Synthetic transcription factor engineering for cell and gene therapy

Synthetic transcription factors (synTFs) that control beneficial transgene expression are an important method to increase the safety and efficacy of cell and gene therapy. Reliance on synTF components from non-human sources has slowed progress in the field because of concerns about immunogenicity and inducer drug properties. Recent advances in human-derived DNA-binding domains (DBDs) and transcriptional activation domains (TADs) paired with novel control modules responsive to clinically approved small molecules have poised the synTF field to overcome these hurdles. Advances include controllers inducible by autonomous signaling inputs and more complex, multi-input synTF circuits. Demonstrations of advanced control strategies with human-derived transcription factor components in clinically relevant vectors and in vivo models will facilitate progression into the clinic.