Sustained Release of Gas6 Through MPEG-PLGA Nanoparticles for Enhancing Therapeutic Effects of Gene Therapy for MERTK-Associated Retinitis Pigmentosa

Abstract

Previous researches utilizing MER proto-oncogene tyrosine kinase (MERTK) gene therapy in Royal College of Surgeons (RCS) rats evidenced its effectiveness in treating MERTK-associated retinitis pigmentosa (RP). Specific ligands for receptor tyrosine kinases, such as growth arrest-specific 6 (Gas6), may enhance retinal phagocytosis via the MERTK receptor, and consequently, enhance the therapeutic effects of gene therapy. In order to overcome the short life effect of the injected Gas6 protein, we constructed a Gas6 loaded methoxy-poly(ethylene glyeol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (Gas6 NPs) system which allowed for localized and sustained Gas6 protein release, and therefore, a prolonged biological effect. Our data demonstrated that Gas6 protein release from Gas6 NPs preserved the bioactivity and promoted retinal pigment epithelium (RPE) phagocytosis in vitro. Furthermore, the co-transplantation of AAV2-BEST1-hMERTK and Gas6 NPs protected photoreceptors from degeneration in RCS rats. Electroretinogram responses in the hMERTK, hMERTK/Gas6, and hMERTK/Gas6 NPs groups were significantly higher than that of the control, with the hMERTK/Gas6 NPs group exhibiting the highest response. These findings strongly suggest that Gas6 NPs are a promising method to enable the sustained release of Gas6 protein within the therapeutic window and could therefore enhance the therapeutic effects of gene therapy for MERTK-associated RP.