Preclinical Long-Term Safety Study of Simian Immunodeficiency Virus (SIV)-Based Lentiviral Vector for Retinal Gene Transfer in Non-Human Primates

Abstract

Purpose: : Recently, we have demonstrated the efficient and stable retinal gene transfer mediated by the non-pathogenic simian immunodeficiency virus (SIV)-based lentiviral vector as well as the therapeutic outcome in some animal models of retinal degeneration using recombinant SIV vectors carrying neurotrophic factors. Here, we report the long-term systemic and local effects following intraocular administration of SIV-hPEDF in Macaca fascicularis, as a preclinical safety study.

Methods: : Seven Macaca fascicularis were enrolled in this study. Approximately 20 µl of SIV-hPEDF (low titer: 2.5x10⁷ transducing units [TU]/ml, n=4 and high titer: 2.5x10⁸ TU/ml, n=3, respectively) were injected into subretinal space via a glass capillary tube. We undertook an ophthalmic examination, including slitlamp biomicroscopy, intraocular pressure (IOP) measurement, fundoscopic examination, fluorescein anigiography, and electroretinogram (ERG) measurement, and a systemic examination, including general body condition, vital sign, hematology, and blood and urine chemistry, during experimental course (2 years).

Results: : Long-lasting hPEDF expression was detected in the aqueous humor at the end of this study. No serious local effect was observed. Functional evaluation via ERGs including multi-focal ERGs revealed no remarkable change of the retinal functions. Neither dead animal nor serious side effect was found during experimental course.

Conclusions: : The current study indicated the long-term systemic and local safety of intraocular administration of SIV-hPEDF. This long-term safety study using large animals is encouraging for clinical application of retinal gene therapy for patients with retinitis pigmentosa.

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