Kidney Week

Abstract: TH-OR050

Nanomolar Potency Inhibitors of SLC26A3 (DRA) Anion Exchanger as First-in-Class Treatment of Enteric Hyperoxaluria and Nephrolithiasis

Session Information

• Bone and Mineral Metabolism: Basic Research
  November 07, 2019 | Location: 145, Walter E. Washington Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Cil, Onur, University of California San Francisco, San Francisco, California, United States

Onur Cil, MD, PhD



Dr. Onur Cil is a pediatric nephrologist and physician-scientist with a special clinical interest in kidney stones, nephrotic syndrome and genetic diseases of the kidney. He actively sees children with all forms of kidney diseases in his clinic. His laboratory research focuses on small molecule drug discovery for epithelial ion transport modulators that can be used for treatment of renal and gastrointestinal diseases. His ultimate goal is advancing his discoveries to clinical trials and establishing better and safer treatments. He discovered multiple first-in-class compounds and is an inventor in multiple patent applications. He is experienced in high-throughput screening, pharmacokinetics, toxicity and animal efficacy studies and showed proof-of-concept efficacy of several compounds in animal models of renal and gastrointestinal diseases including hyperoxaluria, edema, constipation, diarrhea and gastrointestinal motility disorders. He has also performed clinical research on genotype-phenotype correlations in Autosomal Dominant Polycystic Kidney Disease and Nephrotic Syndrome. Dr. Cil earned his medical and doctoral (Pharmacology) degrees from Hacettepe University in Turkey, where he also completed a residency in pediatrics. He first joined UCSF as a researcher and then clinical fellow in pediatric nephrology and currently is a faculty member in Department of Pediatrics.

• Lee, Sujin, University of California San Francisco, San Francisco, California, United States

Sujin Lee,

• Haggie, Peter Michael, University of California San Francisco, San Francisco, California, United States

Peter Michael Haggie,

• Verkman, Alan S., University of California San Francisco, San Francisco, California, United States

Alan S. Verkman,

Background

Nephrolithiasis affects 9% of the US population in their lifetime. Two thirds of kidney stones are composed of calcium oxalate, for which hyperoxaluria is a major risk factor. Dietary oxalate is absorbed by intestine, and oxalate is also generated by liver as a metabolic end product. The majority of oxalate is excreted in urine with some excretion in stool. Gastrointestinal conditions such as bariatric surgery, inflammatory bowel disease and pancreatic insufficiency are associated with hyperabsorption of oxalate in colon (enteric hyperoxaluria). DRA (down-regulated in adenoma, SLC26A3) is an anion (Cl^-, HCO₃^-, oxalate) exchanger predominantly expressed in colon and is the main pathway for colonic oxalate absorption, with knock-out mice having 70% lower urine oxalate excretion. DRA is thus an attractive target for treating enteric and idiopathic hyperoxaluria, and calcium oxalate nephrolithiasis, by redirecting the majority of oxalate excretion through stool rather than urine.

Methods

We previously identified, by high-throughput screening, first-in-class DRA inhibitors (JCI Insight 2018; 3(14): 121370). The work herein includes the synthesis and characterization of a nanomolar potency (IC₅₀ 40 nM) inhibitor (DRA_inh-A270), and demonstration of its efficacy in mouse models of hyperoxaluria and oxalate nephropathy.

Results

Single dose oral or intraperitoneal (ip) DRA_inh-A270 (10 mg/kg) gave predicted therapeutic levels in serum for at least 72 h in mice. In a model of acute hyperoxaluria, bolus oral administration of sodium oxalate (2.5 micromol/kg) produced approximately 3-fold increased urine oxalate/creatinine ratio that was largely prevented by DRA_inh-A270 treatment. In a diet-induced model of oxalate nephropathy involving a high-oxalate, low-calcium diet, vehicle-treated mice developed marked hyperoxaluria and renal failure by day 14; DRA_inh-A270 treatment (10 mg/kg, ip, BID starting day 0) largely prevented hyperoxaluria, renal failure (per serum creatinine), renal injury and calcium oxalate crystal deposition (per histology). In toxicity studies, one week high-dose DRA_inh-A270 administration did not affect CBC or serum chemistries.

Conclusion

DRA inhibition by DRA_inh-A270 represents a novel approach for treatment of enteric and idiopathic hyperoxaluria, and prevention of calcium oxalate nephrolithiasis.

Funding

• NIDDK Support