Targeted delivery of CRISPR/Cas9 to prostate cancer by modified gRNA using a flexible aptamer-cationic liposome

The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical dev...

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Bibliographic Details
Published in:	Oncotarget 2017-02, Vol.8 (6), p.9375-9387
Main Authors:	Zhen, Shuai, Takahashi, Yoichiro, Narita, Shunichi, Yang, Yi-Chen, Li, Xu
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis Aptamers, Nucleotide - genetics Aptamers, Nucleotide - metabolism Cations Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Line, Tumor Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Associated Proteins - genetics CRISPR-Associated Proteins - metabolism CRISPR-Cas Systems Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Gene Silencing Gene Targeting - methods Gene Transfer Techniques Genetic Therapy - methods Humans Kallikreins - metabolism Liposomes Male Mice, Nude Polo-Like Kinase 1 Prostate-Specific Antigen - metabolism Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - therapy Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Research Paper RNA, Guide, CRISPR-Cas Systems - genetics RNA, Guide, CRISPR-Cas Systems - metabolism Xenograft Model Antitumor Assays
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Summary:	The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand. Cationic liposomes were linked to aptamers by the post-insertion method and were used to deliver therapeutic CRISPR/Cas9 that target the survival gene, polo-like kinase 1, in tumor cells. We demonstrate that the aptamer-liposome-CRISPR/Cas9 chimeras had a significant cell-type binding specificity and a remarkable gene silencing effect in vitro. Furthermore, silencing promoted a conspicuous regression of prostate cancer in vivo. Importantly, the approach described here provides a universal means of cell type-specific CRISPR/Cas9 delivery, which is a critical goal for the widespread therapeutic applicability of CRISPR/Cas9 or other nucleic acid drugs.
ISSN:	1949-2553 1949-2553