Programmable Synthetic Gene Circuit As a Potential Therapeutic Intervention for Liver Cancer
Mammalian Synthetic Biology Workshop
2018
Fifth International Mammalian Synthetic Biology Workshop
General Submissions
Viral Vectors and Gene Therapy
Saturday, May 5, 2018 - 5:15pm to 5:30pm
Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without damaging the normal cells. The replication of oncolytic virus can lysis cancer cells and trigger immune responses against cancer cells. However, it remains a great challenge to improve the specificity and efficacy of oncolytic virus in a predictable and programmable manner. Synthetic gene circuits are designed to implement desired cellular functions in living cells through sensing, integration and processing of molecular information. Here, we developed two types of sensory switches by using synthetic TALE repressors and deactivated Cas9 (dCas9) repressors, which can response to cancer specific microRNAs. We demonstrated that using the input-output transfer curves of genetic parts enables accurate prediction of the behavior of modularly assembled switch circuits. We also showed that TALER and dCas9 switches employing feedback regulation exhibit improved accuracy for microRNA-based cancer cell classification. In addition, we cloned the sensory switch circuit into an adenoviral vector to control the virus replication. We demonstrated that the engineered adenovirus can be used to specifically kill hepacellular carcinoma cells in vitro and in the mouse model. Our results provide a novel strategy to program and improve the specificity of oncolytic virus replication in target cancer cells, which may lead to innovative therapeutics for cancers.