{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:08:07Z","timestamp":1780582087430,"version":"3.54.1"},"reference-count":22,"publisher":"SAGE Publications","issue":"13-14","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["P01 HL158506"],"award-info":[{"award-number":["P01 HL158506"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>\n                    Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by mutations in\n                    <jats:italic toggle=\"yes\">SERPINA1<\/jats:italic>\n                    that result in insufficient circulating alpha-1 antitrypsin (AAT) and progressive lung and liver diseases. Adeno-associated virus (AAV)-mediated gene therapy offers the potential for durable AAT expression; however, achieving therapeutic serum concentrations (\u226511 \u00b5M) at clinically acceptable vector doses remains a major challenge. Here, we evaluated multiple AAV vector design strategies to enhance AAT expression and increase vector potency, thereby reducing the required dose to levels below those associated with severe adverse events. Using AAV1- and AAV8-based platforms, we compared promoter and enhancer configurations, codon optimization of the\n                    <jats:italic toggle=\"yes\">SERPINA1<\/jats:italic>\n                    transgene, single-stranded versus self-complementary vector genomes, alternative polyadenylation signals, and an engineered oxidation-resistant AAT variant. Across mouse and ferret models, the chicken \u03b2-actin expression cassette consistently produced higher AAT levels than a liver-specific promoter variant despite comparable vector biodistribution, reflecting superior intrinsic transcriptional activity or an important contribution. Codon optimization did not enhance expression and, in some cases, modestly reduced AAT levels. Self-complementary AAV vectors exhibited reduced overall expression due to required promoter truncation, yielding lower transgene output than full-length single-stranded constructs. Modifications to polyadenylation signals or enhancer combinations did not improve expression. An oxidation-resistant AAT variant resulted in lower circulating levels but may retain therapeutic potential through enhanced functional stability. Collectively, these findings demonstrate that promoter strength and cassette architecture are dominant determinants of AAV-AAT potency and that full-length, single-stranded vectors with robust regulatory elements provide the highest expression. This work defines key parameters governing AAT expression\n                    <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                    and provides a foundation for next-generation AAV designs aimed at achieving therapeutic efficacy at safer, lower vector doses for the treatment of AATD.\n                  <\/jats:p>","DOI":"10.1177\/10430342261444637","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T10:38:39Z","timestamp":1779273519000},"page":"609-617","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of Alpha-1 Antitrypsin Expression from Adeno-Associated Virus Vectors"],"prefix":"10.1177","volume":"37","author":[{"given":"Qiushi","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Pires-Ferreira","sequence":"additional","affiliation":[{"name":"Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mueller","sequence":"additional","affiliation":[{"name":"Genomic Medicine Unit, Sanofi, Waltham, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisha M.","family":"Gruntman","sequence":"additional","affiliation":[{"name":"Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence R.","family":"Flotte","sequence":"additional","affiliation":[{"name":"Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/17476348.2023.2174973"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.08.040"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2023.2183771"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2024.101200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.03.029"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes15091188"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.10.015"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.975803"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7163-3_20"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/104303401300042500"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1089\/10430340460732490"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2006.17.1177"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2020.099"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2021.08.001"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.896"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2466"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/tpj.15970"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3677"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.171"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.11.4062-4074.2000"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2022.192"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135951"}],"container-title":["Human 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