Anti-elastin targeted nanoparticles resolve mineralized subretinal pigment epithelial deposits in a mouse model of age-related macular degeneration.

Rutsch, F.; Nitschke, Y.; Begasse, T.; Heiduschka, P.; Eter, N.; Hansen, U;. Deering, J.; McKee, M.D.; Langer, K.,

Abstract

Purpose : Calcification of subretinal pigment epithelial (sub-RPE) deposits is associated with drusen growth and rapid progression of age-related macular degeneration (AMD). In this study, we developed a mouse model with sub-RPE calcifications and a targeted drug delivery system to resolve them. Methods : Ttw/ttw mice carrying a truncating mutation in Enpp1 received a high-phosphate diet to accelerate ectopic calcification. Eyes were studied by optical coherence tomography (OCT) and fluorescein angiography, and retinal function by electroretinography (ERG). Eye calcification was examined by Alizarin red staining, X-ray microscopy and electron microscopy. Mineral deposits were analyzed by energy-dispersive X-ray spectroscopy. Calcium content was chemically quantified by the O-cresolphthalein-complexon method. For treatment, the chelating agent diethylenetriaminepentaacetic acid (DTPA) was covalently bound to human serum albumin (HSA)-based nanoparticles (NPs). NP surface was modified by an anti-elastin antibody to target elastin in Bruch’s membrane (BM). NPs were injected twice per week at a concentration of 20 µg/g body weight starting from 10 weeks of age (4 injections in total) into the lateral tail vein of ttw/ttw mice. Results : Calcified sub-RPE deposits were evident at 9 weeks of age in ttw/ttw mice fed a high-phosphate diet, and calcifications were more pronounced at 12 weeks of age. Ocular calcifications were absent in wild type mice. Ttw/ttw mice with sub-RPE calcifications displayed decreased amplitudes of ERG a- and b-waves compared to wild type mice. Ocular calcium content in ttw/ttw mice treated with systemically administered NPs targeted to BM was equal to ocular calcium content in wild type mice (Fig. 1), suggesting resolution of sub-RPE calcifications in ttw/ttw mice. Conclusions : Ttw/ttw mice on a high-phosphate diet develop calcified sub-RPE deposits recapitulating parts of the AMD phenotype. Systemic delivery of DTPA-HSA-NPs containing antibodies targeted to BM elastin is a promising approach to resolve calcifications in sub-RPE deposits in the context of AMD.