{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:12:35Z","timestamp":1788333155983,"version":"build-2803163510"},"reference-count":33,"publisher":"American Chemical Society (ACS)","issue":"28","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["NIGMS 73042"],"award-info":[{"award-number":["NIGMS 73042"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-1244"],"award-info":[{"award-number":["I-1244"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder that currently has no curative treatments. DRPLA is caused by an expansion of a CAG trinucleotide repeat region within the protein-encoding sequence of the atrophin-1 (ATN-1) gene. Inhibition of mutant ATN-1 protein expression is one strategy for treating DRPLA, and allele-selective gene silencing agents that block mutant expression over wild-type expression would be lead compounds for therapeutic development. Here we develop an assay for distinguishing mutant from wild-type ATN-1 protein by gel electrophoresis. We use this assay to evaluate duplex RNAs and single-stranded silencing RNAs (ss-siRNAs) for allele-selective inhibition of ATN-1 protein expression. We observed potent and allele-selective inhibition by RNA duplexes that contain mismatched bases relative to the CAG target and have the potential to form miRNA-like complexes. ss-siRNAs that contained mismatches were as selective as mismatch-containing duplexes. We also report allele-selective inhibition by duplex RNAs containing unlocked nucleic acids or abasic substitutions, although selectivities are not as high. Five compounds that showed &amp;gt;8-fold allele selectivity for mutant ATN-1 were also selective for inhibiting the expression of two other trinucleotide repeat disease genes, ataxin-3 (ATXN-3) and huntingtin (HTT). These data demonstrate that the expanded trinucleotide repeat within ATN-1 mRNA is a potential target for compounds designed to achieve allele-selective inhibition of ATN-1 protein, and one agent may allow the targeting of multiple disease genes.<\/jats:p>","DOI":"10.1021\/bi500610r","type":"journal-article","created":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T07:52:47Z","timestamp":1404201167000},"page":"4510-4518","source":"Crossref","is-referenced-by-count":34,"title":["Allele-Selective Inhibition of Mutant Atrophin-1\nExpression by Duplex and Single-Stranded RNAs"],"prefix":"10.1021","volume":"53","author":[{"given":"Jiaxin","family":"Hu","sequence":"first","affiliation":[{"name":"University of Texas Southwestern Medical Center , , 6001 Forest Park Road , , ,","place":["Dallas, Texas, United States, 75390-9041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center , , 6001 Forest Park Road , , ,","place":["Dallas, Texas, United States, 75390-9041"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Jayaprakash","family":"Narayanannair","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals , 300 Third Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy G.","family":"Lackey","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals , 300 Third Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Kuchimanchi","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals , 300 Third Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallanthottathil G.","family":"Rajeev","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals , 300 Third Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthiah","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals , 300 Third Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric E.","family":"Swayze","sequence":"additional","affiliation":[{"name":"ISIS Pharmaceuticals , , , ,","place":["Carlsbad, California, United States, 92101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walt F.","family":"Lima","sequence":"additional","affiliation":[{"name":"ISIS Pharmaceuticals , , , ,","place":["Carlsbad, California, United States, 92101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thazha P.","family":"Prakash","sequence":"additional","affiliation":[{"name":"ISIS Pharmaceuticals , , , ,","place":["Carlsbad, California, United States, 92101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Sigma Custom Products , 9186 Six Pines Drive , , ,","place":["The Woodlands, Texas, United States, 77379"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Martinez","sequence":"additional","affiliation":[{"name":"Sigma Custom Products , 9186 Six Pines Drive , , ,","place":["The Woodlands, Texas, United States, 77379"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Corey","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center , , 6001 Forest Park Road , , ,","place":["Dallas, Texas, United States, 75390-9041"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,7,1]]},"reference":[{"key":"2026090202132746100_cit1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/j.1440-1789.2006.00670.x","article-title":"Polyglutamine\ndisease: Recent advances in the neuropathology of dentatorubral-pallidolusian\natrophy","volume":"26","author":"Yamada","year":"2006","journal-title":"Neuropathology"},{"key":"2026090202132746100_cit2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/ng0194-9","article-title":"Unstable expansion\nof CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA)","volume":"6","author":"Koide","year":"1994","journal-title":"Nat. Genet."