title: Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency.
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.
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Suryanarayan
authors.initials: S
authors.lastname: Somanathan
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rech
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.affiliation: Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.affiliation: Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; wilsonjm@upenn.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D006680:HLA Antigens; D010455:Peptides; D000515:alpha 1-Antitrypsin
keywords: a-1-antitrypsin; adeno-associated virus; gene therapy; immune response; polymorphism