{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:04:45Z","timestamp":1784826285244,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T00:00:00Z","timestamp":1656806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Atlas Biotechnology SA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage\/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1\u03b2 and the endoplasmic reticulum (ER) stress marker ATF3. Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.<\/jats:p>","DOI":"10.3390\/ijms23137405","type":"journal-article","created":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T22:50:46Z","timestamp":1656888646000},"page":"7405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition"],"prefix":"10.3390","volume":"23","author":[{"given":"Nikolay","family":"Zhukovsky","sequence":"first","affiliation":[{"name":"Neurix SA, Av. de la Roseraie 64, 1205 Geneva, Switzerland"},{"name":"Triskel Integrated Services SA, Ch. du Pavillon 5, 1218 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Silvano","sequence":"additional","affiliation":[{"name":"Neurix SA, Av. de la Roseraie 64, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Filloux","sequence":"additional","affiliation":[{"name":"Triskel Integrated Services SA, Ch. du Pavillon 5, 1218 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"In Vivex SAS, Av. Louis Lumi\u00e8re 177b, 34400 Lunel, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9033-6768","authenticated-orcid":false,"given":"Karl-Heinz","family":"Krause","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Ru. Michel-Servet 1, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,3]]},"reference":[{"key":"ref_1","first-page":"26","article-title":"Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease","volume":"6","author":"Goel","year":"2021","journal-title":"US Respir. Pulm. Dis."},{"key":"ref_2","first-page":"20406223211014025","article-title":"Alpha-1 antitrypsin deficiency research and emerging treatment strategies: What\u2019s down the road?","volume":"12","author":"Rahaghi","year":"2021","journal-title":"Ther. Adv. 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