Triple-Targeting Delivery of CRISPR/Cas9 To Reduce the Risk of Cardiovascular Diseases.
Animals
Asialoglycoprotein Receptor
/ metabolism
CRISPR-Cas Systems
Cardiovascular Diseases
/ prevention & control
Cell Nucleus
/ genetics
Cholesterol, LDL
/ blood
Galactose
/ chemistry
Gene Editing
Gold
/ chemistry
Liver
/ metabolism
Mice
Mutagenesis
Mutation
Nanocomposites
/ administration & dosage
PCSK9 Inhibitors
Peptide Fragments
/ metabolism
Proprotein Convertase 9
/ genetics
tat Gene Products, Human Immunodeficiency Virus
/ metabolism
CRISPR/Cas9
drug delivery
gene editing
low-density lipoprotein cholesterol
nanoparticles
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
02 09 2019
02 09 2019
Historique:
received:
25
03
2019
revised:
14
06
2019
pubmed:
19
7
2019
medline:
24
9
2020
entrez:
19
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31318118
doi: 10.1002/anie.201903618
doi:
Substances chimiques
Asialoglycoprotein Receptor
0
Cholesterol, LDL
0
PCSK9 Inhibitors
0
Peptide Fragments
0
tat Gene Products, Human Immunodeficiency Virus
0
Gold
7440-57-5
Pcsk9 protein, mouse
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
Galactose
X2RN3Q8DNE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12404-12408Subventions
Organisme : Minister of Science and Technology of China
ID : 2017YFA0205901
Pays : International
Organisme : National Natural Science Foundation of China
ID : 21535001
Pays : International
Organisme : National Natural Science Foundation of China
ID : 81730051
Pays : International
Organisme : National Natural Science Foundation of China
ID : 81700382
Pays : International
Organisme : National Natural Science Foundation of China
ID : 81673039
Pays : International
Organisme : National Natural Science Foundation of China
ID : 21761142006
Pays : International
Organisme : National Natural Science Foundation of China
ID : 81671784
Pays : International
Organisme : National Natural Science Foundation of China
ID : 21505027
Pays : International
Organisme : National Natural Science Foundation of China
ID : U1601227
Pays : International
Organisme : Chinese Academy of Sciences
ID : 121D11KYSB20170026
Pays : International
Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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