{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:05:45Z","timestamp":1787119545047,"version":"build-2736575974"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T00:00:00Z","timestamp":1677456000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\u03b11-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of <jats:italic toggle=\"yes\">SERPINA1 (SA1-ATZ)<\/jats:italic>, resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic>-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic> transgene in PiZ mice by <jats:italic toggle=\"yes\">in vivo<\/jats:italic> genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>To create a targeted DNA break in exon-7 of the <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic> transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZ mice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5\u00d710<jats:sup>10<\/jats:sup>vg\/mouse, LD) or a high dose (1.5\u00d710<jats:sup>11<\/jats:sup>vg\/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Two weeks after treatment, deep sequencing of the hepatic <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic> transgene pool showed 6%\u00b13% or 15%\u00b14% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%\u00b112% and 36%\u00b112%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%\u00b10.09% and 0.25%\u00b10.14% of <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic> transgenes, respectively, which increased to 5.2%\u00b15.0% and 33%\u00b113%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ\/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>ZFN-mediated <jats:italic toggle=\"yes\">SA1-ATZ<\/jats:italic> transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/hc9.0000000000000070","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T17:00:31Z","timestamp":1677517231000},"page":"e0070-e0070","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":8,"title":["Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human \u03b11-antitrypsin deficiency"],"prefix":"10.1097","volume":"7","author":[{"given":"Yanfeng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandan","family":"Guha","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrik","family":"Asp","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana L.","family":"Tchaikovskya","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Kim","sequence":"additional","affiliation":[{"name":"Sangamo Therapeutics, Richmond, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mendel","sequence":"additional","affiliation":[{"name":"Sangamo Therapeutics, Richmond, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Cost","sequence":"additional","affiliation":[{"name":"Sangamo Therapeutics, Richmond, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Perlmutter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita","family":"Roy-Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Conway","sequence":"additional","affiliation":[{"name":"Sangamo Therapeutics, Richmond, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayanta","family":"Roy-Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, New York, USA"},{"name":"Department of Genetics, Albert Einstein College of Medicine, New York, New York, 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