{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T21:22:23Z","timestamp":1768080143894,"version":"3.49.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alternative pathway complement dysregulation with abnormal glomerular C3 deposits and glomerular damage is a key mechanism of pathology in C3 glomerulopathy (C3G). No disease-specific treatments are currently available for C3G. Therapeutics inhibiting complement are emerging as a potential strategy for the treatment of C3G. In this study, we investigated the effects of N-acetylgalactosamine (GalNAc)\u2013conjugated small interfering RNA (siRNA) targeting the C3 component of complement that inhibits liver C3 expression in the C3G model of mice with heterozygous deficiency of factor H (Cfh+\/\u2212 mice). We showed a duration of action for GalNAc-conjugated C3 siRNA in reducing the liver C3 gene expression in Cfh+\/\u2212 mice that were dosed s.c. once a month for up to 7 mo. C3 siRNA limited fluid-phase alternative pathway activation, reducing circulating C3 fragmentation and activation of factor B. Treatment with GalNAc-conjugated C3 siRNA reduced glomerular C3d deposits in Cfh+\/\u2212 mice to levels similar to those of wild-type mice. Ultrastructural analysis further revealed the efficacy of the C3 siRNA in slowing the formation of mesangial and subendothelial electron-dense deposits. The present data indicate that RNA interference\u2013mediated C3 silencing in the liver may be a relevant therapeutic strategy for treating patients with C3G associated with the haploinsufficiency of complement factor H.<\/jats:p>","DOI":"10.4049\/jimmunol.2100730","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T19:35:12Z","timestamp":1647027312000},"page":"1772-1781","source":"Crossref","is-referenced-by-count":6,"title":["Therapeutic Small Interfering RNA Targeting Complement C3 in a Mouse Model of C3 Glomerulopathy"],"prefix":"10.1093","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1386-1868","authenticated-orcid":false,"given":"Cristina","family":"Zanchi","sequence":"first","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9806-6443","authenticated-orcid":false,"given":"Domenico","family":"Cerullo","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2819-7557","authenticated-orcid":false,"given":"Verena","family":"Aumiller","sequence":"additional","affiliation":[{"name":"Silence Therapeutics GmbH , Berlin,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7907-3047","authenticated-orcid":false,"given":"Daniela","family":"Corna","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2282-871X","authenticated-orcid":false,"given":"Daniela","family":"Rottoli","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6764-2751","authenticated-orcid":false,"given":"Mona","family":"Eisermann","sequence":"additional","affiliation":[{"name":"Silence Therapeutics GmbH , Berlin,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Donadelli","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansoureh","family":"Mousavi","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-5033","authenticated-orcid":false,"given":"Marina","family":"Noris","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4721-5485","authenticated-orcid":false,"given":"Ariela","family":"Benigni","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2507-8894","authenticated-orcid":false,"given":"Carlamaria","family":"Zoja","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori , Bergamo,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"2025021008595158400_r1","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/ki.2013.377","article-title":"C3 glomerulopathy: consensus report","volume":"84","author":"Pickering","year":"2013","journal-title":"Kidney Int."},{"key":"2025021008595158400_r2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/s41581-018-0107-2","article-title":"C3 glomerulopathy - understanding a rare complement-driven renal disease","volume":"15","author":"Smith","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"2025021008595158400_r3","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1159\/000507254","article-title":"Update on C3 glomerulopathy: a complement-mediated disease","volume":"144","author":"Caravaca-Font\u00e1n","year":"2020","journal-title":"Nephron"},{"key":"2025021008595158400_r4","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1007\/s00467-018-3989-0","article-title":"Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy","volume":"34","author":"Noris","year":"2019","journal-title":"Pediatr. Nephrol."},{"key":"2025021008595158400_r5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.2215\/CJN.04700513","article-title":"C3 glomerulopathy: clinicopathologic features and predictors of outcome","volume":"9","author":"Medjeral-Thomas","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"2025021008595158400_r6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1053\/j.ajkd.2017.11.019","article-title":"Patterns of clinical response to eculizumab in patients with C3 glomerulopathy","volume":"72","author":"Le Quintrec","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"2025021008595158400_r7","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1053\/j.ajkd.2018.12.046","article-title":"C5 convertase blockade in membranoproliferative glomerulonephritis: a single-arm clinical trial","volume":"74","author":"Ruggenenti","year":"2019","journal-title":"Am. J. Kidney Dis."},{"key":"2025021008595158400_r8","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/ki.2012.63","article-title":"Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies","volume":"82","author":"Servais","year":"2012","journal-title":"Kidney Int."},{"key":"2025021008595158400_r9","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1055\/s-0034-1376334","article-title":"C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis","volume":"40","author":"Xiao","year":"2014","journal-title":"Semin. Thromb. Hemost."},{"key":"2025021008595158400_r10","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.molimm.2016.01.010","article-title":"Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome","volume":"71","author":"Iatropoulos","year":"2016","journal-title":"Mol. Immunol."