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

Parfitt, DA; Lane, A; Ramsden, CM; Carr, A-JF; Munro, PM; Jovanovic, K; Schwarz, N; ... Cheetham, ME; + view all (2016) Identification and Correction of Mechanisms Underlying Inherited Blindness in Human iPSC-Derived Optic Cups. Cell Stem Cell , 18 (6) pp. 769-781. 10.1016/j.stem.2016.03.021. Green open access

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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.

Type: Article
Title: Identification and Correction of Mechanisms Underlying Inherited Blindness in Human iPSC-Derived Optic Cups
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stem.2016.03.021
Publisher version: http://dx.doi.org/10.1016/j.stem.2016.03.021
Language: English
Additional information: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Cell Biology, LEBER CONGENITAL AMAUROSIS, LINKED RETINITIS-PIGMENTOSA, RETINAL DEGENERATION, CENTROSOMAL PROTEIN, JOUBERT-SYNDROME, TRANSITION ZONE, CEP290, MUTATION, GENES, CELLS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1486093
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