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Sustained Expression of ₁-Antitrypsin after Transplantation of Manipulated Hematopoietic Stem Cells

¹ The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts; and ² The Hebrew University, Institute of Dental Sciences, Jerusalem, Israel

Correspondence and requests for reprints should be addressed to Andrew A. Wilson, M.D., Boston University School of Medicine, The Pulmonary Center, R-304, 715 Albany St., Boston, MA 02118. E-mail: awilson{at}bu.edu

Inherited mutations in the human ₁-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 multipotency, 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.

Key Words: gene therapy • bone marrow • ₁-antitrypsin • lung • stem cells

CLINICAL RELEVANCE This study shows that lentivirally transduced hematopoietic stem cells can be used to deliver a gene systemically, either as a cell-based gene therapy or for laboratory research purposes.