CRISPR-Cas9–mediated therapeutic editing of Rpe65 ameliorates the disease phenotypes in a mouse model of Leber congenital amaurosis

Dong Hyun Jo, Dong Woo Song, Chang Sik Cho, Un Gi Kim, Kyu Jun Lee, Kihwang Lee, Sung Wook Park, Daesik Kim, Jin Hyoung Kim, Jin Soo Kim, Seokjoong Kim, Jeong Hun Kim, Jung Min Lee

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9 Scopus citations

Abstract

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 ~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.

Original languageEnglish
Article numbereaax1210
JournalScience Advances
Volume5
Issue number10
DOIs
StatePublished - 30 Oct 2019

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