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

• DOI: 10.1073/pnas.1617726114
• Publication Date: 2017-01-31T02:50:29Z
• Authors: Roberto Calcedo; Suryanarayan Soma...; Qiuyue Qin; Michael R. Betts; Andrew J. Rech; Robert H. Vonderh...; Christian Mueller; Terence R. Flotte; James M. Wilson
• Keywords: Adult; Male; 0301 basic medicine; Digestive System Diseases; T-Lymphocytes; Respiratory Tract Diseases; adeno-associated virus; Therapeutics; immune response; polymorphism; Congenital; 03 medical and health sciences; HLA Antigens; alpha 1-Antitrypsin Deficiency; Humans; Amino Acid Sequence; Alleles; Aged; Polymorphism, Genetic; Genetics and Genomics; Genetic Therapy; Dependovirus; Middle Aged; gene therapy; 3. Good health; Hereditary; alpha 1-Antitrypsin; Female; a-1-antitrypsin; K562 Cells; Peptides; Medical Genetics; and Neonatal Diseases and Abnormalities

Significance The use of adeno-associated virus (AAV)-mediated gene therapy to treat monogenic disorders is currently being tested in phase I, II, and III clinical trials. An immune response to the newly introduced gene product remains a potential problem because of the patient’s lack of central and peripheral tolerance to foreign epitopes. In this study, we show the induction of a T-cell response to the therapeutic product in a α-1-antitrypsin (AAT)-deficient subject receiving AAV1-AAT treatment. The response was directed to an AAT epitope upstream of the mutation and was associated with a polymorphism present in the subject but not in the wild-type AAT therapeutic product. Our study highlights the importance of considering polymorphisms in the targeted population when designing a transgene.