{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:04:37Z","timestamp":1791428677673,"version":"4.3.3"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T00:00:00Z","timestamp":1670889600000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002108","name":"Friedreich's Ataxia Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS111990"],"award-info":[{"award-number":["R01 NS111990"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS114052"],"award-info":[{"award-number":["R01 NS114052"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015834","name":"Ono Pharma Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015834","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Friedreich\u2019s ataxia is an incurable disease caused by frataxin (FXN) protein deficiency, which is mostly induced by GAA repeat expansion in intron 1 of the FXN gene. Here, we identified antisense oligonucleotides (ASOs), complementary to two regions within the first intron of FXN pre-mRNA, which could increase FXN mRNA by \u223c2-fold in patient fibroblasts. The increase in FXN mRNA was confirmed by the identification of multiple overlapping FXN-activating ASOs at each region, two independent RNA quantification assays, and normalization by multiple housekeeping genes. Experiments on cells with the ASO-binding sites deleted indicate that the ASO-induced FXN activation was driven by indirect effects. RNA sequencing analyses showed that the two ASOs induced similar transcriptome-wide changes, which did not resemble the transcriptome of wild-type cells. This RNA-seq analysis did not identify directly base-paired off-target genes shared across ASOs. Mismatch studies identified two guanosine-rich motifs (CCGG and G4) within the ASOs that were required for FXN activation. The phosphorodiamidate morpholino oligomer analogs of our ASOs did not activate FXN, pointing to a PS-backbone-mediated effect. Our study demonstrates the importance of multiple, detailed control experiments and target validation in oligonucleotide studies employing novel mechanisms such as gene activation.<\/jats:p>","DOI":"10.1093\/nar\/gkac1108","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T16:06:48Z","timestamp":1670947608000},"page":"12657-12673","source":"Crossref","is-referenced-by-count":12,"title":["G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of <i>FXN<\/i> expression through indirect effects"],"prefix":"10.1093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3383-2992","authenticated-orcid":false,"given":"Feng","family":"Wang","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2431-515X","authenticated-orcid":false,"given":"Ezequiel","family":"Calvo-Roitberg","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M","family":"Rembetsy-Brown","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minggang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn","family":"Sousa","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary\u00a0J","family":"Kartje","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranathi Meda","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lee","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0R","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-9948","authenticated-orcid":false,"given":"Athma\u00a0A","family":"Pai","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5706-1734","authenticated-orcid":false,"given":"Jonathan\u00a0K","family":"Watts","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"},{"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School , Worcester, MA, 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,13]]},"reference":[{"key":"2023010721274399800_B1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/jnc.12215","article-title":"Prevalence gradients of Friedreich\u2019s ataxia and R1b haplotype in europe co-localize, suggesting a common palaeolithic origin in the franco-cantabrian ice age refuge","volume":"126","author":"Vankan","year":"2013","journal-title":"J. Neurochem."},{"key":"2023010721274399800_B2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/ana.24595","article-title":"Compound heterozygous FXN mutations and clinical outcome in Friedreich\u2019s ataxia","volume":"79","author":"Galea","year":"2016","journal-title":"Ann. Neurol."},{"key":"2023010721274399800_B3","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1007\/s13311-019-00764-x","article-title":"Molecular mechanisms and therapeutics for the GAA\u00b7TTC expansion disease friedreich ataxia","volume":"16","author":"Gottesfeld","year":"2019","journal-title":"Neurotherapeutics"},{"key":"2023010721274399800_B4","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/d41573-020-00078-0","article-title":"RNA therapeutics on the rise","volume":"19","author":"Wang","year":"2020","journal-title":"Nat. Rev. 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