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AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa
- Source :
- Gene Therapy. 22:619-627
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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 co-localize 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 since 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.
- Subjects :
- medicine.medical_specialty
genetic structures
Genetic enhancement
Genetic Vectors
Leber Congenital Amaurosis
Biology
Retinal Cone Photoreceptor Cells
Article
Pathogenesis
chemistry.chemical_compound
Retinal Rod Photoreceptor Cells
Ophthalmology
Retinitis pigmentosa
Genetics
medicine
Animals
Molecular Biology
Mice, Knockout
Gene therapy of the human retina
Retinal
Genetic Therapy
Dependovirus
medicine.disease
eye diseases
Cell biology
DNA-Binding Proteins
Mice, Inbred C57BL
Disease Models, Animal
chemistry
Knockout mouse
Molecular Medicine
sense organs
Retinitis Pigmentosa
Subjects
Details
- ISSN :
- 14765462 and 09697128
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Gene Therapy
- Accession number :
- edsair.doi.dedup.....c3d5a98b9db4eb5df4a60bca1a5706ed