},{"key":"2026090202132746100_cit3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/ng1094-177","article-title":"Structure and expression\nof the gene responsible for the triplet repeat disorder, dentatorubral\nand pallidoluysian atrophy (DRPLA)","volume":"8","author":"Nagafuchi","year":"1994","journal-title":"Nat. Genet."},{"key":"2026090202132746100_cit4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12311-008-0028-x","article-title":"Study group\non ataxic diseases: Sporadic ataxias in Japan: A population-based\nepidemiological study","volume":"7","author":"Tsuji","year":"2008","journal-title":"Cerebellum"},{"key":"2026090202132746100_cit5","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1002\/mds.22642","article-title":"Clinical\nand genetic characteristics\nof non-asian dentatotrubral-pallidolyusian atrophy: A systematic review","volume":"24","author":"Wardle","year":"2009","journal-title":"Mov. Disord."},{"key":"2026090202132746100_cit6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/hmg\/ddn403","article-title":"Severe neurological\nphenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice","volume":"18","author":"Sata","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2026090202132746100_cit7","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","article-title":"Huntington\u2019s\ndisease","volume":"369","author":"Walker","year":"2007","journal-title":"Lancet"},{"key":"2026090202132746100_cit8","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.neuron.2012.05.009","article-title":"Sustained\nTherapeutic Reversal of Huntington\u2019s Disease by Transient Repression\nof Huntingtin Synthesis","volume":"74","author":"Kordasiewicz","year":"2012","journal-title":"Neuron"},{"key":"2026090202132746100_cit9","doi-asserted-by":"crossref","first-page":"e24308","DOI":"10.1371\/journal.pone.0024308","article-title":"Targeting\nseveral CAG expansion diseases by a single antisense oligonucleotide","volume":"6","author":"Evers","year":"2011","journal-title":"PLoS One"},{"key":"2026090202132746100_cit10","first-page":"634","article-title":"Antisense oligonucleotide\ntherapeutics for inherited neurodegenerative diseases","volume":"18","author":"Southwell","year":"2012","journal-title":"Trends Mol. Biol."},{"key":"2026090202132746100_cit11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1089\/hum.2012.225","article-title":"Antisense oligonucleotides for the treatment of spinal\nmuscular atrophy","volume":"24","author":"Porensky","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"2026090202132746100_cit12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnmol.2011.00010","article-title":"Antisense-mediated RNA targeting:\nVersatile and expedient\ngenetic manipulation in the brain","volume":"4","author":"Zalachoras","year":"2011","journal-title":"Front. Mol.\nNeurosci."},{"key":"2026090202132746100_cit13","doi-asserted-by":"crossref","first-page":"5037","DOI":"10.1074\/jbc.M610274200","article-title":"Functional architecture\nof atrophins","volume":"282","author":"Shen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026090202132746100_cit14","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/nbt.1539","article-title":"Allele-specific silencing of mutant huntingtin and\nataxin-3 genes by targeting expanded CAG repeats in mRNAs","volume":"27","author":"Hu","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2026090202132746100_cit15","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1126\/science.1102513","article-title":"Argonaute2 is the\ncatalytic engine of mammalian RNAi","volume":"305","author":"Liu","year":"2004","journal-title":"Science"},{"key":"2026090202132746100_cit16","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/nature07666","article-title":"Structure of an\nargonaute silencing complex with a\nseed-containing guide DNA and target RNA duplex","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"2026090202132746100_cit17","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.chembiol.2010.10.013","article-title":"Allele-Selective\nInhibition of Huntingtin Expression\nby Switching to an miRNA-like RNAi Mechanism","volume":"17","author":"Hu","year":"2010","journal-title":"Chem. Biol."},{"key":"2026090202132746100_cit18","doi-asserted-by":"crossref","first-page":"11270","DOI":"10.1093\/nar\/gks907","article-title":"Mechanism of allele-selective\ninhibition of huntingtin expression by duplex RNAs that target CAG\nrepeats: Function through the RNAi pathway","volume":"40","author":"Hu","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2026090202132746100_cit19","doi-asserted-by":"crossref","first-page":"5578","DOI":"10.1093\/nar\/gkr156","article-title":"Inhibition of mutant huntingtin expression\nby RNA duplex targeting expanded CAG repeats","volume":"39","author":"Fiszer","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2026090202132746100_cit20","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.1039\/c0ob01085e","article-title":"Unlocked nucleic acid: An RNA modification with broad\npotential","volume":"9","author":"Pasternak","year":"2011","journal-title":"Org. Biomol. Chem."