Simultaneous Retinal Gene Transfer of PEDF and FGF–2 by SIVagm–based Lentiviral Vector Shows Synergistic Neuroprotective Effect in an Animal Model of Retinitis Pigmentosa

Abstract

Abstract: : Purpose: We recently developed a novel lentivirus vector derived from the non–pathogenic simian immunodeficiency virus (SIV), and have demonstrated that SIV vector was efficient and safe for retinal gene transfer. Furthermore, significant therapeutic effect of pigment epithelium–derived factor (PEDF) gene transfer was found in RCS rats. We here assessed the synergistic effect of SIV–mediated subretinal gene transfer of both PEDF and fibroblast growth factor–2 (FGF–2), an alternative neurotrophic factor, during the disease progression in RCS rats, an animal model of Retinitis Pigmentosa (RP). Methods: Vector solutions [SIV–PEDF only, SIV–FGF2 only, SIV–PEDF + SIV–FGF2 (1:1 mixture), and SIV–GFP, final conc. 2.5x10⁷ transducing units (TU)/ml, respectively] were injected into the peripheral subretinal space of 3 weeks old RCS rats. Histopathological and electroretinographic (ERG) assessment were examined at several periods after gene transfer. Results: PEDF and FGF–2 gene transfers were more pronounced to protect the loss of photoreceptor cells, compared to those of GFP. Co–transfection of SIV–PEDF and SIV–FGF–2 showed synergistically highest effect on the prevention for photoreceptor degeneration. ERG examination showed the similar synergistic neuroprotective effect by dual expression. Conclusions: These synergistic results indicate the possibility that much higher therapeutic effect can be obtained by dual expression of PEDF and FGF–2 even if keeping less titer of vectors, therefore, this notion possibly contributes to safer and more effective gene therapy against RP.

Keywords: gene transfer/gene therapy • retinal degenerations: hereditary • neuroprotection