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. In vivo studies showed that RCS rats in the hMERTK/Gas6 NPs group exhibiting the highest electroretinogram responses and more complete retinal structure than that in other groups, further demonstrating that the co-administration of AAV2-BEST1-hMERTK and Gas6 NPs could protect photoreceptors from degeneration. These findings strongly suggest that Gas6 NPs are a promising method to enable the sustained release of Gas6 protein and could therefore enhance the therapeutic effects of gene therapy for MERTK-associated RP.
Highlights
Retinitis pigmentosa (RP), a group of progressive, hereditary diseases that causes irreversible vision loss, is responsible for blindness in more than 2 million people worldwide [1, 2]
We identified that growth arrest-specific 6 (Gas6) NPs preserved Gas6 protein bioactivity and promoted retinal pigment epithelium (RPE) phagocytosis in vitro
We assessed whether Gas6 NPs enhanced the therapeutic effects of gene therapy in Royal College of Surgeons (RCS) rat model of MER proto-oncogene tyrosine kinase (MERTK)-associated retinal dystrophy
Summary
Retinitis pigmentosa (RP), a group of progressive, hereditary diseases that causes irreversible vision loss, is responsible for blindness in more than 2 million people worldwide [1, 2]. Gas NPs Enhances Retinal Phagocytosis dystrophies revealed ∼3% of RP cases are attributable to MERTK mutations [4, 5] Such mutations result in defective phagocytosis, which causes the retinal pigment epithelium (RPE) failing to shed photoreceptor outer segments [6]. Pre-clinical animal models and initial clinical trials suggested a beneficial effect, doubleblinded clinical trials with large cohorts of patients failed to show efficacy [11]. These disappointing results were attributed, at least partially, long-term MerTK mutations can lead to destruction of retina microenvironment [12]. It is important to explore more effective therapies to rescue retinal function and morphology in individuals with MERTK-associated RP, especially after the initiation of retinal degeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
