Department of Pediatrics, Division of Pulmonology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Digestive System Diseases | Genetics and Genomics | Medical Genetics | Respiratory Tract Diseases | Therapeutics
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.
a-1-antitrypsin, adeno-associated virus, gene therapy, immune response, polymorphism
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DOI of Published Version
Proc 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
Proceedings of the National Academy of Sciences of the United States of America
Calcedo, Roberto; Somanathan, Suryanarayan; Qin, Qiuyue; Betts, Michael R.; Rech, Andrew J.; Vonderheide, Robert H.; Mueller, Christian; Flotte, Terence R.; and Wilson, James M., "Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency" (2017). Pediatric Publications and Presentations. 141.
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Digestive System Diseases Commons, Genetics and Genomics Commons, Medical Genetics Commons, Respiratory Tract Diseases Commons, Therapeutics Commons