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B.J. Raisler, V. Chiodo, K.I. Berns, P.A. Campochiaro, W.W. Hauswirth; AAV-mediated Expression of Angiostatin Increases Intraocular Levels of PEDF . Invest. Ophthalmol. Vis. Sci. 2003;44(13):550.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In the ischemic neonatal mouse model of retinal neovascularization (NV), eyes treated with rAAV-PEDF or rAAV-K1K3 have significantly reduced numbers of proliferating retinal vascular endothelial cells. We aimed to answer the question of whether the therapeutic activity of ocular K1K3 and PEDF are linked. Methods: Recombinant AAV vectors expressing K1K3 were injected into one eye of postnatal day 0 (P0) newborn mouse pups. Protein levels for K1K3 expression and subsequent up-regulation of PEDF were measured by indirect sandwich ELISA daily for the time frame corresponding to the neonatal mouse retinal ischemia-induced model from P1 to P17. Protein expression was also followed in adult animals 2, 4, 6, and 8 weeks after an intravitreal injection of rAAV-K1K3. Results: The protein levels measured by ELISA indicate expression of K1K3 (30-90 ng/eye) and the subsequent up-regulation of endogenous PEDF (2-9 ng/eye) are detectable as early as 1 day post-injection of rAAV-K1K3 and both persist at therapeutic levels for the 17-day period of the experimental model. In eyes of adult animals PEDF is also substantially increased (4-7 ng/eye) following the injection of vector expressing only K1K3 at levels of 15-90 ng/eye. In untreated control eyes, endogenous expression of PEDF is measurable at levels typically lower than 1 ng/eye in either adult or neonatal mice. Conclusions: Efficacy of K1K3 in this model of retinal neovascularization may be due in part to the increased intraocular levels of PEDF. Our previous work in a laser-induced model of choriodal neovascularization (CNV) revealed a delay in the control of CNV in eyes injected with rAAV-K1K3 compared with eyes injected with rAAV-PEDF. This may be due to a potential regulatory relationship where angiostatin may act upstream of PEDF in a pathway for the control of angiogenesis. Thus rAAV-K1K3 may act to limit pathogenic retinal NV or CNV through regulation of endogenous ocular PEDF levels.
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