Genetic switch circuit targets tumor cells
In a new study, scientists approached the classic problem of tumor recognition from the perspective of systems/synthetic biology. Instead of targeting cancer-specific antigens, they engineered genetic circuit providing specificity on its own, based on gene expression.
The circuit relies on three inputs: cancer-specific promoter, microRNA-a expressed mainly in healthy cells, and microRNA-b expressed mainly in cancer cells. Levels of their expression are processed by two multiple input gates. One of the gates, if turned on, stimulates expression of E1A gene, which leads to oncolytic activity and death of host cell. Second gate, if turned on, ensures that the virus never enters oncolytic cycle.
Clever design of gates leads to high specificity of the solution. Lysis is initiated only if all three conditions are met: cancer promoter and microRNA-b are in high concentrations, whereas microRNA-a is in low concentrations.
Experiments in cell lines and mice proved specific oncolysis by the circuit loaded in adenoviruses. In addition to viral oncologic therapies, the authors proposed enhancement of anti-PD-1 immunotherapy.
Publication: Huiya Huang, Yiqi Liu, Weixi Liao, Yubing Cao, Qiang Liu, Yakun Guo, Yinying Lu, Zhen Xie (2019). Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy. Doi:10.1038/s41467-019-12794-2.