{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:18:48Z","timestamp":1790774328286,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009268","name":"Alport Syndrome Foundation","doi-asserted-by":"publisher","award":["to Oliver Gross"],"award-info":[{"award-number":["to Oliver Gross"]}],"id":[{"id":"10.13039\/100009268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Col4a3\u2212\/\u2212 Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3\u2212\/\u2212 mouse model with a 129\/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.<\/jats:p>","DOI":"10.3390\/cells11040594","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T21:19:06Z","timestamp":1644441546000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models"],"prefix":"10.3390","volume":"11","author":[{"given":"Diana","family":"Rubel","sequence":"first","affiliation":[{"name":"Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Boulanger","sequence":"additional","affiliation":[{"name":"Sanofi Research & Development, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin","family":"Craciun","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7496-0835","authenticated-orcid":false,"given":"Ethan Y.","family":"Xu","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Excision BioTherapeutics, San Francisco, CA 94111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany"},{"name":"Department of Pediatrics, Peking University First Hospital, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Phillips","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Abbvie Bioresearch Center, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Callahan","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Weber","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Takeda Pharmaceuticals, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenping","family":"Song","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Ngai","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay O.","family":"Bukanov","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Janssen Pharmaceuticals, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7487-5764","authenticated-orcid":false,"given":"Xingyi","family":"Shi","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Novartis Institute for BioMedical Research, Boston, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Hariri","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USA"},{"name":"Eloxx Pharmaceuticals, Watertown, MA 02140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8829-5672","authenticated-orcid":false,"given":"Herv\u00e9","family":"Husson","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oxana","family":"Ibraghimov-Beskrovnaya","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA"},{"name":"Dyne Therapeutics, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiguang","family":"Liu","sequence":"additional","affiliation":[{"name":"Sanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8390-8852","authenticated-orcid":false,"given":"Oliver","family":"Gross","sequence":"additional","affiliation":[{"name":"Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1056\/NEJMra022296","article-title":"Alport\u2019s syndrome, Goodpasture\u2019s syndrome, and type IV collagen","volume":"348","author":"Hudson","year":"2003","journal-title":"N. 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