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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\u2010 and d\u2010ribo\u2010nucleosides 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\u2010G (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\u2010nucleoside 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.<\/jats:p>","DOI":"10.1002\/jimd.12039","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T08:08:54Z","timestamp":1549872534000},"page":"178-185","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inhibiting PNP for the therapy of hyperuricemia in Lesch\u2013Nyhan disease: Preliminary in vitro studies with analogues of immucillin\u2010G"],"prefix":"10.1002","volume":"42","author":[{"given":"Gabriella","family":"Jacomelli","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Baldini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mugnaini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanna","family":"Micheli","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Bernardini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Santucci","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Via A. Moro 2, 53100 Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,2,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-70-1-155"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(64)90104-4"},{"issue":"48","key":"e_1_2_7_4_1","first-page":"1","article-title":"Hypoxanthine\u2010guanine phosphoribosyltransferase (HPRT) deficiency: Lesch\u2010Nyhan syndrome","volume":"2","author":"Torres RJ","year":"2007","journal-title":"Orphanet J Rare Dis"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02172213"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl0563508431"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq0132842514"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802611795347645"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar19093226109"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2007.04.013"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-017-0634-z"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-9877(92)90026-9"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104684\u20105673\u20108_27"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9854-4"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-017-2167-65445154"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000155747.15679.04"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/15257770802143913"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm030305z"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm060547"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2005.03.012"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.160736"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(02)00053-4"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/2103254"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500578"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(99)00205-2"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9829-5"},{"key":"e_1_2_7_27_1","first-page":"2585","volume-title":"Immunodeficiency Diseases Caused by Adenosine Deaminase Deficiency and Purine Nucleoside Phosphorylase Deficiency. 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