Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells.

Here, we present a gene regulation strategy enabling programmable control over eukaryotic translational initiation. By excising the natural poly-adenylation (poly-A) signal of target genes and replacing it with a synthetic control region harboring RNA-binding protein (RBP)-specific aptamers, cap-dependent translation is rendered exclusively dependent on synthetic translation initiation factors (STIFs) containing different RBPs engineered to conditionally associate with different eIF4F-binding proteins (eIFBPs). This modular design framework facilitates the engineering of various gene switches and intracellular sensors responding to many user-defined trigger signals of interest, demonstrating tightly controlled, rapid and reversible regulation of transgene expression in mammalian cells as well as compatibility with various clinically applicable delivery routes of in vivo gene therapy.

Engineering precision therapies: lessons and motivations from the clinic.

In the past decade, gene- and cell-based therapies have been at the forefront of the biomedical revolution. Synthetic biology, the engineering discipline of building sophisticated 'genetic software' to enable precise regulation of gene activities in living cells, has been a decisive success factor of these new therapies. Here, we discuss the core technologies and treatment strategies that have already gained approval for therapeutic applications in humans.