title: Timing of Antioxidant Gene Therapy: Implications for Treating Dry AMD.
abstract: To investigate whether antioxidant gene therapy protects the structure and function of retina in a murine model of RPE atrophy, and to determine whether antioxidant gene therapy can prevent degeneration once it has begun.
  
  
  
  We induced mitochondrial oxidative stress in RPE by conditional deletion of Sod2, the gene for manganese superoxide dismutase (MnSOD). These mice exhibited localized atrophy of the RPE and overlying photoreceptors. We restored Sod2 to the RPE of one eye using adeno-associated virus (AAV) by subretinal injection at an early (6 weeks) and a late stage (6 months), injecting the other eye with an AAV vector expressing green fluorescent protein (GFP). Retinal degeneration was monitored over a period of 9 months by electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT). Immunohistochemical and histologic analyses were conducted to measure oxidative stress markers and to visualize retinal structure.
  
  
  
  One month after delivery, the AAV-Sod2 injection resulted in production of MnSod in the RPE and negligible expression in the neural retina. Electroretinography and OCT suggested no adverse effects due to increased expression of MnSOD or subretinal injection. Decrease in the ERG response and thinning retinal thickness was significantly delayed in eyes with early treatment with the Sod2 vector, but treatment at 6 months of age did not affect the ERG decline seen in these mice.
  
  
  
  We conclude that antioxidant gene therapy may be effective in preventing the detrimental effects of oxidative stress, but may not be beneficial once substantial tissue damage has occurred.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Manas R
authors.initials: MR
authors.lastname: Biswal
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Pingyang
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Huangpu District, Shanghai, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Cristhian J
authors.initials: CJ
authors.lastname: Ildefonso
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States.
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D012160:Retina / Q000378:metabolism* / Q000503:physiopathology; D012162:Retinal Degeneration / Q000628:therapy*; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D041623:Tomography, Optical Coherence; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2