{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:19:40Z","timestamp":1791314380700,"version":"4.3.1"},"reference-count":56,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2013,12,31]],"date-time":"2013-12-31T00:00:00Z","timestamp":1388448000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:p>\n                    Huntington's disease (HD) is a progressive autosomal dominant disorder, caused by a CAG repeat expansion in the\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    gene, which results in expansion of a polyglutamine stretch at the N-terminal end of the huntingtin protein. Several studies have implicated the importance of proteolytic cleavage of mutant huntingtin in HD pathogenesis and it is generally accepted that N-terminal huntingtin fragments are more toxic than full-length protein. Important cleavage sites are encoded by exon 12 of\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    . Here we report proof of concept using antisense oligonucleotides to induce skipping of exon 12 in huntingtin pre-mRNA, thereby preventing the formation of a 586 amino acid N-terminal huntingtin fragment implicated in HD toxicity.\n                    <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                    studies showed successful exon skipping and appearance of a shorter huntingtin protein. Cleavage assays showed reduced 586 amino acid N-terminal huntingtin fragments in the treated samples.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    studies revealed exon skipping after a single injection of antisense oligonucleotides in the mouse striatum. Recent advances to inhibit the formation of mutant huntingtin using oligonucleotides seem promising therapeutic strategies for HD. Nevertheless, huntingtin is an essential protein and total removal has been shown to result in progressive neurodegeneration\n                    <jats:italic toggle=\"yes\">in vivo.<\/jats:italic>\n                    Our proof of concept shows a completely novel approach to reduce mutant huntingtin toxicity not by reducing its expressing levels, but by modifying the huntingtin protein.\n                  <\/jats:p>","DOI":"10.1089\/nat.2013.0452","type":"journal-article","created":{"date-parts":[[2013,12,31]],"date-time":"2013-12-31T11:07:37Z","timestamp":1388488057000},"page":"4-12","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":56,"title":["Preventing Formation of Toxic N-Terminal Huntingtin Fragments Through Antisense Oligonucleotide-Mediated Protein Modification"],"prefix":"10.1177","volume":"24","author":[{"given":"Melvin M.","family":"Evers","sequence":"first","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoang-Dai","family":"Tran","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Zalachoras","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onno C.","family":"Meijer","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan T.","family":"Den Dunnen","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]},{"name":"Leiden University Medical Center","place":["The Netherlands"]},{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert-Jan B.","family":"van Ommen","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Aartsma-Rus","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willeke M.C.","family":"van Roon-Mom","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2013,12,31]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-767-5_8"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(02)00086-X"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/oli.2005.15.284"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.205"},{"key":"e_1_3_3_6_1","first-page":"1118","article-title":"The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington disease","volume":"53","author":"ANDREW S.E.","year":"1993","unstructured":"ANDREW S.E., , GOLDBERG Y.P., , KREMER B., , TELENIUS H., , THEILMANN J., , ADAM S., , STARR E., , SQUITIERI F., , LIN B., , KALCHMAN M.A., et al. 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