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Nundehui Díaz-Lezama, Zhijian Wu, Mayda Ramírez, Bibiana Moreno-Carranza, Gonzalo Martinez de la Escalera, Peter Colosi, Carmen Clapp; Enhancement of AAV2-mediated retinal transduction in diabetic rats. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2716.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular gene therapy based on the adeno-associated virus (AAV) vector-mediated delivery of antiangiogenic molecules offers considerable promise for the treatment of diabetic retinopathy. AAV type-2 (AAV2) uses cell surface heparan sulphate proteoglycans (HSPG) as the primary receptors for cell entry. HSPGs are present on retinal ganglion cells, and likely mediate vector transduction. Here, we compared the transduction of retinal ganglion cells in diabetic and normal rats following intravitreal delivery of AAV2 vectors, and investigated whether such transduction correlates with the level of HSPG expression in the respective retinas.
An AAV2 CMV EGFP reporter vector was delivered by intravitreal injection (2.8e10 vg/eye) to adult non-diabetic rats (controls) and diabetic rats treated two weeks prior with a single injection of streptozotocin. One month after vector administration, retinal flatmounts were examined for EGFP expression, by confocal microscopy, and expression of the HSPGs syndecan, glypican, and perlecan, by quantitative PCR.
In normal rat retinas, transduction was limited to occasional cells in the ganglion cell layer. In the diabetic rats, the transduction was enhanced more than 4-fold in ganglion cell somas and processes. The expression of mRNAs for syndecan and glypican was elevated 2- and 1.5-fold in the diabetic rat retina, respectively, whereas that of perlecan was not modified.
Retinal transduction by AAV2 vectors is enhanced in diabetes and may be mediated by elevated expression of HSPGs on ganglion cells. The diabetes-induced factors responsible for these changes warrant further study. AAV2 vectors may be desirable for gene therapeutics targeting in diabetic retinopathy.
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