Abstract
Top of pageAbstract Purpose: Recently, we have demonstrated the efficient and stable retinal gene transfer mediated by the non-pathogenic simian immunodeficiency virus (SIV)-based lentivirus vector as well as the therapeutic outcome in some animal models of retinal degeneration using recombinant SIV vectors carrying neurotrophic factors, such as pigment epithelium-derived factor (PEDF) and fibroblast growth factor-2 (FGF-2). Here, we report the acute ophthalmic toxicity following intraocular administration of SIV-PEDF in Macaca fascicularis, as a preclinical safety study. Methods: Eleven Macaca fascicularis (body weight=2.35-5.63 kg) were enrolled in this study. Approximately 20 |[mu]|l of SIV-PEDF (low titer: 2.5|[times]|107 transducing units [TU]/ml, equal to clinically available titer, high titer: 2.5|[times]|108 TU)/ml, and max titer: 1.0|[times]|109 TU/ml, n=3, respectively) or control (balanced salt solution: BSS, n=2) were injected into subretinal space via a glass capillary tube. We undertook an ophthalmic examination including slitlamp biomicroscopy, intraocular pressure (IOP) measurement, fundoscopic examination, and fluorescein anigiography, and assessed transgene expression, retinal function with electroretinogram (ERG) and histology for 3 months. Results: SIV vector was efficiently transferred mainly to the retinal pigment epithelium and transgene expression was detected within 3 months. Transient inflammatory cell infiltration to anterior ocular segment and elevation of IOP were observed in some animals, but not dose-dependent. ERGs including multi-focal ERGs revealed no remarkable change of the retinal functions. Retinas treated with both SIV-PEDF and BSS showed no significant inflammatory infiltration and retinal structural destruction. Furthermore, neither dead animal nor serious side effect was found during experimental course. Conclusions: The current study indicated the acute local and systemic safety of intraocular administration of SIV-PEDF, even if it was given at 40-times higher titer than clinical available titer. We are now conducting the long-termed safety study in non-human primates.
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