Sustained expression of α1-antitrypsin after transplantation of manipulated hematopoietic stem cells

Andrew A. Wilson, Letty W. Kwok, Avi Hai Hovav, Sarah J. Ohle, Frederic F. Little, Alan Fine, Darrell N. Kotton

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Inherited mutations in the human α1-antitrypsin (AAT) gene lead to deficient circulating levels of AAT protein and a predisposition to developing emphysema. Gene therapy for individuals deficient in AAT is an attractive goal, because transfer of a normal AAT gene into any cell type able to secrete AAT should reverse deficient AAT levels and attenuate progression of lung disease. Here we present an approach for AAT gene transfer based on the transplantation of lentivirally transduced hematopoietic stem cells (HSCs). We develop a novel dual-promoter lentiviral system to transfer normal human AAT cDNA as well as a fluorescent tracking "reporter gene" into murine HSCs. After transplantation of 3,000 transduced HSCs into irradiated mouse recipients, we demonstrate simultaneous and sustained systemic expression of both genes in vivo for at least 31 weeks. The stem cells transduced with this protocol maintain multi-potency, self-renewal potential, and the ability to reconstitute the hematopoietic systems of both primary and secondary recipients. This lentiviral-based system may be useful for investigations requiring the systemic secretion of anti-proteases or cytokines relevant to the pathogenesis of a variety of lung diseases.

Original languageAmerican English
Pages (from-to)133-141
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number2
StatePublished - 1 Aug 2008


  • Bone marrow
  • Gene therapy
  • Lung
  • Stem cells
  • α-antitrypsin


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