Permanent Alteration of PCSK9 With In Vivo CRISPR-Cas9 Genome Editing
Open accessAbstract
Rationale : Individuals with naturally occurring loss-of-function proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) mutations experience reduced low-density lipoprotein cholesterol levels and protection against cardiovascular disease. Objective : The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo. Methods and Results : We used adenovirus to express CRISPR-associated 9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that <3 to 4 days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as >50%. This resulted in decreased plasma PCSK9 levels, increased hepatic low-density lipoprotein receptor levels, and decreased plasma cholesterol levels (by 35–40%). No off-target mutagenesis was detected in 10 selected sites. Conclusions : Genome editing with the CRISPR–CRISPR-associated 9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.
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In mice liver, CRISPR-Cas9 induced loss-of-function mutation at the PCSK9 gene locus, leading to elevated hepatic LDL receptor level and dropped plasma cholesterol level.
“In mice liver, CRISPR-Cas9 was reported to successfully induce loss-of-function mutation at PCSK9 gene locus, leading to elevated hepatic LDL receptor level and dropped plasma cholesterol level”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [40]
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- Authors
- Ding, Q., Strong, A., Patel, K. M., Ng, S.-L., Gosis, B. S., Regan, S. N., Cowan, C. A., Rader, D. J., & Musunuru, K.
- Affiliations
- Broad Institute (US)
- Venue
- Circulation Research
- Published
- 2014-08-15
- Volume
- 115
- Issue
- 5
- Pages
- 488-492
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4134749
- OpenAlex
- W2107086950
- Cited by
- 522
- References
- 10
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 35 · 2023: 33 · 2022: 51 · 2021: 55 · 2020: 53 · 2019: 46 · 2018: 48 · 2017: 64 · 2016: 38 · 2015: 45 · 2014: 12
- FWCI
- 21.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- University of Pennsylvania
- Harvard University
- National Heart, Lung, and Blood Institute (R01HL109489, U01HL100408)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097768, P30DK019525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- PCSK9, CRISPR/Cas9, in vivo gene editing, loss-of-function mutations, LDL cholesterol, hepatic LDL receptor, plasma cholesterol reduction, cardiovascular disease prevention, adenoviral gene transfer, off-target mutagenesis, mouse liver
- MeSH terms
- Proprotein Convertase 9, RNA, Guide, CRISPR-Cas Systems, Adenoviridae, Animals, Cardiovascular Diseases, Cholesterol, Female, Genetic Vectors, Genotype, Liver, Male, Mice, Inbred C57BL, Mutation, Phenotype, Receptors, LDL, Serine Endopeptidases, Time Factors, Transfection, Biomarkers, Gene Expression Regulation, Enzymologic, RNA Editing, 3T3-L1 Cells, Proprotein Convertases, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, Protective Factors
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