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Ataluren is a compound that has shown promise for clinical use as a readthrough agent. However, some reports suggest that ataluren is ineffective at suppressing PTCs. To further evaluate the effectiveness of ataluren as a readthrough agent, we examined its ability to suppress PTCs in a variety of previously untested models. Using NanoLuc readthrough reporters expressed in two different cell types, we found that ataluren stimulated a significant level of readthrough. We also explored the ability of ataluren to suppress a nonsense mutation associated with Mucopolysaccharidosis I-Hurler (MPS I-H), a genetic disease that is caused by a deficiency of \u03b1-L-iduronidase that leads to lysosomal accumulation of glycosaminoglycans (GAGs). Using mouse embryonic fibroblasts (MEFs) derived from\n                      <jats:italic>Idua-W402X<\/jats:italic>\n                      mice, we found that ataluren partially rescued \u03b1-L-iduronidase function and significantly reduced GAG accumulation relative to controls. Two-week oral administration of ataluren to\n                      <jats:italic>Idua-W402X<\/jats:italic>\n                      mice led to significant GAG reductions in most tissues compared to controls. Together, these data reveal important details concerning the efficiency of ataluren as a readthrough agent and the mechanisms that govern its ability to suppress PTCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Ataluren promotes readthrough of PTCs in a wide variety of contexts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Ataluren reduces glycosaminoglyan storage in MPS I-H cell and mouse models.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Ataluren has a bell-shaped dose\u2013response curve and a narrow effective range.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-022-02232-0","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T07:06:05Z","timestamp":1658300765000},"page":"1223-1235","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ataluren suppresses a premature termination codon in an MPS I-H mouse"],"prefix":"10.1007","volume":"100","author":[{"given":"Dan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojiao","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwen","family":"Gunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna","family":"Siddiqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marla","family":"Weetall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0471-5858","authenticated-orcid":false,"given":"Kim M.","family":"Keeling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"2232_CR1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1146\/annurev-genom-091212-153527","volume":"15","author":"KM Keeling","year":"2014","unstructured":"Keeling KM, Xue X, Gunn G, Bedwell DM (2014) Therapeutics based on stop codon readthrough. 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None of the other authors has relevant financial or non-financial interests to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}