Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency
dc.contributor.author | Calcedo, Roberto | |
dc.contributor.author | Somanathan, Suryanarayan | |
dc.contributor.author | Qin, Qiuyue | |
dc.contributor.author | Betts, Michael R. | |
dc.contributor.author | Rech, Andrew J. | |
dc.contributor.author | Vonderheide, Robert H. | |
dc.contributor.author | Mueller, Christian | |
dc.contributor.author | Flotte, Terence R. | |
dc.contributor.author | Wilson, James M. | |
dc.date | 2022-08-11T08:10:12.000 | |
dc.date.accessioned | 2022-08-23T16:59:23Z | |
dc.date.available | 2022-08-23T16:59:23Z | |
dc.date.issued | 2017-02-14 | |
dc.date.submitted | 2017-06-21 | |
dc.identifier.citation | Proc 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.issn | 0027-8424 (Linking) | |
dc.identifier.doi | 10.1073/pnas.1617726114 | |
dc.identifier.pmid | 28137880 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/43571 | |
dc.description.abstract | 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. | |
dc.language.iso | en_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.rights | Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml. | |
dc.subject | a-1-antitrypsin | |
dc.subject | adeno-associated virus | |
dc.subject | gene therapy | |
dc.subject | immune response | |
dc.subject | polymorphism | |
dc.subject | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | |
dc.subject | Digestive System Diseases | |
dc.subject | Genetics and Genomics | |
dc.subject | Medical Genetics | |
dc.subject | Respiratory Tract Diseases | |
dc.subject | Therapeutics | |
dc.title | Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency | |
dc.type | Journal Article | |
dc.source.journaltitle | Proceedings of the National Academy of Sciences of the United States of America | |
dc.source.volume | 114 | |
dc.source.issue | 7 | |
dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1140&context=peds_pp&unstamped=1 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/peds_pp/141 | |
dc.identifier.contextkey | 10332946 | |
refterms.dateFOA | 2022-08-23T16:59:23Z | |
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.submissionpath | peds_pp/141 | |
dc.contributor.department | Department of Pediatrics, Division of Pulmonology | |
dc.source.pages | 1655-1659 |