{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:19:51Z","timestamp":1785525591337,"version":"3.56.0"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector\u2013meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium\u2013targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR\/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus\u2013 and adenoviral vector\u2013mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0159ps","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T19:06:58Z","timestamp":1594840018000},"page":"560-570","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":30,"title":["Advances in Alpha-1 Antitrypsin Gene Therapy"],"prefix":"10.1093","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9077-3300","authenticated-orcid":false,"given":"Reka","family":"Lorincz","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Biologic Therapeutics Center, School of Medicine, Washington University, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Curiel","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Biologic Therapeutics Center, School of Medicine, Washington University, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,1]]},"reference":[{"key":"2026021100451506300_bib1","doi-asserted-by":"crossref","first-page":"16051","DOI":"10.1038\/nrdp.2016.51","article-title":"\u03b11-Antitrypsin deficiency","volume":"2","author":"Greene","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"2026021100451506300_bib2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1177\/1753465812457113","article-title":"Prevalence of \u03b11-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive 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