{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:55:33Z","timestamp":1790805333071,"version":"4.1.0"},"reference-count":84,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T00:00:00Z","timestamp":1682985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A major challenge to adeno\u2010associated virus (AAV)\u2010mediated gene therapy is the presence of anti\u2010AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse\u2010specific CD20 monoclonal antibody to suppress anti\u2010AAV NAbs and enable readministration of AAV vectors of the same capsid in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An AAV8 vector (AAV8\u2010CB\u2010hGAA) that ubiquitously expresses human \u03b1\u2010glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8\u2010LSP\u2010hSEAP) that contains a liver\u2010specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti\u2010AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B\u2010cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In n\u00e4ive mice, an 8\u2010week IS treatment along with AAV8\u2010CB\u2010hGAA injection effectively depleted CD19<jats:sup>+<\/jats:sup>B220<jats:sup>+<\/jats:sup> B cells from blood, spleen, and bone marrow and prevented the formation of anti\u2010AAV8 NAbs. Following administration of AAV8\u2010LSP\u2010hSEAP, increasing levels of hSEAP were detected in blood for up to 6\u00a0weeks, indicating successful AAV readministration. In mice pre\u2010immunized with AAV8\u2010CB\u2010hGAA, comparison of IS treatment for 8, 12, 16, and 20\u2009weeks revealed that the 16\u2010week IS treatment demonstrated the highest plasma hSEAP level following AAV8\u2010LSP\u2010hSEAP readministration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV\u2010mediated gene therapy. A combination IS treatment with bortezomib and a mouse\u2010specific CD20 monoclonal antibody effectively suppressed anti\u2010AAV NAbs in na\u00efve mice and in mice with pre\u2010existing antibodies, allowing successful readministration of the same AAV capsid vector.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3509","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T15:31:21Z","timestamp":1680190281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Successful AAV8 readministration: Suppression of capsid\u2010specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease"],"prefix":"10.1002","volume":"25","author":[{"given":"Su Jin","family":"Choi","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Yi","sequence":"additional","affiliation":[{"name":"Division of Surgical Sciences, Department of Surgery Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong\u2010A","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Tedder","sequence":"additional","affiliation":[{"name":"Department of Immunology Duke University School of Medicine  Durham NC USA"},{"name":"Division of Allergy and Immunology, Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight D.","family":"Koeberl","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jeck","sequence":"additional","affiliation":[{"name":"Department of Pathology Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit K.","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"EpiVax, Inc.  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