TY - JOUR
T1 - CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy
AU - Rosenblum, Daniel
AU - Gutkin, Anna
AU - Kedmi, Ranit
AU - Ramishetti, Srinivas
AU - Veiga, Nuphar
AU - Jacobi, Ashley M.
AU - Schubert, Mollie S.
AU - Friedmann-Morvinski, Dinorah
AU - Cohen, Zvi R.
AU - Behlke, Mark A.
AU - Lieberman, Judy
AU - Peer, Dan
N1 - Publisher Copyright:
© 2020 American Association for the Advancement of Science. All rights reserved.
PY - 2020/11/18
Y1 - 2020/11/18
N2 - 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 PLK1 (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.
AB - 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 PLK1 (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.
UR - http://www.scopus.com/inward/record.url?scp=85096408295&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abc9450
DO - 10.1126/sciadv.abc9450
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C2 - 33208369
AN - SCOPUS:85096408295
SN - 2375-2548
VL - 6
JO - Science advances
JF - Science advances
IS - 47
M1 - abc9450
ER -
