Gene Therapy Center; Department of Pediatrics, Division of Pediatric Pulmonology; Department of Surgery
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Digestive System Diseases | Genetics and Genomics | Immunoprophylaxis and Therapy | Respiratory Tract Diseases | Therapeutics
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.
AAV, gene therapy, alpha-1 antitrypsin, clinical trial, AAT, A1AT, rAAV, Tregs, exhausted T cells, PD-1, genetic vectors
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© 2017 The Author(s).
DOI of Published Version
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 website
Molecular therapy : the journal of the American Society of Gene Therapy
Mueller C, Gernoux G, Gruntman AM, Borel F, Reeves EP, Calcedo R, Rouhani FN, Yachnis A, Humphries M, Campbell-Thompson M, Messina LM, Chulay JD, Trapnell B, Wilson JM, McElvaney NG, Flotte TR. (2017). 5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.ymthe.2017.03.029. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1308
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Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Digestive System Diseases Commons, Genetics and Genomics Commons, Immunoprophylaxis and Therapy Commons, Respiratory Tract Diseases Commons, Therapeutics Commons