{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:12:37Z","timestamp":1790046757881,"version":"4.0.1"},"reference-count":28,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2019,9,26]],"date-time":"2019-09-26T00:00:00Z","timestamp":1569456000000},"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":[[2019,10,1]]},"abstract":"<jats:p>\n                    Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of huntingtin gene (\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    ) encoding for a toxic polyglutamine protein. This disease is characterized by motor, psychiatric, and cognitive impairments. Currently, there is no disease modifying treatment. However, reducing the expression of the huntingtin protein (HTT) using antisense oligonucleotides (ASOs) has been shown as a promising therapeutic strategy. In this study, we explore the therapeutic potential of ASO made of tricyclo-DNA (tcDNA), a conformationally constrained DNA analog, to silence HTT. We used a gapmer ASO, containing central DNA nucleotides flanked by tcDNA modifications on 5\u2032 and 3\u2032 ends, allowing the recruitment of RNAse H and subsequent degradation of the messenger RNA. After transfection of tcDNA-ASO in patient-derived fibroblast cell lines, we show a strong decrease of HTT mRNA and protein levels. As a control, 2\u2032\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    -methyl-RNA targeting the same region of\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    was also tested and did not induce a significant effect. tcDNA-ASO were also evaluated\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    in the YAC128 mice, containing the full-length human\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    gene with 128 CAG repeat expansion. Single intracerebroventricular (ICV) injections of tcDNA induce a significant decrease of HTT messenger and protein levels in the cortex, hippocampus, striatum, and cerebellum of treated mice. tcDNA-ASO were found well distributed in the central nervous system (CNS) and show long lasting effect with protein levels still low, 12 weeks after a single ICV injection. This proof of concept study suggests the therapeutic potential of gapmer tcDNA ASO to downregulate huntingtin\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1089\/nat.2018.0775","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T16:10:21Z","timestamp":1560269421000},"page":"256-265","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":28,"title":["Lowering Mutant Huntingtin Using Tricyclo-DNA Antisense Oligonucleotides As a Therapeutic Approach for Huntington's Disease"],"prefix":"10.1177","volume":"29","author":[{"given":"Marine","family":"Imbert","sequence":"first","affiliation":[{"name":"U1179 INSERM, UFR des Sciences de la Sant\u00e9-LIA BAHN CSM, Universit\u00e9 de Versailles St-Quentin, Montigny le Bretonneux, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Blandel","sequence":"additional","affiliation":[{"name":"U1179 INSERM, UFR des Sciences de la Sant\u00e9-LIA BAHN CSM, Universit\u00e9 de Versailles St-Quentin, Montigny le Bretonneux, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Leumann","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Garcia","sequence":"additional","affiliation":[{"name":"U1179 INSERM, UFR des Sciences de la Sant\u00e9-LIA BAHN CSM, Universit\u00e9 de Versailles St-Quentin, Montigny le Bretonneux, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelie","family":"Goyenvalle","sequence":"additional","affiliation":[{"name":"U1179 INSERM, UFR des Sciences de la Sant\u00e9-LIA BAHN 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