Human induced pluripotent stem cell‐derived retinal pigment epithelial cell model of Sorsby fundus dystrophy

Abstract

AbstractSorsby fundus dystrophy (SFD) is a rare degenerative disease of the macular retina, caused by mutations in the tissue inhibitor of matrix metalloproteinase‐3 (TIMP3) gene. SFD leads to bilateral loss of central vision and shows significant clinical overlap with the more common age‐related macular degeneration, suggesting shared underlying mechanisms. In SFD the mutant TIMP‐3 deposits under the retinal pigment epithelium (RPE), leading to pathological sub‐RPE thickening, but the initiating pathology is poorly understood. We have established patient specific human induced pluripotent stem cell (hiPSC) lines from three SFD patients carrying Ser204Cys mutation in TIMP3 gene, and three healthy controls. The hiPSC lines were extensively characterized and differentiated to RPE. SFD‐iPSC‐RPE showed no difference in RPE properties such as morphology, gene or protein expression, phagocytosis capacity or growth factor secretion compared to control‐hiPSC‐RPE. SFD‐iPSC‐RPE showed lowered epithelial resistance, and transmission electron microscopy indicated basal laminar changes and deposits under the SFD‐iPSC‐RPE. Quantitative proteomics analyses indicated upregulation of retinal degeneration associated pathways and accumulation of related proteins including apolipoprotein E. Western blotting verified clear accumulation of the TIMP3 protein in the SFD‐iPSC‐RPE cultures. Overall, the SFD‐iPSC‐RPE cell models recapitulate the disease phenotype in vitro for the study of disease mechanisms.