{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:08:08Z","timestamp":1790554088540,"version":"4.1.0"},"reference-count":38,"publisher":"American Society for Clinical Investigation","issue":"4","funder":[{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"crossref","award":["ANR-11-INBS-0009,and,ANR-11-INBS-0011"],"award-info":[{"award-number":["ANR-11-INBS-0009,and,ANR-11-INBS-0011"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,27]]},"abstract":"<jats:p>\n                    Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a target-agnostic\u2013based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiency\u2013associated neuronal phenotypes by promoting metabolism compensations in an HGPRT-independent manner. This included\n                    <jats:italic>S<\/jats:italic>\n                    -adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.132094","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T16:32:03Z","timestamp":1580229123000},"source":"Crossref","is-referenced-by-count":32,"title":["Rescuing compounds for Lesch-Nyhan disease identified using stem cell\u2013based phenotypic screening"],"prefix":"10.1172","volume":"5","author":[{"given":"Valentin","family":"Ruillier","sequence":"first","affiliation":[{"name":"CECS ,"},{"name":"INSERM UMR 861, and"},{"name":"UEVE UMR 861, I-Stem, AFM-T\u00e9l\u00e9thon, Corbeil-Essonnes, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0696-1307","authenticated-orcid":true,"given":"Johana","family":"Tournois","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Boissart","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Lasbareilles","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurvan","family":"Mah\u00e9","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9180-2794","authenticated-orcid":true,"given":"Laure","family":"Chatrousse","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-9875","authenticated-orcid":true,"given":"Michel","family":"Cailleret","sequence":"additional","affiliation":[{"name":"INSERM UMR 861, and"},{"name":"UEVE UMR 861, I-Stem, AFM-T\u00e9l\u00e9thon, Corbeil-Essonnes, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9966-3282","authenticated-orcid":true,"given":"Marc","family":"Peschanski","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Benchoua","sequence":"additional","affiliation":[{"name":"CECS ,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr591"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2017.00941","article-title":"Pathophysiological role of purines and pyrimidines in neurodevelopment: unveiling new pharmacological approaches to congenital brain diseases","volume":"8","author":"Fumagalli","year":"2017","journal-title":"Front Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(64)90104-4"},{"issue":"Pt 5","key":"B4","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1093\/brain\/awt202","article-title":"Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder","volume":"137","author":"Fu","year":"2014","journal-title":"Brain"},{"key":"B5","unstructured":"Nyhan WL, O\u2019Neill JP, Jinnah HA, Harris JC. Lesch-Nyhan Syndrome. In: Adam MP, et al. eds. GeneReviews. Seattle, Washington, USA: University of Washington, Seattle; 1993. http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1149 Updated May 15, 2014. Accessed January 10, 2020"},{"issue":"Pt 5","key":"B6","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/brain\/awl056","article-title":"Delineation of the motor disorder of Lesch-Nyhan disease","volume":"129","author":"Jinnah","year":"2006","journal-title":"Brain"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-2-48","article-title":"Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome","volume":"2","author":"Torres","year":"2007","journal-title":"Orphanet J Rare 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