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Kidney Week

Abstract: TH-PO815

Impact of Enzymatic Degradation of Plasma Cysteine in a Mouse Model of Cystinuria Under Dehydration Challenge

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Agnello, Giulia, Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Wiggins, Jason F., Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Ferrati, Silvia, Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Quinn, Anthony G., Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Rowlinson, Scott W., Aeglea BioTherapeutics, Inc., Austin, Texas, United States

Cystinuria is a genetic disease resulting from mutations in the SLC3A1 and/or SLC7A9 dibasic amino acid transporter genes. Disruption of transporter function leads to increased urine cystine concentrations that exceed the limit of solubility with cystine precipitation and stone formation. In addition to severe episodic symptoms including abdominal pain, affected patients require multiple procedural interventions with an increased risk of hypertension and chronic kidney disease. Although high fluid intake remains a cornerstone of therapy, these regimes are problematic and can lead to nocturia and increased day time frequency. Maintaining an adequate urine output is particularly challenging when oral hydration is compromised or during periods of increased fluid loss including occupational commitments such as troop deployments (PMID:16001591). We previously reported that enzymatic degradation of cystine reduces the propensity for kidney and bladder stone formation in a mouse model of cystinuria. Herein, we investigated the therapeutic potential of cystine enzymatic degradation as a therapeutic approach to prevent cystine stone formation in dehydration prone environments.


We used a murine model of cystinuria (SLC3A1-/-) that develops stones between 4 & 7 weeks of age (PMID:28165480) and rationed water to 65% to model dehydration conditions. During water rationing, mice were administered either vehicle or a cystine degrading enzyme, and urine cystine concentration was monitored at specific timepoints prior to and after treatment.


Pharmacodynamic analysis of urinary cystine demonstrated that enzymatic degradation of plasma cystine results in reduction of total cystine levels in urine despite temporary dehydration.


This study demonstrates that enzymatic degradation of cystine is effective at reducing the levels of cystine in urine in a mouse model of cystinuria in temporary dehydration conditions. Given that the incidence of urolithiasis is higher in conditions causing dehydration (e.g. warmer climates) (PMID:12709088), enzymatic degradation of cystine warrants further investigation as a new potential approach for disease management of cystinuric patients.


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