title: Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.
abstract: Primary hyperoxaluria type 1 (PH1) is caused by deficient alanine-glyoxylate aminotransferase, the human peroxisomal enzyme that detoxifies glyoxylate. Glycolate is one of the best-known substrates leading to glyoxylate production, via peroxisomal glycolate oxidase (GO). Using genetically modified mice, we herein report GO as a safe and efficient target for substrate reduction therapy (SRT) in PH1. We first generated a GO-deficient mouse (Hao1(-/-)) that presented high urine glycolate levels but no additional phenotype. Next, we produced double KO mice (Agxt1(-/-) Hao1(-/-)) that showed low levels of oxalate excretion compared with hyperoxaluric mice model (Agxt1(-/-)). Previous studies have identified some GO inhibitors, such as 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole (CCPST). We herein report that CCPST inhibits GO in Agxt1(-/-) hepatocytes and significantly reduces their oxalate production, starting at 25 µM. We also tested the ability of orally administered CCPST to reduce oxalate excretion in Agxt1(-/-) mice, showing that 30-50% reduction in urine oxalate can be achieved. In summary, we present proof-of-concept evidence for SRT in PH1. These encouraging results should be followed by a medicinal chemistry programme that might yield more potent GO inhibitors and eventually could result in a pharmacological treatment for this rare and severe inborn error of metabolism.
authors.affiliation: Department of Pathology, Centre for Biomedical Research on Rare Diseases (CIBERER), Tenerife, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Martin-Higueras
authors.affiliation: Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad La Laguna, Tenerife, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Luis-Lima
authors.affiliation: Department of Pathology, Centre for Biomedical Research on Rare Diseases (CIBERER), Tenerife, Spain.|Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad La Laguna, Tenerife, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006038:Glyoxylates / Q000652:urine; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000188:drug therapy* / Q000235:genetics / Q000652:urine; D051379:Mice; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000637:Transaminases / Q000172:deficiency*
chemical_list: C547833:4-carboxy-5-((4-chlorophenyl)sulfanyl)-1,2,3-thiadiazole; D006038:Glyoxylates; D013830:Thiadiazoles; D000429:Alcohol Oxidoreductases; C020821:glycollate oxidase; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; C031150:glyoxylic acid