Identification and Correction of Mechanisms Underlying Inherited Blindness in Human IPSC-Derived Optic Cups

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 May 7

PMID 27151457

Citations 171

Authors

David A Parfitt

Amelia Lane

Conor M Ramsden

Amanda-Jayne F Carr

Peter M Munro

Katarina Jovanovic

Nele Schwarz

Naheed Kanuga

Manickam N Muthiah

Sarah Hull

Jean-Marc Gallo

Lyndon da Cruz

Anthony T Moore

Alison J Hardcastle

Peter J Coffey

Michael E Cheetham

Affiliations

Soon will be listed here.

Abstract

Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention.

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