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Published (Version of record)CC BY-NC V4.0, Open Access
Journal article
CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy
Science advances, Vol.6(47), eabc9450
Nov/2020
PMID: 33208369
Abstract
Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid. A single intracerebral injection of CRISPR-LNPs against
(sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.
Details
- Title
- CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy
- Creators
- Daniel Rosenblum - Tel Aviv UniversityAnna Gutkin - Tel Aviv UniversityRanit Kedmi - New York University School of MedicineSrinivas Ramishetti - Tel Aviv UniversityNuphar Veiga - Tel Aviv UniversityAshley M Jacobi - Integrated DNA TechnologiesMollie S Schubert - Integrated DNA TechnologiesDinorah Friedmann-Morvinski - Tel Aviv UniversityZvi R Cohen - Tel Aviv UniversityMark A Behlke - Integrated DNA TechnologiesJudy Lieberman - Harvard Medical SchoolDan Peer (Corresponding Author) - Tel Aviv University
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.6(47), eabc9450; Nov/2020
- Number of pages
- 12
- Language
- English
- DOI
- https://doi.org/10.1126/sciadv.abc9450
- PMID
- 33208369
- Grant note
- We thank N. Dammes for drawing the illustrations and V. Holdengreber for the scientific assistance with electron microscopy. Funding: A.G. thanks the Dr. Albert and Doris Fields Trust, the Marian Gertner Institute for Medical Nanosystems, and the Glaser Foundation for her fellowships. This work was supported, in part, by grants from the Israel Cancer Research Fund (grant no. 16-1285-PG). Author contributions: D.R., A.G., R.K., S.R., N.V., and D.P. conceived and designed the project. D.R., A.G., A.M.J., M.S.S., and D.F.-M. performed the experimental work. D.R., A.G., A.M.J., M.S.S., D.F.-M., Z.R.C., M.A.B., J.L., and D.P. analyzed the data. D.R., A.G., and D.P. wrote the manuscript. All authors discussed the results.
- Record Identifier
- 993419183803596
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