},{"key":"2025021008595158400_r11","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.3389\/fimmu.2018.02329","article-title":"Unraveling the molecular mechanisms underlying complement dysregulation by nephritic factors in C3G and IC-MPGN","volume":"9","author":"Donadelli","year":"2018","journal-title":"Front. Immunol."},{"key":"2025021008595158400_r12","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.it.2017.03.003","article-title":"Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery","volume":"38","author":"Mastellos","year":"2017","journal-title":"Trends Immunol."},{"key":"2025021008595158400_r13","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.smim.2016.06.002","article-title":"Complement inhibition in C3 glomerulopathy","volume":"28","author":"Nester","year":"2016","journal-title":"Semin. Immunol."},{"key":"2025021008595158400_r14","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.imbio.2015.06.012","article-title":"Therapeutic control of complement activation at the level of the central component C3","volume":"221","author":"Ricklin","year":"2016","journal-title":"Immunobiology"},{"key":"2025021008595158400_r15","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1111\/j.1600-6143.2006.01427.x","article-title":"Preventing renal ischemia-reperfusion injury using small interfering RNA by targeting complement 3 gene","volume":"6","author":"Zheng","year":"2006","journal-title":"Am. J. Transplant."},{"key":"2025021008595158400_r16","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.omtm.2020.05.023","article-title":"Liver-specific siRNA-mediated Stat3 or C3 knockdown improves the outcome of experimental autoimmune myocarditis","volume":"18","author":"Avalle","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"2025021008595158400_r17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1089\/nat.2018.0736","article-title":"GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics","volume":"28","author":"Springer","year":"2018","journal-title":"Nucleic Acid Ther."},{"key":"2025021008595158400_r18","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/ng912","article-title":"Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H","volume":"31","author":"Pickering","year":"2002","journal-title":"Nat. Genet."},{"key":"2025021008595158400_r19","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.molimm.2011.06.402","article-title":"Complement factor H (CFH) haploinsufficiency causes spontaneous late onset glomerulonephritis","volume":"48","author":"Noris","year":"2011","journal-title":"Mol. Immunol."},{"key":"2025021008595158400_r20","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1681\/ASN.2017030258","article-title":"Cluster analysis identifies distinct pathogenetic patterns in C3 glomerulopathies\/immune complex-mediated membranoproliferative GN","volume":"29","author":"Iatropoulos","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025021008595158400_r21","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.omtn.2020.05.026","article-title":"Less is more: novel hepatocyte-targeted siRNA conjugates for treatment of liver-related disorders","volume":"21","author":"Weing\u00e4rtner","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"2025021008595158400_r22","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2025021008595158400_r23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"2025021008595158400_r24","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41379-019-0348-z","article-title":"Utility of immunohistochemistry with C3d in C3 glomerulopathy","volume":"33","author":"Snijders","year":"2020","journal-title":"Mod. Pathol."},{"key":"2025021008595158400_r25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.molimm.2016.06.004","article-title":"Sex matters: Systemic complement activity of female C57BL\/6J and BALB\/cJ mice is limited by serum terminal pathway components","volume":"76","author":"Kotimaa","year":"2016","journal-title":"Mol. Immunol."},{"key":"2025021008595158400_r26","doi-asserted-by":"crossref","first-page":"118370","DOI":"10.1016\/j.lfs.2020.118370","article-title":"Complement C3 deficiency ameliorates aging related changes in the kidney","volume":"260","author":"Wu","year":"2020","journal-title":"Life Sci."},{"key":"2025021008595158400_r27","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.omtm.2019.04.009","article-title":"Investigational RNAi therapeutic targeting C5 is efficacious in pre-clinical models of myasthenia gravis","volume":"13","author":"Kusner","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"2025021008595158400_r28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/cei.12244","article-title":"C3 dysregulation due to factor H deficiency is mannan-binding lectin-associated serine proteases (MASP)-1 and MASP-3 independent in vivo","volume":"176","author":"Ruseva","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"2025021008595158400_r29","first-page":"459","article-title":"Characterization of C3 in C3 glomerulopathy","volume":"32","author":"Sethi","year":"2017","journal-title":"Nephrol. Dial. Transplant."},{"key":"2025021008595158400_r30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00467-015-3310-4","article-title":"C3 glomerulopathy","volume":"32","author":"Riedl","year":"2017","journal-title":"Pediatr. Nephrol."},{"key":"2025021008595158400_r31","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/s41573-019-0031-6","article-title":"Clinical promise of next-generation complement therapeutics","volume":"18","author":"Mastellos","year":"2019","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/7\/1772\/61189310\/ji2100730.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/7\/1772\/61189310\/ji2100730.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T09:00:08Z","timestamp":1739178008000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/208\/7\/1772\/7924475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,1]]},"references-count":31,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,4,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2100730","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4]]},"published":{"date-parts":[[2022,4,1]]}}}