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Abstract: TH-OR050

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

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Cil, Onur, University of California San Francisco, San Francisco, California, United States
  • Lee, Sujin, University of California San Francisco, San Francisco, California, United States
  • Haggie, Peter Michael, University of California San Francisco, San Francisco, California, United States
  • Verkman, Alan S., University of California San Francisco, San Francisco, California, United States
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 (DRAinh-A270), and demonstration of its efficacy in mouse models of hyperoxaluria and oxalate nephropathy.

Results

Single dose oral or intraperitoneal (ip) DRAinh-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 DRAinh-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; DRAinh-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 DRAinh-A270 administration did not affect CBC or serum chemistries.

Conclusion

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

Funding

  • NIDDK Support