MAMMALIAN PEG URICASE FOR THERAPY OF INTRACTABLE GOUT

长期目标是为患者提供有效的治疗。 以及目前无法治愈的严重高尿酸血症后果。 这些患者要么对黄嘌呤氧化酶过敏 别嘌醇抑制剂，对传统的低尿酸血症治疗无效， 或使用别嘌醇会干扰器官的必要治疗 移植物排斥反应或白血病。因此，这些患者遭受严重的， 疼痛，并使痛风丧失能力，他们有很高的风险 发展为肾功能衰竭。基于代谢紊乱的观点 是由于缺乏尿酸而导致整个物种的先天错误 尿酸氧化酶(尿酸酶)，以及最近发现的人类表达 一个突变的尿酸氧化酶(尿酸酶)的mRNA，我们请求支持 继续聚乙二醇类药物的临床前研究 修饰的哺乳动物尿酸酶作为一种潜在的非免疫原性治疗 高尿酸血症。我们的具体目标是i)使用生化和 利用重组DNA方法构建聚乙二醇化的重组哺乳动物 尿酸氧化酶，并研究其活性、循环寿命和 免疫原性；2)我们将研究聚乙二醇尿酸酶在 尿酸肾梗阻的动物模型；3)我们将开发GMP 用于临床试验的哺乳动物聚乙二醇尿酸酶的生产方法。 建议的商业应用：商业应用是针对 控制严重高尿酸血症及其后果，包括痛风和 在常规治疗无效的患者中出现肾功能衰竭 或禁忌证。聚乙二醇尿酸酶将作为孤儿药物开发 治疗对别嘌醇过敏的患者(估计约占 接受该药物的患者)，以及器官移植患者 严重的痛风。聚乙二醇类哺乳动物尿酸酶与真菌相比的优势 欧洲目前使用的尿酸酶是一种延长循环寿命的酶 免疫原性降低。

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.