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

Abstract

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.

• Authors: Christian Mueller, Gwladys Gernoux, Alisha M Gruntman, Florie Borel, Emer P Reeves, Roberto Calcedo, Farshid N Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis Messina, Jeffrey D Chulay, Bruce Trapnell, James M Wilson, Noel G McElvaney, Terence R Flotte
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 25 Issue 6 Pg. 1387-1394 (06 07 2017) ISSN: 1525-0024 [Electronic] United States
• PMID: 28408179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Epitopes, T-Lymphocyte
• alpha 1-Antitrypsin

Topics

• Biomarkers
• Biopsy
• Capsid (immunology)
• Dependovirus (genetics, immunology)
• Epitopes, T-Lymphocyte (immunology)
• Gene Expression
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics, immunology)
• Humans
• Immunohistochemistry
• Immunophenotyping
• Muscles (metabolism, pathology)
• Neutrophils (enzymology, metabolism)
• T-Lymphocyte Subsets (immunology, metabolism)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Time Factors
• Transgenes
• alpha 1-Antitrypsin (genetics, metabolism)
• alpha 1-Antitrypsin Deficiency (genetics, metabolism, therapy)