title: AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa.
abstract: Loss of SPATA7 function causes the pathogenesis of Leber congenital amaurosis and retinitis pigmentosa. Spata7 knockout mice mimic human SPATA7-related retinal disease with apparent photoreceptor degeneration observed as early as postnatal day 15 (P15). To test the efficacy of adeno-associated virus (AAV)-mediated gene therapy for rescue of photoreceptor survival and function in Spata7 mutant mice, we employed the AAV8(Y733F) vector carrying hGRK1-driven full-length FLAG-tagged Spata7 cDNA to target both rod and cone photoreceptors. Following subretinal injection of this vector, FLAG-tagged SPATA7 was found to colocalize with endogenous SPATA7 in wild-type mice. In Spata7 mutant mice initially treated at P15, we observed improvement of photoresponse, photoreceptor ultrastructure and significant alleviation of photoreceptor degeneration. Furthermore, we performed treatments at P28 and P56 and found that all treatments (P15-P56) can ameliorate rod and cone loss in the long term (1 year); however, none efficiently protect photoreceptors from degeneration by 86 weeks of age as only a small amount of treated photoreceptors can survive to this time. This study demonstrates long-term improvement of photoreceptor function by AAV8(Y733F)-introduced Spata7 expression in a mouse model as potential treatment of the human disease, but also suggests that treated mutant photoreceptors still undergo progressive degeneration.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.affiliation: 1] HGSC, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [2] Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Moayedi
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Boye
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Chiodo
authors.affiliation: 1] HGSC, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] HGSC, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Nichols
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: 1] HGSC, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA [3] Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA [3] Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA [4] Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA [5] Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mardon
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000628:therapy*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000628:therapy*
chemical_list: D004268:DNA-Binding Proteins; C000606833:SPATA7 protein, mouse