Journal
STEM CELL REPORTS
Volume 16, Issue 2, Pages 252-263Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2020.12.018
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Funding
- Intramural Research Programs of the National Eye Institute [ZIAEY000450, ZIAEY000546]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health
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Mutations in the CRX gene lead to distinct retinopathy phenotypes and early-onset vision impairment. Using iPSCs from patients with CRX mutations, researchers established in vitro models of CRX-LCA and found that AAV-mediated CRX gene augmentation therapy partially restored defective photoreceptor maturation and opsins expression. This study provides proof-of-concept for developing gene therapy for dominant CRX-LCA and other CRX retinopathies.
Mutations in the photoreceptor transcription factor gene cone-rod homeobox (CRX) lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Using induced pluripotent stem cells (iPSCs) from a patient with CRX-I138fs48 mutation, we established an in vitro model of CRX-LCA in retinal organoids that showed defective photoreceptor maturation by histology and gene profiling, with diminished expression of visual opsins. Adeno-associated virus (AAV)-mediated CRX gene augmentation therapy partially restored photoreceptor phenotype and expression of phototransduction-related genes as determined by single-cell RNA-sequencing. Retinal organoids derived from iPSCs of a second dominant CRX-LCA patient carrying K88N mutation revealed the loss of opsin expression as a common phenotype, which was alleviated by AAV-mediated augmentation of CRX. Our studies provide a proof-of-concept for developing gene therapy of dominant CRX-LCA and other CRX retinopathies.
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