Scherman, D. (Daniel)

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    Preclinical evaluation of a cell-based gene therapy using the sleeping beauty transposon system in choroidal neovascularization
    (Elsevier BV, 2019) Ivics, Z. (Zoltán); Garcia-Garcia, L. (Laura); Marie, C. (Corinne); Johnen, S. (S.); Rodriguez-Madoz, J.R. (Juan Roberto); Scherman, D. (Daniel); Pouillot, S. (Severine); Garcia-Layana, A. (Alfredo); Izsvák, Z. (Zsuzsanna); Thumann, G. (Gabriele); Diarra, S. (Sabine); Bezunartea, J. (Jaione); Miskey, C. (Csaba); Fernandez-Robredo, P. (Patricia); Sebe, A. (Attila); Prosper-Cardoso, F. (Felipe); Kropp, M. (Martina); Hernandez, M. (María); Recalde, S. (Sergio)
    Age-related macular degeneration (AMD) is a progressive retinal disorder characterized by imbalanced pro- and antiangiogenic signals. The aim of this study was to evaluate the effect of ex vivo cell-based gene therapy with stable expression of human pigment epithelium-derived factor (PEDF) release using the non-viral Sleeping Beauty (SB100X) transposon system delivered by miniplasmids free of antibiotic resistance markers (pFAR4). Retinal pigment epithelial (RPE) cells and iris pigment epithelial (IPE) cells were co-transfected with pFAR4-inverted terminal repeats (ITRs) CMV-PEDF-BGH and pFAR4-CMV-SB100X-SV40 plasmids. Laser-induced choroidal neovascularization (CNV) was performed in rats, and transfected primary cells (transfected RPE [tRPE] and transfected IPE [tIPE] cells) were injected into the subretinal space. The leakage and CNV areas, vascular endothelial growth factor (VEGF), PEDF protein expression, metalloproteinases 2 and 9 (MMP-2/9), and microglial/macrophage markers were measured. Injection with tRPE/IPE cells significantly reduced the leakage area at 7 and 14 days and the CNV area at 7 days. There was a significant increase in PEDF and the PEDF/VEGF ratio with tRPE cells and a reduction in the MMP-2 activity. Our data demonstrated that ex vivo non-viral gene therapy reduces CNV and could be an effective and safe therapeutic option for angiogenic retinal diseases.