MP43-05 ENZYMATIC LOWERING OF PLASMA CYSTINE PREVENTS FORMATION AND GROWTH OF STONES IN A MOUSE MODEL OF CYSTINURIA UNDER DEHYDRATION CHALLENGE

Abstract

You have accessJournal of UrologyStone Disease: Medical & Dietary Therapy (MP43)1 Apr 2020MP43-05 ENZYMATIC LOWERING OF PLASMA CYSTINE PREVENTS FORMATION AND GROWTH OF STONES IN A MOUSE MODEL OF CYSTINURIA UNDER DEHYDRATION CHALLENGE Giulia Agnello, Jason Wiggins, Silvia Ferrati, Anthony Quinn, Scott Rowlinson, and J Stuart Wolf* Giulia AgnelloGiulia Agnello More articles by this author , Jason WigginsJason Wiggins More articles by this author , Silvia FerratiSilvia Ferrati More articles by this author , Anthony QuinnAnthony Quinn More articles by this author , Scott RowlinsonScott Rowlinson More articles by this author , and J Stuart Wolf*J Stuart Wolf* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000898.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cystinuria is an autosomal recessive disease caused by mutations in the SLC3A1 and/or SLC7A9 dibasic amino acid transporter genes. The defective reabsorption of dibasic amino acids filtered by the glomerulus leads to high urine cystine content, subsequent cystine crystallization and the formation of upper tract urinary calculi, with recurrent stone passages and/or need for multiple procedural interventions. Symptomatic stone events include severe abdominal pain, hydronephrosis, hematuria, infective syndromes and chronic pain. Although high fluid intake remains a cornerstone of therapy, this regimen is inadequate at reaching the target cystine urine concentration owing to poor compliance, periods of increased fluid loss (fever, diarrhea/vomiting, high ambient temperature; PMID:16001591, 7996811) or impact on quality of life (e.g. nocturia and increased day time micturition frequency). We are developing a highly novel approach for the treatment of cystinuria patients that works by reducing cystine delivery into the kidney tubules through enzymatic lowering of plasma cystine. Herein, we investigated the therapeutic potential of this approach to prevent cystine stone formation in dehydration prone environments. METHODS: We used a murine model of cystinuria (SLC3A1-/-) that develops cystine stones in the kidneys and bladder (PMID:28165480) and rationed water to 65% to model dehydration conditions. During water rationing, mice were dosed with a human enzyme with novel activity for cystine. Stone burden in the kidneys and bladder was assessed by microcomputed tomography, and plasma and urine cystine concentration was monitored over time. RESULTS: Enzymatic reduction of plasma cystine prevented stone formation and growth in the kidneys and bladder, even under dehydration challenge. Lowering of plasma cystine resulted in reduction of cystine concentration in urine despite temporary dehydration. CONCLUSIONS: This study provides proof of concept that enzymatic lowering of plasma cystine levels is effective at reducing the cystine concentration in the urine in a mouse model of cystinuria in temporary dehydration conditions, and prevents formation and growth of cystine stones. Enzymatic lowering of plasma cystine warrants further investigation as a new potential approach for disease management of cystinuric patients unresponsive or intolerant to current treatment, or facing quality of life factors that impact the ability to comply with current treatment approaches. Source of Funding: This study was funded by Aeglea BioTherapeutics, Inc. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e648-e649 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giulia Agnello More articles by this author Jason Wiggins More articles by this author Silvia Ferrati More articles by this author Anthony Quinn More articles by this author Scott Rowlinson More articles by this author J Stuart Wolf* More articles by this author Expand All Advertisement PDF downloadLoading ...