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dc.contributor.authorBorel, Florie
dc.contributor.authorTang, Qiushi
dc.contributor.authorGernoux, Gwladys
dc.contributor.authorGreer, Cynthia
dc.contributor.authorWang, Ziqiong
dc.contributor.authorBarzel, Adi
dc.contributor.authorKay, Mark A.
dc.contributor.authorShultz, Leonard D.
dc.contributor.authorGreiner, Dale L.
dc.contributor.authorFlotte, Terence R.
dc.contributor.authorBrehm, Michael A.
dc.contributor.authorMueller, Christian
dc.date2022-08-11T08:10:13.000
dc.date.accessioned2022-08-23T16:59:33Z
dc.date.available2022-08-23T16:59:33Z
dc.date.issued2017-11-01
dc.date.submitted2017-11-27
dc.identifier.citationMol Ther. 2017 Nov 1;25(11):2477-2489. doi: 10.1016/j.ymthe.2017.09.020. Epub 2017 Sep 25. <a href="https://doi.org/10.1016/j.ymthe.2017.09.020">Link to article on publisher's site</a>
dc.identifier.issn1525-0016 (Linking)
dc.identifier.doi10.1016/j.ymthe.2017.09.020
dc.identifier.pmid29032169
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43614
dc.description.abstractHepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29032169&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1016/j.ymthe.2017.09.020
dc.rightsCopyright 2017 The Author(s).
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectA1AT
dc.subjectAAT
dc.subjectAATD
dc.subjectAAV
dc.subjectRNAi
dc.subjectgene editing
dc.subjecthumanized liver mouse model
dc.subjectliver regeneration
dc.subjectliver xenograft
dc.subjectmiRNA
dc.subjectnuclease-free genome editing
dc.subjectshRNA
dc.subjectα-1 antitrypsin deficiency
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectDigestive System Diseases
dc.subjectGenetics and Genomics
dc.subjectMedical Genetics
dc.subjectTherapeutics
dc.titleSurvival Advantage of Both Human Hepatocyte Xenografts and Genome-Edited Hepatocytes for Treatment of alpha-1 Antitrypsin Deficiency
dc.typeJournal Article
dc.source.journaltitleMolecular therapy : the journal of the American Society of Gene Therapy
dc.source.volume25
dc.source.issue11
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1185&amp;context=peds_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pp/186
dc.identifier.contextkey11154096
refterms.dateFOA2022-08-23T16:59:34Z
html.description.abstract<p>Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create a recipient strain (NSG-PiZ) for human hepatocyte xenotransplantation. Results indicate that NSG-PiZ recipients support heightened engraftment of normal human primary hepatocytes as compared with NSG recipients. This model can therefore be used to test hepatocyte cell therapies for AATD, but more broadly it serves as a simple, highly reproducible liver xenograft model. Finally, a promoterless adeno-associated virus (AAV) vector, expressing a wild-type AAT and a synthetic miRNA to silence the endogenous allele, was integrated into the albumin locus. This gene-editing approach leads to a selective advantage of edited hepatocytes, by silencing the mutant protein and augmenting normal AAT production, and improvement of the liver pathology.</p>
dc.identifier.submissionpathpeds_pp/186
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentHorae Gene Therapy Center
dc.contributor.departmentDepartment of Pediatrics, Division of Pediatric Pulmonology
dc.source.pages2477-2489


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