Abstract: FR-PO1002
A Novel, Small Molecule Inhibitor of Gut Microbial Choline Trimethylamine Lyase (CutC) Slows the Loss of Kidney Function in a Rat Model of CKD
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Buysse, Jerry, Zehna Therapeutics Inc., Cleveland, Ohio, United States
- Matunas, Robert, Zehna Therapeutics Inc., Cleveland, Ohio, United States
- Simpson, Camilla V., Zehna Therapeutics Inc., Cleveland, Ohio, United States
Background
Trimethylamine N-oxide (TMAO), a gut microbiota-dependent uremic toxin, is both a cause and driver of chronic kidney disease (CKD). Choline trimethylamine (TMA) lyase (CutC) is a microbial enzyme that plays a key role in the formation of TMA, a precursor of TMAO, in the gut. Here we describe the pharmacological effects of a novel, small molecule CutC inhibitor on serum TMAO level and kidney function in an adenine-induced rat model of CKD.
Methods
CKD was induced in rats by adding 0.75% adenine to a standard chow diet for 2 weeks (induction phase) and maintained by adding 0.25% adenine to the diet supplemented with 1% choline in the drinking water for 4 weeks (maintenance phase). The small molecule CutC inhibitor, ZTx101, was administered via ileal-cecal catheter directly into the colon at doses of 15, 50, and 150 mg/kg of body weight, twice a day, during the maintenance phase. Serum TMAO was quantified using LC-MS/MS. Kidney function was assessed by serum levels of creatinine and blood urea nitrogen (BUN). Renal fibrosis was assessed by biomarker analysis and histology.
Results
Serum levels of TMAO, creatinine, and BUN were elevated in rats with adenine-induced CKD supplemented with choline. Administration of ZTx101 at all three doses resulted in rapid and sustained reduction of serum TMAO to the normal range (<5 μM) during the maintenance phase of the study. At the end of study, ZTx101 significantly reduced serum levels of creatinine (1.5 mg/dL in 150 mg/kg ZTx101 vs. 3.1 mg/dL in untreated; P<0.0001) and BUN (102.6 mg/dL in 150 mg/kg ZTx101 vs. 140.0 mg/dL in untreated; P<0.05). ZTx101 also significantly reduced TGF-β level in the kidney (36.6 pg/mg tissue in 150 mg/kg ZTx101 vs. 70.2 pg/mg tissue in untreated; P<0.0001), a biomarker of renal fibrosis. In addition, neutrophilic tubulitis and tubulointerstitial nephritis were reduced in animals treated with ZTx101, compared to untreated controls.
Conclusion
The small molecule CutC inhibitor ZTx101 is effective in reducing and normalizing elevated levels of uremic toxin TMAO and slowing the loss of kidney function in a rat model of CKD. Reduction of serum TMAO level by the CutC inhibitor ZTx101 may provide a potential new approach to slow disease progression in persons with CKD.
Funding
- Commercial Support – Zehna Therapeutics Inc.