AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa.

TitleAAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa.
Publication TypeJournal Article
Year of Publication2015
AuthorsZhong, H, Eblimit, A, Moayedi, Y, Boye, SL, Chiodo, VA, Chen, Y, Li, Y, Nichols, RM, Hauswirth, WW, Chen, R, Mardon, G
JournalGene Ther
Date Published2015 Aug
KeywordsAnimals, Dependovirus, Disease Models, Animal, DNA-Binding Proteins, Genetic Therapy, Genetic Vectors, Leber Congenital Amaurosis, Mice, Inbred C57BL, Mice, Knockout, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa

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.

Alternate JournalGene Ther.
PubMed ID25965394
PubMed Central IDPMC5026120
Grant ListCA125123 / CA / NCI NIH HHS / United States
HD007495 / HD / NICHD NIH HHS / United States
R01 EY020540 / EY / NEI NIH HHS / United States
EY020540 / EY / NEI NIH HHS / United States
DK56338 / DK / NIDDK NIH HHS / United States
EY018571 / EY / NEI NIH HHS / United States
EY021721 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
P30 EY021721 / EY / NEI NIH HHS / United States

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