},{"key":"2026090202132746100_cit21","doi-asserted-by":"crossref","first-page":"5680","DOI":"10.1039\/c1cs15048k","article-title":"Locked vs. unlocked\nnucleic acids (LNA vs. UNA): Contrasting\nstructures work towards common therapeutic goals","volume":"40","author":"Campbell","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"2026090202132746100_cit22","doi-asserted-by":"crossref","first-page":"9329","DOI":"10.1021\/bi4014209","article-title":"Effect\nof unlocked nucleic acids (UNA) modifications on RNAi and allele-selective\ninhibition of huntingtin and ataxin-3","volume":"52","author":"Aiba","year":"2013","journal-title":"Biochemistry"},{"key":"2026090202132746100_cit23","doi-asserted-by":"crossref","first-page":"8788","DOI":"10.1093\/nar\/gkt594","article-title":"RNA duplexes\nwith abasic substitutions are potent and allele-selective inhibitors\nof huntingtin and ataxin-3 expression","volume":"41","author":"Liu","year":"2013","journal-title":"Nucleic\nAcids Res."},{"key":"2026090202132746100_cit24","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2012.08.014","article-title":"Single-stranded\nsiRNAs activate RNAi in animals","volume":"150","author":"Lima","year":"2012","journal-title":"Cell"},{"key":"2026090202132746100_cit25","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.cell.2012.08.002","article-title":"Single-Stranded RNAs Use RNAi to\nPotently and Allele-Selectively Inhibit Mutant Huntingtin Expression","volume":"150","author":"Yu","year":"2012","journal-title":"Cell"},{"key":"2026090202132746100_cit26","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1089\/nat.2013.0476","article-title":"Allele-selective\ninhibition of mutant huntingtin expression\nby single-stranded silencing RNAs","volume":"24","author":"Hu","year":"2014","journal-title":"Nucleic Acid\nTher."},{"key":"2026090202132746100_cit27","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.pneurobio.2011.11.006","article-title":"Toward understanding Machado-Joseph disease","volume":"97","author":"Costa Mdo","year":"2012","journal-title":"Prog. Neurobiol."},{"key":"2026090202132746100_cit28","doi-asserted-by":"crossref","first-page":"9570","DOI":"10.1093\/nar\/gkt693","article-title":"ss-siRNAs allele selectively inhibit\nataxin-3 expression: Multiple mechanisms for an alternative gene silencing\nstrategy","volume":"41","author":"Liu","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2026090202132746100_cit29","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1515\/bc.2011.045","article-title":"Allele-selective inhibition of ataxin-3 (ATXN3) expression\nby antisense oligomers and duplex RNAs","volume":"392","author":"Hu","year":"2011","journal-title":"Biol.\nChem."},{"key":"2026090202132746100_cit30","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/ng0595-99","article-title":"Abnormal gene product\nidentified in hereditary dentatorubral-pallidoluysian\natrophy (DRPLA) brain","volume":"10","author":"Yazawa","year":"1995","journal-title":"Nat. Genet."},{"key":"2026090202132746100_cit31","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.chembiol.2012.07.011","article-title":"Designing chemically\nmodified oligonucleotides for\ntargeted gene silencing","volume":"19","author":"Deleavey","year":"2112","journal-title":"Chem. Biol."},{"key":"2026090202132746100_cit32","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1038\/mtna.2013.65","article-title":"Lipid nanoparticle\ndelivery of siRNA to silencing neuronal gene expression in the brain","volume":"2","author":"Rungta","year":"2013","journal-title":"Mol. Ther.\u2500Nucleic Acids"},{"key":"2026090202132746100_cit33","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/path.2993","article-title":"Gene silencing by synthetic nucleic acids in the laboratory\nand the clinic","volume":"226","author":"Watts","year":"2012","journal-title":"J. Pathol."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi500610r","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/28\/4510\/15693185\/bi500610r.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/28\/4510\/15693185\/bi500610r.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:13:37Z","timestamp":1788329617000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/28\/4510\/1476752\/Allele-Selective-Inhibition-of-Mutant-Atrophin-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,1]]},"references-count":33,"journal-issue":{"issue":"28","published-online":{"date-parts":[[2014,7,1]]},"published-print":{"date-parts":[[2014,7,22]]}},"URL":"https:\/\/doi.org\/10.1021\/bi500610r","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,1]]}}}