MAMMALIAN PEG URICASE FOR THERAPY OF INTRACTABLE GOUT

哺乳动物聚乙二醇尿酸酶治疗顽固性痛风

• 批准号: 2518391
• 负责人: MICHAEL S HERSHFIELD
• 金额: $ 25万
• 依托单位: MOUNTAIN VIEW PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518391
• 关键词: MAMMALIAN; PEG; URICASE; THERAPY; INTRACTABLE

The long-term objective is to provide effective treatment for patients with severe, and presently untreatable, consequences of hyperuricemia. These patients are either hypersensitive to the xanthine oxidase inhibitor allopurinol, refractory to conventional hypouricemic therapy, or use of allopurinol would interfere with necessary therapy for organ graft rejection or leukemia. As a result, these patients suffer severe, painful, and disabling tophaceous gout, and they are at high risk of developing renal failure. Based on the view that the metabolic disorder is due to a species-wide inborn error of uric acid breakdown due to lack of urate oxidase (uricase), and the recent discovery that humans express a mutated mRNA for the enzyme urate oxidase (uricase), we request support to continue the pre-clinical investigation of polyethyleneglycol (PEG) modified mammalian uricase as a potentially nonimmunogenic treatment for hyperuricemia. Our specific aims are I) to use biochemical and recombinant DNA methods to engineer PEG-modified recombinant mammalian urate oxidase and investigate its activity, circulating life and immunogenicity; 2) we will investigate the efficacy of the PEG-uricase in an animal model of uric acid renal obstruction; 3) we will develop GMP methods for producing mammalian PEG-uricase for use in clinical trials. PROPOSED COMMERCIAL APPLICATION: Commercial application is for the control of severe hyperuricemia and its consequences, including gout and renal failure, in patients for whom conventional therapy is ineffective or contraindicated. PEG-uricase would be developed as an Orphan Drug to treat patients allergic to allopurinol (estimated to be about 2% of patients receiving that drug), and organ transplant patients who develop severe gout. The advantages of the PEG-mammalian uricase over fungal uricase currently used in Europe are a prolonged circulating life and reduced immunogenicity.

长远目标是为病人提供有效的治疗 具有严重的目前无法治疗的高尿酸血症的后果。 这些病人要么对黄嘌呤氧化酶过敏 抑制剂别嘌呤醇，常规低尿酸血症治疗难治， 或使用别嘌呤醇会干扰器官的必要治疗 移植排斥或白血病因此，这些患者遭受严重的， 疼痛，致残痛风石，他们有很高的风险， 发展成肾衰竭基于代谢紊乱 是由于一个物种的先天性错误的尿酸分解，由于缺乏 尿酸氧化酶（尿酸酶），以及最近发现，人类表达 尿酸氧化酶（尿酸酶）的突变mRNA，我们请求支持 继续进行聚乙二醇（PEG）的临床前研究 修饰的哺乳动物尿酸酶作为潜在的非免疫原性治疗 高尿酸血症我们的具体目标是：I）使用生物化学和 工程化PEG修饰的重组哺乳动物细胞的重组DNA方法 尿酸氧化酶的活性、循环寿命和 免疫原性; 2）我们将研究PEG-尿酸酶在免疫原性中的功效。 建立尿酸性肾梗阻动物模型; 3）建立GMP 生产用于临床试验的哺乳动物PEG-尿酸酶的方法。 建议的商业应用：商业应用是为了 控制严重的高尿酸血症及其后果，包括痛风， 肾衰竭，常规治疗无效的患者 或禁忌。PEG-尿酸酶将被开发为孤儿药， 治疗对别嘌呤醇过敏的患者（估计约占 接受该药物的患者）和器官移植患者 严重的痛风PEG-哺乳动物尿酸酶相对于真菌尿酸酶的优势 目前在欧洲使用的尿酸酶具有延长的循环寿命， 降低免疫原性。