Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases

Lingmin Zhang; Le Wang; Yangzhouyun Xie; Peng Wang; Sai Deng; Aiping Qin; Jiangjiang Zhang; Xiyong Yu; Wenfu Zheng; Xingyu Jiang

doi:10.1002/anie.201903618

Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases

Lingmin Zhang, Le Wang, Yangzhouyun Xie, Peng Wang, Sai Deng, Aiping Qin, Jiangjiang Zhang, Xiyong Yu^*, Wenfu Zheng, Xingyu Jiang

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

119 Citations (Scopus)

Abstract

A high level of low-density lipoprotein cholesterol (LDL-C) in the blood is a major risk factor for coronary heart disease. Herein, we present a triple-targeting strategy to generate a loss-of-function mutation in Pcsk9, which regulates plasma cholesterol levels, using a nanocarrier-delivered CRISPR/Cas9 system. Nuclear localization signal (NLS)-tagged Cas9 and Pcsk9-targeted single guide RNA (sgPcsk9) were complexed with gold nanoclusters (GNCs) modified with cationic HIV-1-transactivating transcriptor (TAT) peptide and further encapsulated in a galactose-modified lipid layer to target the nanoclusters to the liver. The resulting nanoclusters had an in vitro Pcsk9-editing efficiency of about 60 % and resulting in a decrease in plasma LDL-C in mice of approximately 30%. No off-target mutagenesis was detected in 10 sites with high similarity. This approach may have therapeutic potential for the prevention and treatment of cardiovascular disease without side effects.

Original language	English
Pages (from-to)	12404-12408
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	58
Issue number	36
DOIs	https://doi.org/10.1002/anie.201903618
Publication status	Published - 2 Sept 2019
Externally published	Yes

Keywords

CRISPR/Cas9
drug delivery
gene editing
low-density lipoprotein cholesterol
nanoparticles

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.201903618

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Zhang, L., Wang, L., Xie, Y., Wang, P., Deng, S., Qin, A., Zhang, J., Yu, X., Zheng, W., & Jiang, X. (2019). Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases. Angewandte Chemie - International Edition, 58(36), 12404-12408. https://doi.org/10.1002/anie.201903618

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abstract = "A high level of low-density lipoprotein cholesterol (LDL-C) in the blood is a major risk factor for coronary heart disease. Herein, we present a triple-targeting strategy to generate a loss-of-function mutation in Pcsk9, which regulates plasma cholesterol levels, using a nanocarrier-delivered CRISPR/Cas9 system. Nuclear localization signal (NLS)-tagged Cas9 and Pcsk9-targeted single guide RNA (sgPcsk9) were complexed with gold nanoclusters (GNCs) modified with cationic HIV-1-transactivating transcriptor (TAT) peptide and further encapsulated in a galactose-modified lipid layer to target the nanoclusters to the liver. The resulting nanoclusters had an in vitro Pcsk9-editing efficiency of about 60 % and resulting in a decrease in plasma LDL-C in mice of approximately 30%. No off-target mutagenesis was detected in 10 sites with high similarity. This approach may have therapeutic potential for the prevention and treatment of cardiovascular disease without side effects.",

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author = "Lingmin Zhang and Le Wang and Yangzhouyun Xie and Peng Wang and Sai Deng and Aiping Qin and Jiangjiang Zhang and Xiyong Yu and Wenfu Zheng and Xingyu Jiang",

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AU - Qin, Aiping

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AB - A high level of low-density lipoprotein cholesterol (LDL-C) in the blood is a major risk factor for coronary heart disease. Herein, we present a triple-targeting strategy to generate a loss-of-function mutation in Pcsk9, which regulates plasma cholesterol levels, using a nanocarrier-delivered CRISPR/Cas9 system. Nuclear localization signal (NLS)-tagged Cas9 and Pcsk9-targeted single guide RNA (sgPcsk9) were complexed with gold nanoclusters (GNCs) modified with cationic HIV-1-transactivating transcriptor (TAT) peptide and further encapsulated in a galactose-modified lipid layer to target the nanoclusters to the liver. The resulting nanoclusters had an in vitro Pcsk9-editing efficiency of about 60 % and resulting in a decrease in plasma LDL-C in mice of approximately 30%. No off-target mutagenesis was detected in 10 sites with high similarity. This approach may have therapeutic potential for the prevention and treatment of cardiovascular disease without side effects.

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KW - nanoparticles

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Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases

Abstract

Keywords

UN SDGs

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