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K.P. Callahan, P. Gehlbach, A. Demetriades, L. Lu, S. Yamamoto, T. Deering, H. Liu, L. Wei, P.A. Campochiaro; Adenoviral-Vectored TGF-ß1 Does Not Inhibit Retinal or Choroidal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3579.
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Purpose: Transforming growth factor-ß (TGF-ß) is an inhibitor of endothelial cell proliferation in vitro, and the type 1 isoform (TGF-ß1) is particularly potent in this regard. In vivo, TGF-ß inhibits angiogenesis in some settings, but in other settings it is stimulatory. The aim of this study was to assess the effect of adenoviral-vectored TGF-ß1 on ocular neovascularization (NV). Methods: Neonatal C57BL/6 mice were exposed to 75% oxygen between postnatal day (P) 7 and P12. At P12, they were given an intravitreous (IV) injection of 3x108 viral particles (vp) or periocular (PO) injection of 3x109 vp of E1- and E3-deleted type 5 adenoviral vector with a CMV promoter expressing active human TGF-ß1 (AdTGF-ß1.10) in the right eye and the same concentration of a corresponding null vector (AdNull.10) in the left eye. At P17, mice were euthanized and retinal NV was measured. Adult C57BL/6 mice had laser-induced rupture of Bruch’s membrane in each eye and then received either an IV injection of 1x108 vp or PO injection of either 3x108 vp or 3x109 vp of AdTGF-ß1.10 in the right eye and no injection in the left. After two weeks, mice were perfused with fluorescein labeled dextran and the area of choroidal NV was measured on choroidal flat mounts. Twenty-four hours after IV injection of 1x108 vp or PO injection of 3x108 vp of AdTGF-ß1.10, whole eye levels of VEGF were measured by ELISA. Results: In mice with ischemic retinopathy, neither IV (0.11vs.0.117mm2, p=0.61) nor PO injection of AdTGF-ß1.10 (0.112vs.0.126mm2, p=0.60) caused a significant decrease in retinal NV compared to injection of AdNull.10. There was also no significant decrease in choroidal NV from PO injection of 3x108 vp (0.04vs.0.038mm2, p=0.86) or 3x109 vp (0.04vs.0.035mm2, p=0.56) of AdTGF-ß1.10 or IV injection of 1x108 vp (0.038vs.0.046mm2, p=0.66) compared to no injection. ELISA for TGF-ß1 following PO injection showed mean levels (pg TGF-ß1/µg total protein) in orbit (0.002), sclera (0.022), choroid (0.01) but not retina (0.004) to be significantly elevated (p<0.05) as compared to corresponding control. Twenty-four hours after IV injection, but not PO injection, of AdTGF-ß1.10 VEGF levels (pg VEGF/ µg total protein) in the whole eye were significantly elevated (0.004) compared to uninjected controls (0.002; p=0.04). Conclusions: Adenoviral-mediated ocular gene transfer of TGF-ß1 does not inhibit retinal or choroidal NV. Induction of VEGF expression may be one contributing factor to the lack of TGF-ß-mediated antiangiogenic activity in vascular beds of the eye.
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