CRISPR-Cas12a with an oAd Induces Precise and Cancer-Specific Genomic Reprogramming of EGFR and Efficient Tumor Regression

A. Rum Yoon, Bo Kyeong Jung, Eunyoung Choi, Eugene Chung, Jin Woo Hong, Jin Soo Kim, Taeyoung Koo, Chae Ok Yun

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

CRISPR-Cas12a represents a class 2/type V CRISPR RNA-guided endonuclease, holding promise as a precise genome-editing tool in vitro and in vivo. For efficient delivery of the CRISPR-Cas system into cancer, oncolytic adenovirus (oAd) has been recognized as a promising alternative vehicle to conventional cancer therapy, owing to its cancer specificity; however, to our knowledge, it has not been used for genome editing. In this study, we show that CRISPR-Cas12a mediated by oAd disrupts the oncogenic signaling pathway with excellent cancer specificity. The intratumoral delivery of a single oAd co-expressing a Cas12a and a CRISPR RNA (crRNA) targeting the epidermal growth factor receptor (EGFR) gene (oAd/Cas12a/crEGFR) induces efficient and precise editing of the targeted EGFR gene in a cancer-specific manner, without detectable off-target nuclease activity. Importantly, oAd/Cas12a/crEGFR elicits a potent antitumor effect via robust induction of apoptosis and inhibition of tumor cell proliferation, ultimately leading to complete tumor regression in a subset of treated mice. Collectively, in this study we show precise genomic reprogramming via a single oAd vector-mediated CRISPR-Cas system and the feasibility of such system as an alternative cancer therapy. Oncolytic adenovirus expressing CRISPR-Cas12a, which combines the strong oncolytic effect of oAd with precise and cancer-specific CRISPR-mediated oncogene disruption, potentiates antitumor effects.

Original languageEnglish
Pages (from-to)2286-2296
Number of pages11
JournalMolecular Therapy
Volume28
Issue number10
DOIs
StatePublished - 2020 Oct 7

Keywords

  • CRISPR
  • Cas12a
  • Cpf1
  • EGFR
  • anti-tumor effect
  • genome editing
  • oncolytic virus
  • out-of-frame

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