Abstract
Presentation Description :
Age-related macular degeneration is a multifactorial disease, and it is challenging to develop models recapitulating key features of AMD pathobiology. Human induced pluripotent stem cell (iPSC)-based atrophic AMD (aAMD) disease modeling is a promising platform for studying disease mechanisms and drug screening. Our goal is to simulate retinal pigment epithelium (RPE) mitochondrial disorders, identify functional deficiencies, characterize clinically relevant RPE disease phenotypes, and rejuvenate RPE for autologous therapies. The novel conceptual hypothesis of this project is that mitophagy impairment and dysfunctional mitochondrial bioenergetics contribute to RPE structural and functional deficiencies in aging and macular degeneration. We validated this hypothesis using mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patient iPSCS harboring the m.3243A>GtRNA leu mutation. The patient iPSCs were differentiated into RPE cells with different levels of mitochondrial heteroplasmy. Using this newly published model, we will modulate mitochondrial bioenergetics and mitophagy pathways to rejuvenate diseased RPE for the treatment of aAMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.