{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:38:49Z","timestamp":1792791529780,"version":"4.5.0"},"reference-count":68,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"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":[[2023,4,1]]},"abstract":"<jats:p>\n                    Huntington's disease is a neurodegenerative, trinucleotide repeat (TNR) disorder affecting both males and females. It is caused by an abnormal increase in the length of CAG\u2022CTG TNR in exon 1 of the\n                    <jats:italic toggle=\"yes\">Huntingtin<\/jats:italic>\n                    gene (\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    ). The resultant, mutant HTT mRNA and protein cause neuronal toxicity, suggesting that reduction of their levels would constitute a promising therapeutic approach. We previously reported a novel strategy in which chemically modified oligonucleotides (ONs) directly target chromosomal DNA. These anti-gene ONs were able to downregulate both\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    mRNA and protein. In this study, various locked nucleic acid (LNA)\/DNA mixmer anti-gene ONs were tested to investigate the effects of varying ON length, LNA content, and fatty acid modification on\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    expression. Altering the length did not significantly influence the ON potency, while LNA content was critical for activity. Utilization of palmitoyl-modified LNA monomers enhanced the ON activity relatively to the corresponding nonmodified LNA under serum starvation conditions. Furthermore, the number of palmitoylated LNA monomers and their positioning greatly affected ON potency. In addition, we performed RNA sequencing analysis, which showed that the anti-gene ONs affect the \u201cimmune system process, mRNA processing, and neurogenesis.\u201d Furthermore, we observed that for repeat containing genes, there is a higher tendency for antisense off-targeting. Taken together, our findings provide an optimized design of anti-gene ONs that could potentially be developed as DNA-targeting therapeutics for this class of TNR-related diseases.\n                  <\/jats:p>","DOI":"10.1089\/nat.2022.0046","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T12:51:44Z","timestamp":1675428704000},"page":"117-131","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["Chemical Modifications and Design Influence the Potency of\n                    <i>Huntingtin<\/i>\n                    Anti-Gene Oligonucleotides"],"prefix":"10.1177","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3286-5706","authenticated-orcid":false,"given":"Osama","family":"Saher","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."},{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman M.","family":"Zaghloul","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."},{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea","family":"Umek","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Hagey","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negin","family":"Mozafari","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias B.","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, Biomolecular Nanoscale Engineering Center, University of Southern Denmark, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa S.","family":"Gouda","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, Biomolecular Nanoscale Engineering Center, University of Southern Denmark, Odense, Denmark."},{"name":"Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin E.","family":"Lundin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per T.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, Biomolecular Nanoscale Engineering Center, University of Southern Denmark, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Wengel","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, Biomolecular Nanoscale Engineering Center, University of Southern Denmark, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.I. Edvard","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rula","family":"Zain","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-14186 Huddinge, Sweden."},{"name":"Centre for Rare Diseases, Department of Clinical Genetics, Karolinska University Hospital, SE-17176 Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1967.00470270110014"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1159\/000443738"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13413"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg352"},{"key":"e_1_3_4_7_2","first-page":"303","article-title":"Huntington disease","author":"Parsons MP","year":"2015","unstructured":"Parsons MP, and Raymond LA. 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