Type

Journal Article

Authors

Terence R Flotte
Noel G McElvaney
James M Wilson
Bruce Trapnell
Jeffrey D Chulay
Louis Messina
Martha Campbell-Thompson
Margaret Humphries
Anthony Yachnis
Farshid N Rouhani
and 6 others

Subjects

Biochemistry

Topics
regulatory t cell year 1 neutrophil elastase type 1 gene therapy gene expression immune response alpha 1 antitrypsin deficiency

5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency. (2016)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Terence R Flotte, Noel G McElvaney, James M Wilson, Bruce Trapnell, Jeffrey D Chulay, Louis Messina, Martha Campbell-Thompson, Margaret Humphries, Anthony Yachnis, Farshid N Rouhani and 6 others

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194