Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency
Betts, Michael R.
Rech, Andrew J.
Vonderheide, Robert H.
Flotte, Terence R.
Wilson, James M.
UMass Chan AffiliationsDepartment of Pediatrics, Division of Pulmonology
Document TypeJournal Article
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Digestive System Diseases
Genetics and Genomics
Respiratory Tract Diseases
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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.
SourceProc Natl Acad Sci U S A. 2017 Feb 14;114(7):1655-1659. doi: 10.1073/pnas.1617726114. Epub 2017 Jan 30. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/43571
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