Sviluppo di una terapia enzimatica per la sindrome di Lesch-Nyhan

Because of the evolutionary loss of the uricolytic pathway, humans accumulate poorly soluble urate as the final product of purine catabolism and are affected by hyperuricemia, gout, and uric acid stones. Impairment of purine salvage caused by hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) determines early-onset hyperuricemia and severe neurological disabilities, as observed in Lesch-Nyhan disease (LND). There are no satisfactory treatments or animal models for LND. Restoration of uricolysis through enzyme replacement therapy represents a promising treatment. The generation of a HPRT and urate oxidase (Uox) double-deficient mouse could provide a useful animal model. In the framework of this Telethon project, we obtained a pharmaceutical preparation of a triad of PEGylated uricolytic enzymes suitable for testing in the animal model. Hprt/Uox-KO mice have been generated that exhibited renal damage and perinatal mortality. Our data indicate that restoration a complete metabolic pathway through administration of multiple enzymatic activities can be pursued, providing a more sound treatment for HPRT deficiency and improving the current standards of therapy for hyperuricemia. We established the allopurinol-treated HPRT-deficient mouse as an experimental model of the renal damage of allopurinol-treated Lesch-Nyhan patients. These results provided insights into the generation of a useful animal model for LND.