title: Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease.
abstract: Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients andAbca4-/-(STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-oldAbca4-/-mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY-treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY-treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lenis
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Shanta
authors.initials: S
authors.lastname: Sarfare
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Zhichun
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Marcia B
authors.initials: MB
authors.lastname: Lloyd
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Dean
authors.initials: D
authors.lastname: Bok
authors.affiliation: Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; radu@jsei.ucla.edu.|Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Roxana A
authors.identifier: 0000-0002-5064-6403
authors.initials: RA
authors.lastname: Radu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001343:Autophagy; D003176:Complement C3 / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056965:Injections, Intraocular; D008062:Lipofuscin / Q000378:metabolism; D008268:Macular Degeneration / Q000151:congenital* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D017463:Receptors, Complement 3b; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D012176:Retinoids / Q000378:metabolism; D000080362:Stargardt Disease
chemical_list: D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D003176:Complement C3; C081470:Cr1l protein, mouse; D008062:Lipofuscin; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D012176:Retinoids
keywords: bisretinoids; complement system; gene therapy; recessive Stargardt macular degeneration; retinal pigment epithelium