title: Pulmonary vasculature directed adenovirus increases epithelial lining fluid alpha-1 antitrypsin levels.
abstract: BACKGROUND
  Gene therapy for inherited serum deficiency disorders has previously been limited by the balance between obtaining adequate expression and causing hepatic toxicity. Our group has previously described modifications of a replication deficient human adenovirus serotype 5 that increase pulmonary vasculature transgene expression.
  
  
  METHODS
  In the present study, we use a modified pulmonary targeted adenovirus to express human alpha-1 antitrypsin (A1AT) in C57BL/6 J mice.
  
  
  RESULTS
  Using the targeted adenovirus, we were able to achieve similar increases in serum A1AT levels with less liver viral uptake. We also increased pulmonary epithelial lining fluid A1AT levels by more than an order of magnitude compared to that of untargeted adenovirus expressing A1AT in a mouse model. These gains are achieved along with evidence of decreased systemic inflammation and no evidence for increased inflammation within the vector-targeted end organ.
  
  
  CONCLUSIONS
  In addition to comprising a step towards clinically viable gene therapy for A1AT, maximization of protein production at the site of action represents a significant technical advancement in the field of systemically delivered pulmonary targeted gene therapy. It also provides an alternative to the previous limitations of hepatic viral transduction and associated toxicities.
authors.affiliation: Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, USA.|Present address: Institute of Inflammation and Repair, Nanomedicine Laboratory, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Buggio
authors.affiliation: Department of Pediatrics, Washington University in St Louis, St Louis, MO, USA.|Present address: Rare Lung Diseases Program, Department of Pediatrics, Cincinnati Children's Hospital, Cincinatti, OH, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Towe
authors.affiliation: Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, USA.|Present address: Department of Pathology, University of Oklahoma Health Sciences Centre, Oklahoma City, OK, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Annan
authors.affiliation: Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kaliberov
authors.affiliation: Department of Surgery, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Zhi Hong
authors.initials: ZH
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Stephens
authors.affiliation: Department of Surgery, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.affiliation: Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000260:Adenoviruses, Human; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting / Q000009:adverse effects / Q000379:methods*; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000009:adverse effects; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000209:etiology; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D019076:Transgenes; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000628:therapy*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: adenovirus; alpha-1 antitrypsin; gene therapy