A novel bioengineered RPE-choroid interface to study dry Age-related Macular Degeneration

Abstract

Purpose :
Age-related Macular degeneration (AMD) represents the most common blinding disease of the elderly in industrialized countries. The disease manifests in two forms (dry and wet): While pathological neovascularization can be readily treated by neutralizing VEGF/ANG2 (VABYSMO™), there are only limited therapeutic options for patients developing the dry form. The initial signs of AMD manifest at the retinal pigment epithelium (RPE)-choroid interface, where atrophy of the RPE, degeneration of the blood vessels and photoreceptor cell death lead to blindness. The lack of suitable animal models that translate into human disease is one of the primary factors hindering the development of effective therapies. Since only humans develop AMD, we set out to construct a microphysiological system replicating salient features of the disease.

Methods :
First, we developed a novel bioengineered in vitro model of the RPE-choroid interface that recapitulates normal tissue physiology and function. As a next step, we used different methods to induce pathological hallmarks of dry AMD, such as the formation of drusen-like deposits and the concomitant patchy loss of the RPE cells resembling geographic atrophy (GA). Finally, to better benchmark and refine our system, we are working on a spatial-omic reference of eyes affected by dry AMD.

Results :
We devised an RPE-choroid co-culture system on a chip that can be maintained over 4 weeks. Human iPSC-derived RPE cells were seeded and differentiated on top of a perfusable vascular bed consisting of retinal endothelial cells. RPE cells developed polarity similar to the in vivo situation, produced a collagen-rich layer resembling the Bruch’s membrane, and promoted long-term endothelial cells survival. Additionally, we show that lipid droplets accumulate in stressed RPE cells and that it is possible to induce RPE atrophic regions on chip, which can be used to model GA in vitro.

Conclusions :
Our novel RPE-choroid co-culture model lays the foundation for a 3D model of the back of the eye, where the symptoms of dry AMD manifest. Moreover, additional cell types can be added to the RPE-choroid interface in order to interrogate their interplay and contribution to pathological changes. We believe that this new bioengineered model will pave the way for the identification of new targets and enable the testing of drug candidates in an in vitro system.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.