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Kidney Week

Abstract: FR-OR075

Enzymatic Degradation of Cystine Decreases Nephrolithiasis in a Mouse Model of Cystinuria

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Agnello, Giulia, Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Wiggins, Jason F., Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Alters, Susan E., Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Stone, Everett, University of Texas at Austin, Austin, Texas, United States
  • Wooldridge, James E., Aeglea BioTherapeutics, Inc., Austin, Texas, United States
  • Rowlinson, Scott W., Aeglea BioTherapeutics, Inc., Austin, Texas, United States

Cystinuria is a genetic disease characterized by frequent recurrent stone formation in the kidneys requiring multiple procedural interventions with an increased risk of chronic kidney disease. Stone formation is the result of increased urinary excretion of insoluble cystine due to mutations in the SLC3A1 and/or SLC7A9 genes. Current disease management with hyperhydration, alkalization and cystine binding thiol drugs (CBTD) is challenging and problematic. Effectiveness is limited with continued stone formation and frequent adverse effects to CBTD requiring treatment withdrawal in some patients (Biyani and Cartledge, EAU-EBU update series 4, 2006). We investigated the potential of an alternative approach to disease management utilizing novel cystine degrading enzyme derived from human cystathionine gamma lyase (CGL).


In vivo efficacy of ACN00107 was tested in a murine model of cystinuria (SLC3A1-/-) that develops stones between 4 and 7 weeks of age (PMID: 28165480). ACN00107 (100 mg/kg, i.p., every other day) was administered to 5-week-old SLC3A1 -/- mice for up to 6 weeks. At specific timepoints prior to, during, and after ACN00107 treatment, bladder and kidneys were weighed and imaged by micro computed tomography (µCT) analysis.


µCT analysis demonstrated a reduction in both volume and number of total kidney stones after 6 weeks of treatment which was associated with reduced kidney weights. A trend towards reduced bladder weight and total bladder stone volume compared to control was also observed.


This study demonstrates for the first time that enzymatic degradation of cystine reduces the propensity for kidney and bladder stone formation in a mouse model of cystinuria. Given the high morbidity, frequent requirement for procedural intervention, and the safety and tolerability profile of current medical approaches, enzymatic degradation of cystine warrants further investigation as a new potential approach for disease management.


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