5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency
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Authors
Mueller, ChristianGernoux, Gwladys
Gruntman, Alisha M.
Borel, Florie
Reeves, Emer P.
Calcedo, Roberto
Rouhani, Farshid N.
Yachnis, Anthony
Humphries, Margaret
Campbell-Thompson, Martha
Messina, Louis M.
Chulay, Jeffrey D.
Trapnell, Bruce
Wilson, James M.
McElvaney, Noel G.
Flotte, Terence R.
UMass Chan Affiliations
Department of SurgeryDepartment of Pediatrics, Division of Pediatric Pulmonology
Gene Therapy Center
Document Type
Journal ArticlePublication Date
2017-06-07Keywords
AAVgene therapy
alpha-1 antitrypsin
clinical trial
AAT
A1AT
rAAV
Tregs
exhausted T cells
PD-1
genetic vectors
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Digestive System Diseases
Genetics and Genomics
Immunoprophylaxis and Therapy
Respiratory Tract Diseases
Therapeutics
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Show full item recordAbstract
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.Source
Mol Ther. 2017 Jun 7;25(6):1387-1394. doi: 10.1016/j.ymthe.2017.03.029. Epub 2017 Apr 10. Link to article on publisher's websiteDOI
10.1016/j.ymthe.2017.03.029Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29081PubMed ID
28408179Related Resources
Rights
© 2017 The Author(s).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.ymthe.2017.03.029