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  • Title: Evaluation of recombinant adeno-associated virus as a gene transfer vector for the retina.
    Author: Grant CA, Ponnazhagan S, Wang XS, Srivastava A, Li T.
    Journal: Curr Eye Res; 1997 Sep; 16(9):949-56. PubMed ID: 9288458.
    Abstract:
    PURPOSE: To evaluate recombinant adeno-associated virus (AAV) as an in vivo gene transfer vector for the retina. METHODS: A recombinant AAV, vCMVp-lacZ, in which the bacterial beta-galactosidase reporter gene (lacZ) was placed under the control of a cytomegalovirus (CMV) early promoter, was injected into the vitreous body or the subretinal space of mouse eyes. The reporter gene expression was followed by histochemical analyses from 10 to 100 days post-injection. The effect of several variables on the extent of AAV-mediated gene transfer was examined, including routes of delivery, presence of an underlying mutation that caused retinal degeneration, and prior treatment with hydroxyurea. RESULTS: As measured by reporter gene expression, the AAV vector mediated gene transfer to three major cell types in the retina: the retinal pigment epithelium (RPE), ganglion cells and photoreceptor cells. Following a single injection, more than half of the total retinal areas were typically positive for gene transfer. Reporter gene expression was stable for at least 3 months, the farthest time point examined. Gene transfer to photoreceptor cells was observed only following subretinal delivery, and was greatly enhanced in mice undergoing early retinal degeneration. Cells in the inner nuclear layer were rarely transduced. Systemic administration of a genotoxic drug, hydroxyurea, 2 days prior to AAV delivery did not affect the patterns and extent of reporter gene expression. There was minimal histopathology associated with AAV transduction in the retinas of recipient mice, as determined by light microscopy. CONCLUSION: Recombinant AAV mediates efficient gene transfer to RPE and ganglion cells, and to photoreceptor cells under certain conditions. Persistence of transgene expression is of long duration and without apparent histopathology. The greater stability, lower cytopathicity, and the ability to transduce retinal ganglion cells are three distinct features of the AAV vector compared to current adenovirus-based vectors.
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