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

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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

Original languageEnglish
Pages (from-to)769-781
Number of pages13
JournalCell Stem Cell
Issue number6
Early online date14 Apr 2016
Accepted/In press29 Mar 2016
E-pub ahead of print14 Apr 2016
Published2 Jun 2016


King's Authors


Summary 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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