For Cancer Therapy
LOGENEGATE for Cancer Therapy
Protecting healthy tissue from off-tumor toxicity is a major challenge facing all strategies for cancer immuno-gene therapy. Implementing logic AND gates to strictly confine the expression of therapeutic genes or their effects to selected target cells is an intriguing concept in this direction. In a 2017 Cell paper Nissim et al. presented a revolutionary AND gate device comprising a two-module mRNA circuit and demonstrated the expression of a multi-component immunostimulatory cassette only in cancer cells in which two distinct promoters are active. A major safety concern associated with this design is inevitable, potentially detrimental, basal off-target expression of genes of interest. To obviate this risk we have created LoGENEgate, an entirely new AND gate apparatus based on mRNA trans-splicing. Here we show that unlike the original Cell modules, LoGENEgate totally precludes expression of a model gene in off-target cells. Our findings pave the way for numerous therapeutic applications of LoGENEgate.