Clinically-Driven Design of Synthetic Gene Regulatory Programs in Therapeutic Human Cells

Synthetic biology seeks to enable the rational design of regulatory circuits to reprogram and control cellular function. The application of this approach to human cells could lead to powerful gene and cell-based therapies that provide transformative ways to combat complex diseases. Realizing this vision will require engineering synthetic tools and systems to meet clinical requirements. In this talk, I will describe our clinically-driven design process to create synthetic toolkits for custom gene regulation in therapeutic human cells. Specifically, we have developed synthetic transcription regulators (SynZiFTRs) that feature a compact human protein-based design, enable precise genome-orthogonal regulation, and can be modulated by FDA-approved small molecules. Using SynZiFTRs, we engineer human primary T cells with genetic programs that enable external, drug-regulated control over immunotherapeutic genes and therapeutic cellular activity in vivo. SynZiFTRs can also be used in the context of compact, fully humanized, and customizable synthetic receptors (termed SNIPRs) for autonomous control of therapeutic T cells. These developments establish synthetic platforms for custom gene regulation in human cells with the potential to accelerate clinical translation of synthetic systems.