5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency

• Published in: Molecular therapy Vol. 25; no. 6; pp. 1387 - 1394
• Main Authors: Mueller, Christian, Gernoux, Gwladys, Gruntman, Alisha M., Borel, Florie, Reeves, Emer P., Calcedo, Roberto, Rouhani, Farshid N., Yachnis, Anthony, Humphries, Margaret, Campbell-Thompson, Martha, Messina, Louis, Chulay, Jeffrey D., Trapnell, Bruce, Wilson, James M., McElvaney, Noel G., Flotte, Terence R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.06.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: A1AT; AAT; AAV; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - metabolism; alpha 1-Antitrypsin Deficiency - therapy; alpha-1 antitrypsin; Biomarkers; Biopsy; Capsid - immunology; clinical trial; Cytotoxicity; Degranulation; Dependovirus - genetics; Dependovirus - immunology; Elastase; Emphysema; Epitopes, T-Lymphocyte - immunology; exhausted T cells; Flow cytometry; Gene Expression; Gene therapy; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - immunology; Histology; Humans; Immunohistochemistry; Immunophenotyping; Lung diseases; Lymphocytes; Lymphocytes T; Muscles - metabolism; Muscles - pathology; Mutation; Neutrophils; Neutrophils - enzymology; Neutrophils - metabolism; Original; Patients; PD-1; Proteins; rAAV; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Time Factors; Transgenes; Tregs; Washington DC; alpha-1 antitrypsin; clinical trial; rAAV; AAT; AAV; Tregs; gene therapy; A1AT; PD-1; exhausted T cells
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.03.029

Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%–3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%–2.5% of the target level from years 1–5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated. Alpha-1 antitrypsin deficient patients injected intramuscularly with a rAAV1 vector demonstrated 5 years of stable transgene expression after a single dose, coincident with an anti-capsid Treg response and exhaustion of CD8 cells. Mueller et al. also observed partial correction of disease biomarkers despite serum levels below the target level for protein replacement.