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These expansions give rise to pathogenic sense and antisense repeat RNAs that form nuclear foci and undergo repeat-associated non-AUG translation, producing dipeptide repeat proteins with cellular toxicity. Directly targeting the causative repeat RNAs with antisense oligonucleotides represents a promising therapeutic strategy. One barrier to further development is the propensity of this G-rich repeat-containing RNA target to form stable secondary structures, which may hinder efficient hybridization. In this study, we designed a panel of fluorine-modified ASOs that target the sense repeat expansions. We identified C-rich F-ASO gapmers that reduced translation from sense repeat RNAs in a cell-based reporter assay and lowered the RNA foci burden in patient-derived cells. Structural analyses in vitro revealed that the 2\u2032F-RNA gapmer formed a stable hairpin structure. Our results demonstrate that structural properties of fluorine modifications can be leveraged for effective binding of repeat RNA and highlight the potential for F-ASOs to serve as therapeutic tools when targeting toxic repeat RNAs in C9ORF72-mediated FTD\/ALS and other repeat expansion diseases.<\/jats:p>","DOI":"10.1093\/nar\/gkag343","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T11:20:46Z","timestamp":1775474446000},"source":"Crossref","is-referenced-by-count":0,"title":["Direct targeting of\n                    <i>C9ORF72<\/i>\n                    repeat RNA with fluorinated antisense oligonucleotides"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3514-7240","authenticated-orcid":false,"given":"Halle M","family":"Barber","sequence":"first","affiliation":[{"name":"Department of Chemistry, McGill University , Montreal, QC H3A 0B8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansi A","family":"Parasrampuria","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Wake Forest University School of Medicine , Winston-Salem, NC 27101 ,","place":["United States"]},{"name":"Division of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine , Carbondale, IL 62901 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jer\u00f3nimo","family":"Jurado-Arjona","sequence":"additional","affiliation":[{"name":"Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London , London SE1 1UL ,","place":["United Kingdom"]},{"name":"Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University , Mainz 55128 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Gamir-Morralla","sequence":"additional","affiliation":[{"name":"Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London , London SE1 1UL ,","place":["United Kingdom"]},{"name":"Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University , Mainz 55128 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Berninger","sequence":"additional","affiliation":[{"name":"Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London , London SE1 1UL ,","place":["United Kingdom"]},{"name":"Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University , Mainz 55128 ,","place":["Germany"]},{"name":"MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London , London SE1 1UL ,","place":["United Kingdom"]},{"name":"Focus Program Translational Neuroscience, Johannes Gutenberg University , Mainz 55131 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica F\u00edsica \u2018Blas Cabrera\u2019, IQF-CSIC , Madrid 28006 ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5868-675X","authenticated-orcid":false,"given":"Keith T","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Wake Forest University School of Medicine , Winston-Salem, NC 27101 ,","place":["United States"]},{"name":"Division of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine , Carbondale, IL 62901 ,","place":["United 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