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Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1655-1659. doi: 10.1073/pnas.1617726114. Epub 2017 Jan 30.

Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency.

Author information

1
Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
2
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
4
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655.
5
Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; wilsonjm@upenn.edu.

Abstract

Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-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.

KEYWORDS:

a-1-antitrypsin; adeno-associated virus; gene therapy; immune response; polymorphism

PMID:
28137880
PMCID:
PMC5320988
DOI:
10.1073/pnas.1617726114
[Indexed for MEDLINE]
Free PMC Article

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