| Full text | |
| Author(s): Show less - |
Scott, Benjamin M.
[1, 2, 3, 4]
;
Gutierrez-Vazquez, Cristina
[5]
;
Sanmarco, Liliana M.
[5]
;
Pereira, Jessica A. da Silva
[5]
;
Li, Zhaorong
[5]
;
Plasencia, Agustin
[5]
;
Hewson, Patrick
[5]
;
Cox, Laura M.
[5]
;
O'Brien, Madelynn
[5]
;
Chen, Steven K.
[2]
;
Moraes-Vieira, Pedro M.
[6, 7, 8]
;
Chang, Belinda S. W.
[9, 2, 10]
;
Peisajovich, Sergio G.
[2, 10, 11]
;
Quintana, Francisco J.
[12, 5]
Total Authors: 14
|
| Affiliation: Show less - | [1] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 - USA
[2] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON - Canada
[3] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 - USA
[4] Concordia Univ, Montreal, PQ - Canada
[5] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 - USA
[6] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Campinas, SP - Brazil
[7] Univ Estadual Campinas, Expt Med Res Cluster EMRC, Campinas, SP - Brazil
[8] Univ Estadual Campinas, Obes & Comorbid Res Ctr OCRC, Campinas, SP - Brazil
[9] Univ Toronto, Dept Ecol & Evolutionary Biol, Toronto, ON - Canada
[10] Univ Toronto, Ctr Anal Genome Evolut & Funct, Toronto, ON - Canada
[11] Illumina Inc, San Diego, CA - USA
[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 - USA
Total Affiliations: 12
|
| Document type: | Journal article |
| Source: | Nature Medicine; v. 27, n. 7, p. 1212+, JUL 2021. |
| Web of Science Citations: | 3 |
| Abstract | |
A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis. Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies. (AU) | |
| FAPESP's process: | 19/04780-7 - AHR and LXR Transcriptional factors as targets to treat immune-mediated degenerative diseases |
| Grantee: | Jéssica Aparecida da Silva Pereira |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |