Identifying Drugs That Block AMD Using Stem Cells With AMD-Associated Mutations

Macular degenerative disease affects millions worldwide and models to study the condition in humans are generally lacking. We have developed human disease-based stem cell lines (created from adult stem cells) that can be readily converted into retinal pigment epithelium (RPE) in order to study the disease process in the laboratory. Unique to this project, we have also designed a fluorescent protein reporter that will allow us to study the temporal dynamics of RPE cell dystrophy, thus allowing the systematic optimization of drug screening aimed at reducing protein deposits typical of AMD.

Age-related macular degeneration (AMD) is a major cause of blindness worldwide and a hallmark of this disease includes protein deposits, called drusen, which lie underneath the retinal pigment epithelium (RPE) in the back of the eye. In AMD, can evolve into geographic atrophy or choroidal neovascularization with consequent loss of photoreceptors (PRs). Therefore, a critical need is to develop human-based models of AMD which can recapitulate drusen formation and are amenable to high throughput approaches for drug discovery. Using genetically engineered pluripotent stem cells harboring the complement factor H (CFH) R1210C mutation, we will develop an in vitro assay to monitor the progression of sub-RPE deposits in laboratory. These cells will then be used to perform a small-molecule drug screen aimed at reducing sub-RPE deposits, which may in turn lead to new therapeutic targets for macular degenerative disease.