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CRISPR/Cas9 mediated specific ablation of vegfa in retinal pigment epithelium efficiently regresses choroidal neovascularization

 Jinkyu Park  ;  Gang Cui  ;  Hyundong Lee  ;  Han Jeong  ;  Jay Jiyong Kwak  ;  Junwon Lee  ;  Suk Ho Byeon 
 SCIENTIFIC REPORTS, Vol.13(1) : 3715, 2023-03 
Journal Title
Issue Date
Animals ; CRISPR-Cas Systems ; Choroidal Neovascularization* / genetics ; Choroidal Neovascularization* / therapy ; Craniocerebral Trauma* ; Disease Models, Animal ; Humans ; Mice ; Retina ; Retinal Pigment Epithelium ; Vascular Endothelial Growth Factor A / genetics
The CRISPR/Cas9 system easily edits target genes in various organisms and is used to treat human diseases. In most therapeutic CRISPR studies, ubiquitously expressed promoters, such as CMV, CAG, and EF1α, are used; however, gene editing is sometimes necessary only in specific cell types relevant to the disease. Therefore, we aimed to develop a retinal pigment epithelium (RPE)-specific CRISPR/Cas9 system. We developed a CRISPR/Cas9 system that operates only in retinal pigment epithelium (RPE) by expressing Cas9 under the RPE-specific vitelliform macular dystrophy 2 promoter (pVMD2). This RPE-specific CRISPR/pVMD2-Cas9 system was tested in human retinal organoid and mouse model. We confirmed that this system works specifically in the RPE of human retinal organoids and mouse retina. In addition, the RPE-specific Vegfa ablation using the novel CRISPR-pVMD2-Cas9 system caused regression of choroidal neovascularization (CNV) without unwanted knock-out in the neural retina in laser-induced CNV mice, which is a widely used animal model of neovascular age-related macular degeneration. RPE-specific Vegfa knock-out (KO) and ubiquitous Vegfa KO were comparable in the efficient regression of CNV. The promoter substituted, cell type-specific CRISPR/Cas9 systems can be used in specific 'target cell' therapy, which edits genes while reducing unwanted off- 'target cell' effects. © 2023. The Author(s).
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Kwak, Jiyong(곽지용) ORCID logo https://orcid.org/0000-0002-7738-9136
Byeon, Suk Ho(변석호) ORCID logo https://orcid.org/0000-0001-8101-0830
Lee, Jun Won(이준원) ORCID logo https://orcid.org/0000-0003-0543-7132
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