Preclinical Development of Uricase-PEG 20

高尿酸血症(血尿酸升高)会导致痛风性关节炎和慢性肾脏疾病。癌症化疗(肿瘤溶解综合征)和器官移植(最常见于心脏和肾脏移植患者)后可能发生严重的高尿酸血症，这可能导致急性尿酸肾病，并由此导致代谢紊乱和死亡。此外，除了疼痛，高尿酸血症还可能导致破坏性痛风性关节炎，并伴随着关节和结缔组织的永久性损害。尿酸水平升高(高尿酸血症)在大多数哺乳动物中不会发生，因为它们具有编码尿酸氧化酶的基因，该基因将较难溶的尿酸代谢成更易溶的代谢物尿囊素。然而，在人类中，尿酸氧化酶基因已经进化到包含一个无义密码子，导致酶活性完全丧失。许多不同的研究小组给患者注射了从微生物中提纯的尿酸酶。尽管这些治疗方法降低了血浆尿酸水平，但所有使用的酶都具有高度的免疫原性，并会引起过敏反应和过敏反应。用聚乙二醇(PEG)配制其他治疗性蛋白质已被证明降低了它们的抗原性并延长了它们的循环半衰期。我们已经开始了一种名为Uricase-PEG20的聚乙二醇化尿酸酶的第一阶段临床测试。在这项提案中，我们寻求资金来执行FDA要求的额外研究，以便该药物进入第二阶段人类临床试验。拟议的商业应用：这项提议的重点是执行FDA要求的额外临床前实验，以使该药物进入第二阶段人体试验。尽管非聚乙二醇式尿酸酶在欧洲被使用，但由于与其使用相关的过敏反应发生率很高，它在美国还没有被批准。尿酸酶-PEG20是用聚乙二醇制得的，这是一种已知的降低异源蛋白质抗原性的技术。

Hyperuricemia (elevated serum uric acid) results in gouty arthritis and chronic renal disease. Severe hyperuricemia can occur following cancer chemotherapy (tumor lysis syndrome) and organ transplantation (most common in heart and kidney transplant patients) which may result in acute uric acid nephropathy with resultant metabolic disorders and death. Moreover, in addition to pain, hyperuricemia can result in destructive gouty arthritis, with concomitant permanent damage to joints and connective tissue. Elevated uric acid levels (hyperuricemia) do not develop in most mammals because they have the gene which encodes urate oxidase which metabolizes the less soluble uric acid into a much more soluble metabolite, allantoin. However, in humans, the urate oxidase gene has evolved to contain a nonsense codon which results in a complete loss of enzyme activity. Many different groups of investigators have administered uricase, purified from micro organisms, to patients. Although these treatments lower plasma uric acid levels, all of the enzymes used are highly immunogenic and cause allergic reactions and anaphylaxis. Formulation of other therapeutic proteins with polyethylene glycol (PEG) has been shown to reduce their anti-genicity and prolong their circulating half-life. We have initiated Phase I clinical testing of a PEG modified uricase termed Uricase-PEG20. In this proposal we seek funding to perform the additional studies requested by the FDA in order for this drug to move into Phase 2 human clinical testing. PROPOSED COMMERCIAL APPLICATIONS: This proposal focuses on performing the additional preclinical experiments requested by the FDA in order for this drug to enter Phase 2 human testing. Although non-PEG formulated uricase is used in Europe, it has not been approved in the USA because of the high incidence of allergic reactions associated with its use. uricase-PEG 20 is formulated with polyethylene glycol (PEG), a technology known to reduce the antigenicity of heterologous proteins.