title: Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration.
abstract: Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis. Importantly, electroretinography and optokinetic response tests confirmed that visual function was significantly improved. Mice treated with non-modified BMDCs or BMDCs pre-programmed with LacZ did not exhibit significant improvement in visual deficit. RPE65-BMDC administration was most effective in early disease, when visual function and retinal morphology returned to near normal, and less effective in late-stage disease. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential to arrest progression in early AMD and other RPE-based diseases.
authors.affiliation: Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: S Louise
authors.initials: SL
authors.lastname: Pay
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: mboulton@iupui.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D060846:Cell Engineering; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D013482:Superoxide Dismutase / Q000172:deficiency; D019745:cis-trans-Isomerases / Q000235:genetics*; D000099178:Retinoid Isomerohydrolase; D000099156:Superoxide Dismutase 2
chemical_list: D013482:Superoxide Dismutase; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; D000099156:Superoxide Dismutase 2
keywords: RPE65; adoptive transfer; age-related macular degeneration; bone marrow-derived cells; cellular reprogramming; retinal degeneration; retinal pigment epithelium