated expression of complement component C3 (AdCMVC3) in the murine retina recapitulates many of the pathological features found in human AMD. In the present study, utilizing a gene therapy approach, we examine whether Ad-mediated expression of complement Factor H (AdCAGfH) attenuates AdCMVC3-mediated retinal pathology.
  
  
  METHODS
  AdCMVC3 was co-injected with either AdCAGfH or a negative control virus expressing green fluorescent protein (AdCMVGFP) into the subretinal space of adult mice. The resulting retinal pathology was analyzed by histology and immunocytochemistry and retinal function was quantified by electroretinography.
  
  
  RESULTS
  Morphological and functional analyses indicated that AdCMVC3-mediated retinal pathology could be attenuated by AdCAGfH. Specifically, endothelial cell proliferation was reduced by 91% and atrophy of retinal pigment epithelium (RPE) could be attenuated by 69%. AdCAGfH injected eyes exhibited 90-150% greater A-wave and 120-180% greater B-wave amplitudes relative to control eyes. Immunocytochemical analysis of rhodopsin and RPE65 was consistent with the rescue of photoreceptors and RPE in AdCAGfH injected eyes.
  
  
  CONCLUSIONS
  C3-induced pathology in murine retina can be attenuated by Ad-mediated expression of Factor H. Expression of Factor H is worthy of further study as a potential gene therapy for AMD.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology and the Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Cashman
authors.affiliation: Department of Developmental, Molecular and Chemical Biology and the Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gracias
authors.affiliation: Department of Developmental, Molecular and Chemical Biology and the Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Mehreen
authors.initials: M
authors.lastname: Adhi
authors.affiliation: Department of Developmental, Molecular and Chemical Biology and the Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar-Singh
mesh_terms: D000256:Adenoviridae; D000818:Animals; D003176:Complement C3 / Q000009:adverse effects / Q000378:metabolism*; D017242:Complement Factor H / Q000008:administration & dosage / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008268:Macular Degeneration / Q000628:therapy; D051379:Mice; D012160:Retina / Q000187:drug effects / Q000473:pathology
chemical_list: D003176:Complement C3; D017242:Complement Factor H
keywords: AMD; Factor H; complement; gene therapy; mouse model; retina