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Mohamed El Sanharawi, Elodie Touchard, Romain Benard, Pascal Bigey, Virginie Escriou, Chadi Mehanna, Marie-Chritine Naud, Jean-Claude Jeanny, Marianne Berdugo Polak, Francine Behar-Cohen, INSERM UMRS 872; Long-term efficacy of ciliary muscle gene transfer of three sFlt-1 variants in a rat model of laser-induced choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3285.
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Inhibition of vascular endothelial growth factor (VEGF) has become the standard of care for patients presenting wet age-related macular degeneration. However, monthly intravitreal injections are required for optimal efficacy. We have previously shown that electroporation enabled ciliary muscle gene transfer results in sustained protein secretion into the vitreous for up to 9 months.
Here we evaluated the long-term efficacy of ciliary muscle gene transfer of three soluble VEGF receptor-1 (sFlt-1) variants in a rat model of laser-induced choroidal neovascularization (CNV). Fluorescein angiography (FA) was performed to evaluate vascular leakage. CNV growth was evaluated using retinal pigment epithelium (RPE)/choroid flatmount and infracyanine angiography. Intra-ocular VEGF levels were measured using ELISA. The mRNA expression of VEGF was determined using RT-PCR in the RPE/choroid complexes.
All three sFlt-1 variants significantly diminished vascular leakage and neovascularization as measured by FA and flatmount choroid at 3 weeks. FA and infracyanine angiography demonstrated that inhibition of CNV was maintained for up to 6 months after gene transfer of the two shortest sFlt-1 variants. Throughout, clinical efficacy was correlated with sustained VEGF neutralization in the ocular media. Interestingly, treatment with sFlt-1 induced a 50% down-regulation of VEGF mRNA levels in the retinal pigment epithelium and the choroid.
We demonstrate for the first time that non-viral gene transfer can achieve a long-term reduction of VEGF levels and efficacy in the treatment of choroidal neovascularization.
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