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Nundehui Diaz-Lezama, Zhijian Wu, Elva Hortencia Adan-Castro, David Arredondo, Gonzalo Martínez de la Escalera, Stephanie Thebault, Peter Colosi, Carmen Clapp; Diabetes enhances the efficacy of adeno-associated virus vectors in rat retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3323.
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© ARVO (1962-2015); The Authors (2016-present)
We previously showed that retinal transduction of adeno-associated virus type 2 (AAV2) vectors is enhanced in diabetes (ARVO 2013). Here, we investigated whether inducing diabetes prior to the intravitreal administration of AAV2 vectors encoding vasoinhibins (Vi) or soluble VEGF receptor 1 (sFlt-1) increases their ability to reduce blood-retinal barrier breakdown (BRBB).
AAV2Vi or AAV2sFlt-1 vectors were delivered by intravitreal injection (2.8e9 vg/eye) to adult rats two weeks after a single injection of streptozotocin (STZ)] to induced diabetes. One month after vector administration the BRBB was examined by the Evans blue dye method. The same dose of AAV2Vi or AAV2sFlt-1 vectors was also injected to non-diabetic rats and, after one month, diabetes was induced with STZ and BRBB was evaluated six weeks later. Finally, 2.8e9 vg/eye of the AAV2sFlt-1 vector was injected intravitreally into non-diabetic and diabetic rats, and one month after vector administration retinal flat mounts were examined for sFlt-1 expression by immunohistochemistry and confocal microscopy.
AAV2-Vi and AAV2sFlt1 vectors inhibited the diabetes-mediated increase in tracer accumulation when diabetes was induced prior to the intravitreal delivery of the vectors. However, neither vector affected tracer accumulation when injected before the onset of diabetes. Transduction of sFlt-1 was substantially increased in the ganglion cell layer of retinas from diabetic rats compared to non-diabetic controls.
These results confirm that retinal transduction by AAV2 vectors is enhanced in diabetes and show that this effect results in higher transgene efficacy. The diabetes-induced factors responsible for these changes warrant further study.
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