Journal
SCIENCE ADVANCES
Volume 5, Issue 10, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aax1210
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Funding
- Ministry of Food and Drug Safety [17172MFDS213]
- National Research Foundation of Korea (NRF) - Korean government (MSIT) [2017M3A9B4061406]
- Bio and Medical Technology Development Program of the National Research Foundation - Korean government, MSIP [NRF-2015M3A9E6028949, 2017M3A9B4062654]
- Creative Materials Discovery Program through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [2018M3D1A1058826]
- Development of Platform Technology for Innovative Medical Measurements - Korea Research Institute of Standards and Science [KRISS-2018-GP2018-0018]
- National Research Foundation of Korea (NRF) - Ministry of Education [2017R1A6A3A04004741]
- Korea Bio Grand Challenge program through the National Research Foundation of Korea [NRF-2018M3A9H3020844]
- BioYouCell
- National Research Foundation of Korea [2017M3A9B4061406] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Leber congenital amaurosis (LCA), one of the leading causes of childhood-onset blindness, is caused by autosomal recessive mutations in several genes including RPE65. In this study, we performed CRISPR-Cas9-mediated therapeutic correction of a disease-associated nonsense mutation in Rpe65 in rd12 mice, a model of human LCA. Subretinal injection of adeno-associated virus carrying CRISPR-Cas9 and donor DNA resulted in >1% homology-directed repair and similar to 1.6% deletion of the pathogenic stop codon in Rpe65 in retinal pigment epithelial tissues of rd12 mice. The a- and b-waves of electroretinograms were recovered to levels up to 21.2 +/- 4.1% and 39.8 +/- 3.2% of their wild-type mice counterparts upon bright stimuli after dark adaptation 7 months after injection. There was no definite evidence of histologic perturbation or tumorigenesis during 7 months of observation. Collectively, we present the first therapeutic correction of an Rpe65 nonsense mutation using CRISPR-Cas9, providing new insight for developing therapeutics for LCA.
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