Establishing 3-Dimensional (3D) Retinal Optic Cups using patient-specific CRB1 Induced Pluripotent Stem Cells.

PI: Jason A. Mills, PhD

Institution:  University of Pennsylvania

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Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are blinding disorders with a range of retinal dystrophy severity. LCA is the most severe nonsyndromic retinal dystrophy, resulting in blindness or severe visual impairment as early as birth, and RP has a later onset and is characterized progressive loss of photoreceptors, and thus causes reductions in visual field and light sensitivity. Crumbs-homolog-1 (CRB1) mutations accounts for 9-13% of overall LCA causes (~450 patients in US) and 4-5% of RP families (~3,300 patients in US). Importantly, CRB1-associated disease in humans is characterized by night blindness subsequently leading to loss of peripheral vision, photoreceptor degeneration, and eventual complete blindness.

Our work aims to develop a retina model for studying the cellular and molecular abnormalities that are associated with CRB1 mutations and blinding clinical phenotypes.  We will focus on identifying differences in cellular dynamics (proliferation, apoptosis, cell cycle), how mutations in the CRB complex affect gene expression in retinal cells and cell polarity (apical-basal localization), and establish an in vitro 3-Dimensional retinal developmental model.  We anticipate this system will provide a thorough description of the cellular and molecular landscape of disruptions in the Crumbs (CRB) complex in retinal cells, and increase our understanding of how biomarkers established in this system can be used as a readout for translational approaches such as gene augmentation or proteomic therapeutics for CRB-blinding disease.