Living Bacterial Therapeutics

We seek to develop therapeutics composed of living engineered bacteria, targeted to the tissues of the gastrointestinal tract.

The mucosal tissue of the gastrointestinal tract plays a key role in maintaining a barrier between the gut lumen and the rest of the body. When the mucosa is damaged, through injury, chronic inflammation, or other forms of disease, barrier function is compromised. This leads to digested food particles and microbes crossing the barrier and creates a positive feedback loop of inflammation. Though there are drugs that inhibit inflammatory signaling processes below the mucosal surface, there are few effective options for healing the gut mucosa from the luminal side. We seek to address this unmet clinical need by leveraging our BIND platform, which produces customizable protein nanofibers from engineered non-pathogenic E. coli. In this approach, the engineered bacterium is administered orally, transits the upper GI tract, and proliferates in the lower GI tract while producing a nanofibrous matrix displaying a therapeutic protein domain. The matrix, produced in situ, can play multiple roles simultaneously – it can be programmed to adhere specifically to certain mucosal tissues, it can serve as a mucin replacement to temporarily reinforce barrier function, and it can provide biological cues to promote mucosal wound healing. Other projects in the group seek to treat other gut diseases and health problems that arise in the GI tract using a similar approach.

A paper describing our initial demonstration of our approach to ameliorate the symptoms of inflammation in a mouse model for colitis:

 

Praveschotinunt, P., Duraj-Thatte, A. M., Gelfat, I., Bahl, F., Chou, D. B., & Joshi, N. S. (2019). Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gutNature Communications10(1), 1-14.

A paper describing our initial characterization of the interaction between engineered protein fibers and mammalian cells in vitro:

 

Duraj-Thatte, A. M., Praveschotinunt, P., Nash, T. R., Ward, F. R., & Joshi, N. S. (2018). Modulating bacterial and gut mucosal interactions with engineered biofilm matrix proteinsScientific reports8(1), 1-8.

A paper describing the use of our system to track living microbes in vivo using click chemistry:

 

Praveschotinunt, P., Dorval Courchesne, N. M., den Hartog, I., Lu, C., Kim, J. J., Nguyen, P. Q., & Joshi, N. S. (2018). Tracking of engineered bacteria in vivo using nonstandard amino acid incorporationACS synthetic biology7(6), 1640-1650.

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