Multidimensional control of therapeutic human cell function with synthetic gene circuits

Area of Science:

• Synthetic biology
• Molecular and cellular biology
• Biotechnology

Background:

• Gene and cell therapies require precise control over human cell function.
• Existing platforms for developing synthetic gene circuits in primary human cells are limited, hindering clinical translation.
• There is a need for robust, clinically applicable platforms for engineering synthetic gene circuits in human cells.

Purpose of the Study:

• To develop a novel platform for engineering synthetic gene circuits in primary human cells.
• To demonstrate precise, user-defined control over therapeutically relevant genes using these circuits.
• To enable sequential activation of cellular programs for synergistic therapeutic effects.

Main Methods:

• Development of synthetic zinc finger transcription regulators (synZiFTRs) based on human-derived proteins.
• Engineering of gene switches and circuits for orthogonal control using FDA-approved small-molecule inducers.
• Application of the platform in primary T cells to control proliferation and antitumor activity.

Main Results:

• Demonstrated precise, user-defined control over therapeutically relevant genes in primary T cells.
• Engineered circuits capable of sequentially activating multiple cellular programs.
• Achieved synergistic therapeutic responses through coordinated T cell activation.

Conclusions:

• The developed synZiFTR platform provides a robust method for engineering synthetic gene circuits in primary human cells.
• This platform facilitates the precise control of cellular functions for gene- and cell-based therapies.
• Accelerates the development and clinical translation of synthetic gene circuits for diverse therapeutic applications.