Preclinical Development of Uricase-PEG 20

高尿酸血症（血清尿酸升高）导致痛风性关节炎和慢性肾脏疾病。严重的高尿酸血症可发生在癌症化疗（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，可能导致急性尿酸肾病，并导致代谢紊乱和死亡。此外，除疼痛外，高尿酸血症还可导致破坏性痛风性关节炎，伴随着对关节和结缔组织的永久性损伤。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，该基因将不太可溶的尿酸代谢成更可溶的代谢物尿囊素。然而，在人类中，尿酸氧化酶基因已经进化为包含导致酶活性完全丧失的无义密码子。许多不同的研究小组已经将从微生物中纯化的尿酸酶给予患者。虽然这些治疗降低了血浆尿酸水平，但所有使用的酶都具有高度免疫原性，并引起过敏反应和过敏反应。其他治疗性蛋白质与聚乙二醇（PEG）的制剂已显示出降低其抗原性并延长其循环半衰期。我们已经启动了PEG修饰的尿酸酶（称为Uricase-PEG 20）的I期临床试验。在这项提案中，我们寻求资金来进行FDA要求的额外研究，以便使这种药物进入2期人体临床试验。拟议的商业应用：该提案的重点是执行FDA要求的额外临床前实验，以便该药物进入2期人体测试。虽然非PEG配制的尿酸酶在欧洲使用，但由于其使用相关的过敏反应发生率高，因此尚未在美国获得批准。尿酸酶-PEG 20与聚乙二醇（PEG）一起配制，这是一种已知的降低异源蛋白抗原性的技术。

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.