{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:49:05Z","timestamp":1791726545331,"version":"4.3.4"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T00:00:00Z","timestamp":1441670400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T00:00:00Z","timestamp":1441670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sanfilippo syndrome is a rare lysosomal storage disorder caused by an impaired degradation of heparan sulfate (HS). It presents severe and progressive neurodegeneration and currently there is no effective treatment. Substrate reduction therapy (SRT) may be a useful option for neurological disorders of this kind and several approaches have been tested to date. Here we use different siRNAs targeting <jats:italic>EXTL2<\/jats:italic> and <jats:italic>EXTL3<\/jats:italic> genes, which are important for HS synthesis, as SRT in Sanfilippo C patients\u2019 fibroblasts in order to decrease glycosaminoglycan (GAG) storage inside the lysosomes. The results show a high inhibition of the <jats:italic>EXTL<\/jats:italic> gene mRNAs (around 90%), a decrease in GAG synthesis after three days (30\u201360%) and a decrease in GAG storage after 14 days (up to 24%). Moreover, immunocytochemistry analyses showed a clear reversion of the phenotype after treatment. The <jats:italic>in vitro<\/jats:italic> inhibition of HS synthesis genes using siRNAs shown here is a first step in the development of a future therapeutic option for Sanfilippo C syndrome.<\/jats:p>","DOI":"10.1038\/srep13654","type":"journal-article","created":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T09:25:04Z","timestamp":1441704304000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome"],"prefix":"10.1038","volume":"5","author":[{"given":"Isaac","family":"Canals","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelia","family":"Benet\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Cozar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Llu\u00efsa","family":"Vilageliu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Grinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,9,8]]},"reference":[{"key":"BFsrep13654_CR1","unstructured":"Neufeld, E. F. & Muenzer, J. The Mucopolysaccharidoses in The metabolic and molecular bases of inherited disease (eds. Scriver, C. R. et al.) 3421\u20133452 (McGraw-Hill, 2001)."},{"key":"BFsrep13654_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/cshperspect.a004952","volume":"3","author":"S Sarrazin","year":"2011","unstructured":"Sarrazin, S., Lamanna, W. C. & Esko, J. D. Heparan sulfate proteoglycans. Cold Spring Harb. Perspect. Biol. 3, 1\u201333 (2011).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"BFsrep13654_CR3","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1369\/0022155412464972","volume":"60","author":"J Kreuger","year":"2012","unstructured":"Kreuger, J. & Kjell\u00e9n, L. Heparan sulfate biosynthesis: regulation and variability. J. Histochem. Cytochem. 60, 898\u2013907 (2012).","journal-title":"J. Histochem. Cytochem."},{"key":"BFsrep13654_CR4","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/35888","volume":"391","author":"A Fire","year":"1998","unstructured":"Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806\u2013811 (1998).","journal-title":"Nature"},{"key":"BFsrep13654_CR5","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/35078107","volume":"411","author":"SM Elbashir","year":"2001","unstructured":"Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494\u2013498 (2001).","journal-title":"Nature"},{"key":"BFsrep13654_CR6","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/ejhg.2009.144","volume":"18","author":"D Dziedzic","year":"2010","unstructured":"Dziedzic, D., Wegrzyn, G. & Jak\u00f3bkiewicz-Banecka, J. Impairment of glycosaminoglycan synthesis in mucopolysaccharidosis type IIIA cells by using siRNA: a potential therapeutic approach for Sanfilippo disease. Eur. J. Hum. Genet. 18, 200\u2013205 (2010).","journal-title":"Eur. J. Hum. Genet."},{"key":"BFsrep13654_CR7","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/ejhg.2009.143","volume":"18","author":"X Kaidonis","year":"2010","unstructured":"Kaidonis, X. et al. Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses. Eur. J. Hum. Genet. 18, 194\u2013199 (2010).","journal-title":"Eur. J. Hum. Genet."},{"key":"BFsrep13654_CR8","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1111\/j.1399-0004.2010.01525.x","volume":"80","author":"I Canals","year":"2011","unstructured":"Canals, I. et al. Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles. Clin. Genet. 80, 367\u2013374 (2011).","journal-title":"Clin. Genet."},{"key":"BFsrep13654_CR9","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1093\/glycob\/cwg082","volume":"13","author":"I Barbosa","year":"2003","unstructured":"Barbosa, I. et al. Improved and simple micro assay for sulfated glycosaminoglycans quantification in biological extracts and its use in skin and muscle tissue studies. Glycobiology 13, 647\u2013653 (2003).","journal-title":"Glycobiology"},{"key":"BFsrep13654_CR10","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676\u2013682 (2012).","journal-title":"Nat. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep13654","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13654.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep13654.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T23:52:20Z","timestamp":1672962740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep13654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,8]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,11,26]]}},"alternative-id":["BFsrep13654"],"URL":"https:\/\/doi.org\/10.1038\/srep13654","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,8]]},"assertion":[{"value":"30 November 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13654"}}