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Nat Commun. 2018 May 10;9(1):1855. doi: 10.1038/s41467-018-04175-y.

CRISPR-LbCpf1 prevents choroidal neovascularization in a mouse model of age-related macular degeneration.

Koo T1,2, Park SW3,4,5, Jo DH3, Kim D6, Kim JH3, Cho HY1, Kim J6, Kim JH7,8,9, Kim JS10,11,12.

Author information

1
Center for Genome Engineering, Institute for Basic Science, Seoul, 151-747, Republic of Korea.
2
Department of Basic Science, University of Science and Technology, Daejeon, 34113, Republic of Korea.
3
FARB Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea.
4
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
5
Department of Ophthalmology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
6
Department of Chemistry, Seoul National University, Seoul, 151-747, South Korea.
7
FARB Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Republic of Korea. steph25@snu.ac.kr.
8
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. steph25@snu.ac.kr.
9
Department of Ophthalmology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. steph25@snu.ac.kr.
10
Center for Genome Engineering, Institute for Basic Science, Seoul, 151-747, Republic of Korea. jskim01@snu.ac.kr.
11
Department of Basic Science, University of Science and Technology, Daejeon, 34113, Republic of Korea. jskim01@snu.ac.kr.
12
Department of Chemistry, Seoul National University, Seoul, 151-747, South Korea. jskim01@snu.ac.kr.

Abstract

LbCpf1, derived from Lachnospiraceae bacterium ND2006, is a CRISPR RNA-guided endonuclease and holds promise for therapeutic applications. Here we show that LbCpf1 can be used for therapeutic gene editing in a mouse model of age-related macular degeneration (AMD). The intravitreal delivery of LbCpf1, targeted to two angiogenesis-associated genes encoding vascular endothelial growth factor A (Vegfa) and hypoxia inducing factor 1a (Hif1a), using adeno-associated virus, led to efficient gene disruption with no apparent off-target effects in the retina and retinal pigment epithelium (RPE) cells. Importantly, LbCpf1 targeted to Vegfa or Hif1a in RPE cells reduced the area of laser-induced choroidal neovascularization as efficiently as aflibercept, an anti-VEGF drug currently used in the clinic, without inducing cone dysfunction. Unlike aflibercept, LbCpf1 targeted to Vegfa or Hif1a achieved a long-term therapeutic effect on CNV, potentially avoiding repetitive injections. Taken together, these results indicate that LbCpf1-mediated in vivo genome editing to ablate pathologic angiogenesis provides an effective strategy for the treatment of AMD and other neovascularization-associated diseases.

PMID:
29748595
PMCID:
PMC5945874
DOI:
10.1038/s41467-018-04175-y
[Indexed for MEDLINE]
Free PMC Article

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