Rapid screening of engineered microbial therapies in a 3D multicellular model.

Authors:
Tetsuhiro Harimoto
Tetsuhiro Harimoto
University of Toronto
Canada
Zakary S Singer
Zakary S Singer
California Institute of Technology
United States
Samuel Castro
Samuel Castro
University Hospital Ambroise Paré
France
Taylor E Hinchliffe
Taylor E Hinchliffe
University of Houston
Chihuahua | Mexico
Tal Danino
Tal Danino
University of California
United States

Proc Natl Acad Sci U S A 2019 Apr 17;116(18):9002-9007. Epub 2019 Apr 17.

Department of Biomedical Engineering, Columbia University, New York, NY 10027;

Synthetic biology is transforming therapeutic paradigms by engineering living cells and microbes to intelligently sense and respond to diseases including inflammation, infections, metabolic disorders, and cancer. However, the ability to rapidly engineer new therapies far outpaces the throughput of animal-based testing regimes, creating a major bottleneck for clinical translation. In vitro approaches to address this challenge have been limited in scalability and broad applicability. Here, we present a bacteria-in-spheroid coculture (BSCC) platform that simultaneously tests host species, therapeutic payloads, and synthetic gene circuits of engineered bacteria within multicellular spheroids over a timescale of weeks. Long-term monitoring of bacterial dynamics and disease progression enables quantitative comparison of critical therapeutic parameters such as efficacy and biocontainment. Specifically, we screen strains expressing and delivering a library of antitumor therapeutic molecules via several synthetic gene circuits. We identify candidates exhibiting significant tumor reduction and demonstrate high similarity in their efficacies, using a syngeneic mouse model. Last, we show that our platform can be expanded to dynamically profile diverse microbial species including , , and in various host cell types. This high-throughput framework may serve to accelerate synthetic biology for clinical applications and for understanding the host-microbe interactions in disease sites.

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Source
http://dx.doi.org/10.1073/pnas.1820824116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500119PMC
April 2019
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