Complement Factor H Mutant Pluripotent Stem Cells to Model Early Onset Macular Degeneration and Their Application in Drug Discovery.
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.
About the Researcher
Dr. Karl Wahlin received his PhD in neuroscience from the Johns Hopkins School of Medicine, where he studied retinal synaptic development under the guidance of Drs. Ruben Adler and Donald Zack. He then went on to a post-doc position at the Wilmer Eye Institute, where he used human pluripotent stem cells to study human eye development and disease. Currently, he is an assistant professor in the Department of Ophthalmology at the University of California, San Diego, where his main research interests lie with investigating the cell signaling in eye development and disease using 3D retinal organoids and retinal pigment epithelium. His lab is developing novel gene-editing tools to further this research. The goal is to translate these cell-based tools into interventional targets for treating AMD and other retinal dystrophies.
High-quality vision is an important ingredient to a happy healthy life. It is unfortunate that later in life when individuals have more time to enjoy the things they love most, their vision often declines. Many of us with friends or family with AMD know first-hand how retinal degenerative disease affects the quality of life. It is this connection to real people with real problems that drives the daily efforts of our lab. We know how much individuals with AMD, as well as their friends and family, rely on scientists like us to bring hope and new treatments, and I am extremely grateful to the generous donors of the BrightFocus Foundation who are helping to make this hope a reality.
First published on: January 10, 2019
Last modified on: July 20, 2020