title: Current status of gene therapy for α-1 antitrypsin deficiency.
abstract: BACKGROUND
  As a common monogenic disease, α-1 antitrypsin (AAT) deficiency has undergone thorough investigation for the development of gene therapy. The most common pathology associated with AAT deficiency occurs in the lung, where the loss of function due to impaired secretion of mutant AAT prevents the inhibition of neutrophil elastase and leads to loss of elastin content from the alveolar interstitium.
  
  
  METHODS
  Current treatment in the USA consists of recurrent intravenous protein replacement therapy to augment serum AAT levels. In an attempt to replace recurring treatments with a single dose of gene therapy, recombinant adenovirus, plasmid, and recombinant adeno-associated virus (rAAV) vectors have been investigated as vectors for transgene delivery.
  
  
  CONCLUSIONS
  Large strides in gene therapy for AAT deficiency lung disease have led to the development of rAAV1-AAT capable of producing sustained serum AAT levels in clinical trials after intramuscular administration in humans at 3% of the target level. Further increases in levels are anticipated as limb perfusion targets greater muscle mass. The future roles of intrapleural and airway delivery, miRNA-expressing vectors, iPS cell platforms, and genome editing are anticipated.
authors.affiliation: University of Massachusetts Medical School, Gene Therapy Center, Department of Pediatrics , Suite 340 55 Lake Avenue North Worcester, MA 01655 , USA +1 508 856 2107 ; +1 508 856 8181 ; terry.flotte@umassmed.edu.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Loring
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D019076:Transgenes / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000628:therapy*
chemical_list: D000515:alpha 1-Antitrypsin
keywords: adeno-associated virus; emphysema; gene therapy; liver disease; vectors; α-1 antitrypsin