Synthetic transcription factor engineering for cell and gene therapy

Synthetic transcription factors (synTFs) that are inducible by exogenous or autonomous inputs are useful in cell and gene therapy for temporal and dosage control of the expression of beneficial transgenes.Recent progress in engineering DNA-binding domains (DBDs) and transcriptional activation domains (TADs) composed primarily of human sequences reduces concerns about the immunogenicity of synTF components.Control modules for synTFs have been developed that prioritize the use of clinically approved small-molecule drugs.Novel autonomous control strategies enable the programming of cell and gene therapies that can sense and respond to conditions in their environment or intracellular signaling state.Human-based components and controllers responsive to diverse inputs are clearing the way for the adoption of synTF systems in the clinic for cancer immunotherapy and gene therapy of metabolic or genetic diseases. 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. 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