In Vivo Ovarian Cancer Gene Therapy Using CRISPR-Cas9.

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR)-caspase 9 (Cas9) genome editing technology holds great promise for the field of human gene therapy. However, a lack of safe and effective delivery systems restricts its biomedical application. Here, a folate receptor-targeted liposome (F-LP) was used to deliver CRISPR plasmid DNA co-expressing Cas9 and single-guide RNA targeting the ovarian cancer-related DNA methyltransferase 1 (DNMT1) gene (gDNMT1). F-LP efficiently bound the gDNMT1 plasmid and formed a stable complex (F-LP/gDNMT1) that was safe for injection. F-LP/gDNMT1 effectively mutated endogenous DNMT1 in vitro, and then expressed the Cas9 endonuclease and downregulated DNMT1 in vivo. The tumor growth of both paclitaxel-sensitive and -resistant ovarian cancers were inhibited by F-LP/gDNMT1, which shows fewer adverse effects than paclitaxel injection. Therefore, CRISPR-Cas9-targeted DNMT1 manipulation may be a potential therapeutic regimen for ovarian cancer, and lipid-mediated delivery systems represent promising delivery vectors of CRISPR-Cas9 technology for precise genome editing therapeutics.

• Authors: Zhi-Yao He, Ya-Guang Zhang, Yu-Han Yang, Cui-Cui Ma, Ping Wang, Wei Du, Ling Li, Rong Xiang, Xiang-Rong Song, Xia Zhao, Shao-Hua Yao, Yu-Quan Wei
• Journal: Human gene therapy (Hum Gene Ther) Vol. 29 Issue 2 Pg. 223-233 (02 2018) ISSN: 1557-7422 [Electronic] United States
• PMID: 29338433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Folate Receptor 1
• Liposomes
• DNA (Cytosine-5-)-Methyltransferase 1
• DNMT1 protein, human
• Paclitaxel

Topics

• CRISPR-Cas Systems (genetics)
• Cell Proliferation (drug effects)
• DNA (Cytosine-5-)-Methyltransferase 1 (genetics, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Female
• Folate Receptor 1 (genetics, therapeutic use)
• Gene Editing
• Gene Expression Regulation, Neoplastic
• Gene Transfer Techniques
• Genetic Therapy
• Humans
• Liposomes (administration & dosage, chemistry)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Paclitaxel (administration & dosage, adverse effects)