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 for pre- clinical investigation of polyethylene glycol (PEG) modified mammalian uricase as a nonimmunogenic treatment for hyperuricemia. Our specific aims are 1) to use biochemical and recombinant DNA methods to prepare recombinant mammalian, and possibly human, urate oxidase; and 2) to develop conditions for modifying the enzyme(s) with various forms of PEG to yield and enzymatically active, stable, and nonimmunogenic PEG-uricase preparation for use in clinical trials.
