Multidimensional control of therapeutic human cell function with synthetic gene circuits

Synthetic gene circuits that precisely control human cell function could expand the capabilities of gene- and cell-based therapies. However, platforms for developing circuits in primary human cells that drive robust functional changes in vivo and have compositions suitable for clinical use are lacking. Here, we developed synthetic zinc finger transcription regulators (synZiFTRs), which are compact and based largely on human-derived proteins. As a proof of principle, we engineered gene switches and circuits that allow precise, user-defined control over therapeutically relevant genes in primary T cells using orthogonal, US Food and Drug Administration–approved small-molecule inducers. Our circuits can instruct T cells to sequentially activate multiple cellular programs such as proliferation and antitumor activity to drive synergistic therapeutic responses. This platform should accelerate the development and clinical translation of synthetic gene circuits in diverse human cell types and contexts. Description Building blocks for synthetic circuits The promise of chimeric antigen receptor T cell therapy, in which human T cells are engineered to attack tumors, has heightened interest in cell-based therapies. Li et al. developed a toolkit of programmable synthetic transcription regulators that feature a compact, human protein–based design and allow transcription to be regulated by US Food & Drug Administration–approved small molecules (see the Perspective by Salazar-Cavazos and Altan-Bonnet). The authors engineered human immune cells that kill tumors when activated by the appropriate small molecule, and they also demonstrated a dual-switch system that allows sequential control of immune cell function. This platform could be adapted to design cell therapies in a variety of contexts. —VV Synthetic circuits built from modular components allow user-defined control over immune cell function.