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Cell Stem Cell. 2016 Jun 2;18(6):769-81. doi: 10.1016/j.stem.2016.03.021. Epub 2016 Apr 14.

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

Author information

1
Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
2
Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK.
3
Maurice Wohl Clinical Neurosciences Institute, Institute of Psychiatry, Psychology, and Neuroscience, Kings College London, London SE5 9NU, UK.
4
Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: michael.cheetham@ucl.ac.uk.

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.

PMID:
27151457
PMCID:
PMC4899423
DOI:
10.1016/j.stem.2016.03.021
[Indexed for MEDLINE]
Free PMC Article
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