Lesch-Nyhan disease (LND) is a rare X-linked
genetic disorder, with complete
hypoxanthine-guanine phosphoribosyltransferase (
HGPRT) deficiency,
uric acid (UA),
hypoxanthine and
xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing
renal failure, is commonly decreased by
xanthine oxidoreductase (XOR) inhibitors, such as
allopurinol, yielding a
xanthine and
hypoxanthine increase.
Xanthine accumulation may result in renal stones, while
hypoxanthine excess seems involved in the
neurological disorder. Inhibition of
purine nucleoside phosphorylase (PNP) represents a different strategy for lowering
urate. PNP catalyzes the cleavage of
purine ribo- and d-ribo-
nucleosides into
ribose/
deoxyribose phosphate and free bases, starting catabolism to
uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with
allopurinol. The present study tested the reliability of an analogue of
immucillin-G (C1a), a PNP inhibitor, as a
therapy for
urate,
hypoxanthine, and
xanthine excess in LND patients by blocking
hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-
nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular
nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added
inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced
hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND
hyperuricemia.