{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T10:10:55Z","timestamp":1787220655423,"version":"build-2736575974"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["5R01DK102572"],"award-info":[{"award-number":["5R01DK102572"]}]},{"name":"PKD-RRC Sprint"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3\u2032UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes\u00a0PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1538","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:27:25Z","timestamp":1767702445000},"source":"Crossref","is-referenced-by-count":4,"title":["Disruption of a six-nucleotide miRNA motif improves\n                    <i>PKD1<\/i>\n                    dosage and ameliorates polycystic kidney disease"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4511-5341","authenticated-orcid":false,"given":"Ronak","family":"Lakhia","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunzi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Biggers","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Zumwalt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Somasundaram","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harini","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Cobo-Stark","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"2026012019024186500_B1","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"2026012019024186500_B2","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/nrg1328nrg1328","article-title":"Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs","volume":"5","author":"Bartel","year":"2004","journal-title":"Nat Rev Genet"},{"key":"2026012019024186500_B3","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.1038\/s41588-025-02326-8","article-title":"Genetic variants affecting RNA stability influence complex traits and disease risk","volume":"57","author":"Huang","year":"2025","journal-title":"Nat Genet"},{"key":"2026012019024186500_B4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.cell.2005.06.036","article-title":"miRNAs, cancer, and stem cell division","volume":"122","author":"Croce","year":"2005","journal-title":"Cell"},{"key":"2026012019024186500_B5","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.1038\/s41467-022-32543-2","article-title":"PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression","volume":"13","author":"Lakhia","year":"2022","journal-title":"Nat Commun"},{"key":"2026012019024186500_B6","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.1097\/01.ASN.0000028643.17901.42","article-title":"Genetics and pathogenesis of polycystic kidney disease","volume":"13","author":"Igarashi","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"2026012019024186500_B7","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1056\/NEJMoa1205511","article-title":"Tolvaptan in patients with autosomal dominant polycystic kidney disease","volume":"367","author":"Torres","year":"2012","journal-title":"N Engl J Med"},{"key":"2026012019024186500_B8","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1056\/NEJMoa1710030","article-title":"Tolvaptan in later-stage autosomal dominant polycystic kidney disease","volume":"377","author":"Torres","year":"2017","journal-title":"N Engl J Med"},{"key":"2026012019024186500_B9","doi-asserted-by":"publisher","first-page":"10765","DOI":"10.1073\/pnas.1301693110","article-title":"miR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease","volume":"110","author":"Patel","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012019024186500_B10","doi-asserted-by":"publisher","first-page":"4148","DOI":"10.1038\/s41467-019-11918-y","article-title":"Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease","volume":"10","author":"Lee","year":"2019","journal-title":"Nat Commun"},{"key":"2026012019024186500_B11","doi-asserted-by":"publisher","first-page":"14395","DOI":"10.1038\/ncomms14395","article-title":"microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism","volume":"8","author":"Hajarnis","year":"2017","journal-title":"Nat Commun"},{"key":"2026012019024186500_B12","article-title":"Novartis to acquire Regulus Therapeutics and farabursen, an investigational microRNA inhibitor to treat ADPKD, the most common genetic cause of renal failure","author":"Novartis"},{"key":"2026012019024186500_B13","doi-asserted-by":"publisher","first-page":"10762","DOI":"10.1038\/s41467-025-65799-5","article-title":"The nucleobase guanine at the 3\u2032-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity","volume":"16","author":"Valencia","year":"2025","journal-title":"Nat Commun"},{"key":"2026012019024186500_B14","doi-asserted-by":"publisher","first-page":"4257","DOI":"10.1172\/JCI64313","article-title":"Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity","volume":"122","author":"Hopp","year":"2012","journal-title":"J Clin Invest"},{"key":"2026012019024186500_B15","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1097\/01.ASN.0000016444.90348.50","article-title":"Epithelial-specific Cre\/lox recombination in the developing kidney and genitourinary tract","volume":"13","author":"Shao","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"2026012019024186500_B16","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/hmg\/ddn039","article-title":"A viable model of autosomal dominant polycystic kidney disease through kidney-specific inactivation of Pkd1","volume":"17","author":"Shibazaki","year":"2008","journal-title":"Hum Mol Genet"},{"key":"2026012019024186500_B17","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.kint.2022.08.039","article-title":"Enhancer and super-enhancer landscape in polycystic kidney disease","volume":"103","author":"Lakhia","year":"2023","journal-title":"Kidney Int"},{"key":"2026012019024186500_B18","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1038\/s41587-022-01649-9","article-title":"Precise transcript targeting by CRISPR\u2013Csm complexes","volume":"41","author":"Colognori","year":"2023","journal-title":"Nat Biotechnol"},{"key":"2026012019024186500_B19","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1093\/hmg\/ddy379","article-title":"c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis","volume":"28","author":"Parrot","year":"2019","journal-title":"Hum Mol Genet"},{"key":"2026012019024186500_B20","doi-asserted-by":"publisher","first-page":"F122","DOI":"10.1152\/ajprenal.00352.2017","article-title":"PPARalpha agonist fenofibrate enhances fatty acid beta-oxidation and attenuates polycystic kidney and liver disease in mice","volume":"314","author":"Lakhia","year":"2018","journal-title":"Am J Physiol Renal Physiol"},{"key":"2026012019024186500_B21","doi-asserted-by":"publisher","first-page":"109495","DOI":"10.1016\/j.cellsig.2019.109495","article-title":"Metabolic reprogramming and the role of mitochondria in polycystic kidney disease","volume":"67","author":"Podrini","year":"2020","journal-title":"Cell Signal"},{"key":"2026012019024186500_B22","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1681\/ASN.2015060634","article-title":"MicroRNA-21 aggravates cyst growth in a model of polycystic kidney disease","volume":"27","author":"Lakhia","year":"2016","journal-title":"JASN"},{"key":"2026012019024186500_B23","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1073\/pnas.89.2.768","article-title":"Mechanisms of the inhibition of reverse transcription by antisense oligonucleotides","volume":"89","author":"Boiziau","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012019024186500_B24","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/S0092-8674(00)81793-6","article-title":"The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I","volume":"87","author":"Qian","year":"1996","journal-title":"Cell"},{"key":"2026012019024186500_B25","doi-asserted-by":"publisher","first-page":"3114","DOI":"10.1681\/ASN.2021050690","article-title":"Detection of PKD1 and PKD2 somatic variants in autosomal dominant polycystic kidney Cyst epithelial cells by whole-genome sequencing","volume":"32","author":"Zhang","year":"2021","journal-title":"JASN"},{"key":"2026012019024186500_B26","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41525-024-00452-6","article-title":"Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts","volume":"9","author":"Mallawaarachchi","year":"2024","journal-title":"Npj Genom Med"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/2\/gkaf1538\/66471063\/gkaf1538.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/2\/gkaf1538\/66471063\/gkaf1538.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:02:48Z","timestamp":1768953768000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/doi\/10.1093\/nar\/gkaf1538\/8431135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,14]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,1,14]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkaf1538","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,1,27]]},"published":{"date-parts":[[2026,1,14]]},"article-number":"gkaf1538"}}