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

Taeyoung Koo, Sung Wook Park, Dong Hyun Jo, Daesik Kim, Jin Hyoung Kim, Hee-Yeon Cho, Jeungeun Kim, Jeong Hun Kim () and Jin-Soo Kim ()
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Taeyoung Koo: Institute for Basic Science
Sung Wook Park: Biomedical Research Institute, Seoul National University Hospital
Dong Hyun Jo: Biomedical Research Institute, Seoul National University Hospital
Daesik Kim: Seoul National University
Jin Hyoung Kim: Biomedical Research Institute, Seoul National University Hospital
Hee-Yeon Cho: Institute for Basic Science
Jeungeun Kim: Seoul National University
Jeong Hun Kim: Biomedical Research Institute, Seoul National University Hospital
Jin-Soo Kim: Institute for Basic Science

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04175-y

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