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dc.contributor.authorCalcedo, Roberto
dc.contributor.authorSomanathan, Suryanarayan
dc.contributor.authorQin, Qiuyue
dc.contributor.authorBetts, Michael R.
dc.contributor.authorRech, Andrew J.
dc.contributor.authorVonderheide, Robert H.
dc.contributor.authorMueller, Christian
dc.contributor.authorFlotte, Terence R.
dc.contributor.authorWilson, James M.
dc.date2022-08-11T08:10:12.000
dc.date.accessioned2022-08-23T16:59:23Z
dc.date.available2022-08-23T16:59:23Z
dc.date.issued2017-02-14
dc.date.submitted2017-06-21
dc.identifier.citationProc Natl Acad Sci U S A. 2017 Feb 14;114(7):1655-1659. doi: 10.1073/pnas.1617726114. Epub 2017 Jan 30. <a href="https://doi.org/10.1073/pnas.1617726114">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1617726114
dc.identifier.pmid28137880
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43571
dc.description.abstractAdeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder alpha-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28137880&dopt=Abstract">Link to Article in PubMed</a>
dc.rightsPublisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
dc.subjecta-1-antitrypsin
dc.subjectadeno-associated virus
dc.subjectgene therapy
dc.subjectimmune response
dc.subjectpolymorphism
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectDigestive System Diseases
dc.subjectGenetics and Genomics
dc.subjectMedical Genetics
dc.subjectRespiratory Tract Diseases
dc.subjectTherapeutics
dc.titleClass I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume114
dc.source.issue7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1140&amp;context=peds_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pp/141
dc.identifier.contextkey10332946
refterms.dateFOA2022-08-23T16:59:23Z
html.description.abstract<p>Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder alpha-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy.</p>
dc.identifier.submissionpathpeds_pp/141
dc.contributor.departmentDepartment of Pediatrics, Division of Pulmonology
dc.source.pages1655-1659


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