{"title":"OxDc-A0:一种口服胃耐受草酸脱羧酶,用于治疗继发性高草酸尿。","authors":"Hai-Feng Liu, Chun-Yan Li, Yan-Hong Liu, Qi Yao, Qing-Shan Li, Long-Jiang Yu","doi":"10.1007/s00240-025-01698-0","DOIUrl":null,"url":null,"abstract":"<p><p>Secondary hyperoxaluria is an acquired oxalate metabolic disorder characterized by increased urinary oxalate excretion. Reducing exogenous oxalate absorption through enzyme therapy represents a promising therapeutic strategy. However, the extremely acidic pH and protease-rich environment of the upper gastrointestinal tract pose major obstacles for the oral administration of protein therapeutics. OxDc-A0, a novel gastro-tolerant recombinant oxalate decarboxylase, can degrade oxalate in the stomach, thereby limiting the oxalate pool in the gastrointestinal tract and reducing oxalate absorption and urinary excretion. This study aimed to investigate the pharmacodynamics, pharmacokinetics, and safety profile of OxDc-A0 to assess its drug likeliness. The pharmacodynamics were evaluated in vitro and in hyperoxaluria beagle dog model induced by a high-oxalate diet. OxDc-A0 exhibited excellent gastric tolerance and significant efficacy in reducing urinary oxalate excretion in the dog model with hyperoxaluria. The safety of OxDc-A0 was evaluated in Sprague-Dawley rats, beagle dogs, and golden hamsters according to the guidelines for preclinical safety studies. No adverse effects were observed on the central nervous, cardiovascular, or respiratory system in rats or dogs treated orally with OxDc-A0 up to 37,500 U/kg. Pharmacokinetic studies showed that OxDc-A0 is non-systemically absorbed and is mainly distributed in the gastrointestinal tract. Toxicological studies showed that OxDc-A0 has excellent tolerance, with a NOAEL of 37,500 U/kg/day in both rats and dogs. The maximum tolerated dose was ≥ 105,000 U/kg in rats and ≥ 87,000 U/kg in dogs. Overall, OxDc-A0 shows great potential as a new drug candidate for treating secondary hyperoxaluria.</p>","PeriodicalId":23411,"journal":{"name":"Urolithiasis","volume":"53 1","pages":"47"},"PeriodicalIF":2.0000,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"OxDc-A0: an oral gastro-tolerant oxalate decarboxylase for treating secondary hyperoxaluria.\",\"authors\":\"Hai-Feng Liu, Chun-Yan Li, Yan-Hong Liu, Qi Yao, Qing-Shan Li, Long-Jiang Yu\",\"doi\":\"10.1007/s00240-025-01698-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Secondary hyperoxaluria is an acquired oxalate metabolic disorder characterized by increased urinary oxalate excretion. Reducing exogenous oxalate absorption through enzyme therapy represents a promising therapeutic strategy. However, the extremely acidic pH and protease-rich environment of the upper gastrointestinal tract pose major obstacles for the oral administration of protein therapeutics. OxDc-A0, a novel gastro-tolerant recombinant oxalate decarboxylase, can degrade oxalate in the stomach, thereby limiting the oxalate pool in the gastrointestinal tract and reducing oxalate absorption and urinary excretion. This study aimed to investigate the pharmacodynamics, pharmacokinetics, and safety profile of OxDc-A0 to assess its drug likeliness. The pharmacodynamics were evaluated in vitro and in hyperoxaluria beagle dog model induced by a high-oxalate diet. OxDc-A0 exhibited excellent gastric tolerance and significant efficacy in reducing urinary oxalate excretion in the dog model with hyperoxaluria. The safety of OxDc-A0 was evaluated in Sprague-Dawley rats, beagle dogs, and golden hamsters according to the guidelines for preclinical safety studies. No adverse effects were observed on the central nervous, cardiovascular, or respiratory system in rats or dogs treated orally with OxDc-A0 up to 37,500 U/kg. Pharmacokinetic studies showed that OxDc-A0 is non-systemically absorbed and is mainly distributed in the gastrointestinal tract. Toxicological studies showed that OxDc-A0 has excellent tolerance, with a NOAEL of 37,500 U/kg/day in both rats and dogs. The maximum tolerated dose was ≥ 105,000 U/kg in rats and ≥ 87,000 U/kg in dogs. Overall, OxDc-A0 shows great potential as a new drug candidate for treating secondary hyperoxaluria.</p>\",\"PeriodicalId\":23411,\"journal\":{\"name\":\"Urolithiasis\",\"volume\":\"53 1\",\"pages\":\"47\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2025-03-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Urolithiasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00240-025-01698-0\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Urolithiasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00240-025-01698-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
OxDc-A0: an oral gastro-tolerant oxalate decarboxylase for treating secondary hyperoxaluria.
Secondary hyperoxaluria is an acquired oxalate metabolic disorder characterized by increased urinary oxalate excretion. Reducing exogenous oxalate absorption through enzyme therapy represents a promising therapeutic strategy. However, the extremely acidic pH and protease-rich environment of the upper gastrointestinal tract pose major obstacles for the oral administration of protein therapeutics. OxDc-A0, a novel gastro-tolerant recombinant oxalate decarboxylase, can degrade oxalate in the stomach, thereby limiting the oxalate pool in the gastrointestinal tract and reducing oxalate absorption and urinary excretion. This study aimed to investigate the pharmacodynamics, pharmacokinetics, and safety profile of OxDc-A0 to assess its drug likeliness. The pharmacodynamics were evaluated in vitro and in hyperoxaluria beagle dog model induced by a high-oxalate diet. OxDc-A0 exhibited excellent gastric tolerance and significant efficacy in reducing urinary oxalate excretion in the dog model with hyperoxaluria. The safety of OxDc-A0 was evaluated in Sprague-Dawley rats, beagle dogs, and golden hamsters according to the guidelines for preclinical safety studies. No adverse effects were observed on the central nervous, cardiovascular, or respiratory system in rats or dogs treated orally with OxDc-A0 up to 37,500 U/kg. Pharmacokinetic studies showed that OxDc-A0 is non-systemically absorbed and is mainly distributed in the gastrointestinal tract. Toxicological studies showed that OxDc-A0 has excellent tolerance, with a NOAEL of 37,500 U/kg/day in both rats and dogs. The maximum tolerated dose was ≥ 105,000 U/kg in rats and ≥ 87,000 U/kg in dogs. Overall, OxDc-A0 shows great potential as a new drug candidate for treating secondary hyperoxaluria.
期刊介绍:
Official Journal of the International Urolithiasis Society
The journal aims to publish original articles in the fields of clinical and experimental investigation only within the sphere of urolithiasis and its related areas of research. The journal covers all aspects of urolithiasis research including the diagnosis, epidemiology, pathogenesis, genetics, clinical biochemistry, open and non-invasive surgical intervention, nephrological investigation, chemistry and prophylaxis of the disorder. The Editor welcomes contributions on topics of interest to urologists, nephrologists, radiologists, clinical biochemists, epidemiologists, nutritionists, basic scientists and nurses working in that field.
Contributions may be submitted as full-length articles or as rapid communications in the form of Letters to the Editor. Articles should be original and should contain important new findings from carefully conducted studies designed to produce statistically significant data. Please note that we no longer publish articles classified as Case Reports. Editorials and review articles may be published by invitation from the Editorial Board. All submissions are peer-reviewed. Through an electronic system for the submission and review of manuscripts, the Editor and Associate Editors aim to make publication accessible as quickly as possible to a large number of readers throughout the world.