Abstract
Age‐related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease; however, these do not exist for the dry form. Complement factor H polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, RPE damage, and visual decline. We have derived and characterized induced pluripotent stem cell (iPSC) lines from two subjects without AMD and low‐risk genotype and two patients with advanced AMD and high‐risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H, factor I, and factor H‐like protein 1. The iPSC RPE cells derived from high‐risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy, and deposition of “drüsen”‐like deposits. The low‐ and high‐risk RPE cells respond differently to intermittent exposure to UV light, which leads to an improvement in cellular and functional phenotype only in the high‐risk AMD‐RPE cells. Taken together, our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing. Stem Cells 2017;35:2305–2320
Highlights
Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world, affecting one in three people by age 75 years, and is characterized by loss of central vision, affecting the macular area of the retina
To investigate how the Y402H polymorphism in complement factor H (CFH) leads to the pathology associated with AMD, DNA was extracted from donor cell fibroblasts and sequenced to detect single nucleotide polymorphisms in the CFH, HTRA1, and ARMS2 genes (Supporting Information Fig. S1A)
Availability of patient specific models which can generate large numbers of retinal pigment epithelium (RPE) cells would provide a significant advance for a better understanding of AMD physiopathology, the contribution of environmental, lifestyle, and dietary factors and drug testing
Summary
Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world, affecting one in three people by age 75 years, and is characterized by loss of central vision, affecting the macular area of the retina. It accounts for 50% of blind and partially sighted registration with an estimated prevalence of 600,000 significantly visually impaired people in the U.K. and over 8 million worldwide [1,2,3,4]. Treatments are evolving for wet AMD including anti-vascular endothelial growth factor (VEGF) treatments, photodynamic, and laser therapy [6,7,8]; there are no effective treatments to prevent progression of the underlying disease process and advanced dry AMD
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