ArticleMolecular therapy : the journal of the American Society of Gene Therapy2016
Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02795325 (A Phase 1 Study of DCR-PH1 in Patients With Primary Hyperoxaluria Type 1), which is not on this map. Cited by 46 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1 Study of DCR-PH1 in Patients With Primary Hyperoxaluria Type 1 (PH1)
Who cites it
46 citing papers in PubMed, 82 citations in OpenAlex.
- Adeno-Associated Viral Vector (AAV)-Mediated In Vivo CRISPR-Cas9 Delivery.Methods in molecular biology (Clifton, N.J.) · 2027Article
- RNA therapeutics: current status and future directions.Signal transduction and targeted therapy · 2026Review
- Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1.Journal of medicinal chemistry · 2026Article
- Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Opportunities in Primary and Enteric Hyperoxaluria at the Cross-Roads Between the Clinic and Laboratory.Kidney international reports · 2024Article
- Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs.Biomolecules · 2024Review
- Efficient and safe therapeutic use of paired Cas9-nickases for primary hyperoxaluria type 1.EMBO molecular medicine · 2024Article
- Multiplex gene editing reduces oxalate production in primary hyperoxaluria type 1.Zoological research · 2023Article
- Lipid-based nucleic acid therapeutics with in vivo efficacy.Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology · 2023Review
- Searching glycolate oxidase inhibitors based on QSAR, molecular docking, and molecular dynamic simulation approaches.Scientific reports · 2022Article
- Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.ACS pharmacology & translational science · 2022Review
- Review
- Role of insulin resistance and the gut microbiome on urine oxalate excretion in ob/ob mice.Physiological reports · 2022Article
- HAO1-mediated oxalate metabolism promotes lung pre-metastatic niche formation by inducing neutrophil extracellular traps.Oncogene · 2022Article
- Therapeutic RNA-silencing oligonucleotides in metabolic diseases.Nature reviews. Drug discovery · 2022Review
- Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria.British journal of clinical pharmacology · 2022Review
- Perspectives in primary hyperoxaluria - historical, current and future clinical interventions.Nature reviews. Urology · 2022Review
- Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo.Metabolites · 2022Article
- Lumasiran for primary hyperoxaluria type 1: What we have learned?Frontiers in pediatrics · 2022Review
- Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside.International journal of nephrology and renovascular disease · 2022Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.