Glycolate oxidase is a safe and efficient target for substrate reduction therapy in a mouse model of primary hyperoxaluria type I
Open accessAbstract
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.
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Dutta et al. adopted siRNA LNPs to target and downregulate HAO1 for treating primary hyperoxaluria type 1 (PH-1).
“Dutta et al. adopted siRNA LNPs to target and downregulate hydroxyacid oxidase 1 (HAO1).”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [73]
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RNA delivery biomaterials for the treatment of genetic and rare diseases
Zhao, W., Hou, X., Vick, O. G., & Dong, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119291 · Cited by 82 · see citing works
Dutta, C., Avitahl-Curtis, N., Pursell, N., Larsson Cohen, M., Holmes, B., Diwanji, R., Zhou, W., Apponi, L., Koser, M., Ying, B., et al. (2016) · Molecular Therapy · doi:10.1038/mt.2016.4 · Cited by 81 · see citing works
Self-citation
- Authors
- Martin-Higueras, C., Luis-Lima, S., & Salido, E.
- Affiliations
- Universidad de La Laguna (ES)
- Corresponding author
- Salido, Eduardo
- ORCID
- Salido, Eduardo
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 24
- Issue
- 4
- Pages
- 719-725
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4886931
- OpenAlex
- W2220036626
- Cited by
- 83
- References
- 20
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 8 · 2023: 3 · 2022: 18 · 2021: 9 · 2020: 13 · 2019: 7 · 2018: 11 · 2017: 5 · 2016: 4
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerio de Ciencia e Innovación
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Kidney Stones and Urolithiasis Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- primary hyperoxaluria type 1, glycolate oxidase, substrate reduction therapy, glycolate, oxalate excretion, alanine:glyoxylate aminotransferase, peroxisomal enzyme deficiency, enzyme inhibitors, hepatocytes, inborn errors of metabolism, mouse model
- MeSH terms
- Alcohol Oxidoreductases, Transaminases, Animals, Cells, Cultured, Disease Models, Animal, Glyoxylates, Humans, Hyperoxaluria, Primary, Thiadiazoles, Hepatocytes, Mice, Gene Knockout Techniques
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