Abstract: FR-PO233
Consumption of Uric Acid in the Gastrointestinal Tract (GI) With Engineered Escherichia coli Nissle as a Potential Treatment for Gout
Session Information
- Pharmacology
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
- 1900 Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
Authors
- Xu, Julia, Synlogic, Cambridge, Massachusetts, United States
- Pettiford, Sharee, Synlogic, Cambridge, Massachusetts, United States
- Cotton, Sean, Synlogic, Cambridge, Massachusetts, United States
- Moore, Theodore C., Ginkgo BioWorks, Boston, Massachusetts, United States
- Isabella, Vincent, Synlogic, Cambridge, Massachusetts, United States
- Perreault, Mylene, Synlogic, Cambridge, Massachusetts, United States
- Hava, David, Synlogic, Cambridge, Massachusetts, United States
Background
Elevated circulating levels of uric acid (UA) are associated with an increased risk of developing gout and other chronic diseases such as CKD, T2D, and CVD. Despite advancements in treatment options, gout continues to be characterized by suboptimal quality of care. In healthy individuals, about 70% of circulating UA is metabolized and excreted by the kidneys, while the remaining 30% is processed through the GI tract. Emerging evidence has demonstrated a role for the gut microbiome in degrading UA. Furthermore, a remarkable gut dysbiosis in association with dysregulated host urate degradation has been reported in gout patients. In light of these findings, we engineered a Synthetic Biotic that is capable of degrading UA within the GI tract.
Methods
SYN-GOUT is a modified strain of Escherichia coli Nissle 1917 engineered to express bacterial and fungal urate oxidase enzymes, as well as to overexpress a urate transporter. The strain converts UA into 5-hydroxyisourate, which then spontaneously degrades into allantoin, a highly soluble and readily eliminated purine derivative.
Results
In vitro, SYN-GOUT effectively metabolized ~2 mM UA within 120 min, resulting in concomitant increase in its metabolite allantoin. Activity assay showed that SYN-GOUT was effective at consuming UA under hypoxic (2-7% oxygen) conditions, an environment that mimics the gastrointestinal tract. Administration of labeled UA (1,3-15N2) via intraperitoneal route in mice was associated with appearance of 1,3-15N2-UA in the small intestine, indicating the existence of an enterorecirculation loop. Finally, urinary UA output decreased more than 2-fold when non-human primates (NHPs) were given a single dose of SYN-GOUT, demonstrating that SYN-GOUT was active in vivo.
Conclusion
As a novel Synthetic Biotic, SYN-GOUT effectively consumed UA in vitro, and remained active under hypoxic conditions. In vivo, SYN-GOUT was safe and well-tolerated, and it lowered urinary UA levels in NHPs. The findings that a pool of UA circulates between systemic and GI compartments implies that SYN-GOUT, by consuming UA within the GI tract, has the potential to lower UA systemically. Therefore, SYN-GOUT could be an effective alternative for the treatment of gout, especially in individuals with compromised kidney function.
Funding
- Commercial Support –