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Marrow-Derived Cells as Vehicles for Delivery of Gene Therapy to Pulmonary Epithelium

Departments of Laboratory Medicine and Genetics, Yale University, New Haven, Connecticut; Department of Immunology Research/Bone Marrow Transplantation, Los Angeles Childrens Hospital, Los Angeles, California; Department of Neurology, Charité, Humboldt-University Berlin, Berlin, Germany; and Department of Pathology, New York University School of Medicine, New York, New York

Address correspondence to: Dr. Diane S. Krause, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8035. E-mail: diane.krause{at}yale.edu

Gene therapy application to pulmonary airways and alveolar spaces holds tremendous promise for the treatment of lung diseases. However, safe and effective long-term gene expression using viral and nonviral vectors has not yet been achieved. Adenoviral vectors, with a natural affinity for airway epithelia, have been partially effective, but are inflammatory and induce only transient gene expression. We investigate the novel approach of using retrovirally transduced multipotent bone marrow–derived stem cells (BMSC) to deliver gene therapy to lung epithelium. We have shown previously that up to 20% of lung epithelial cells can be derived from marrow following BMSC transplantation. Here, irradiated female mice were transplanted with male marrow that had been transduced with retrovirus encoding eGFP. Transgene expressing lung epithelial cells were present in all recipients analyzed at 2, 5, or 11 mo after transplant (n = 10), demonstrating that highly plastic BMSC can be stably transduced in vitro and retain their ability to differentiate into lung epithelium while maintaining long-term transgene expression.

Abbreviations: bone marrow transplant, BMT • bone marrow–derived stem cells, BSMC • fluorescence in situ hybridization, FISH • fluorescein isothiocyanate, FITC • hematopoietic stem cells, HSC • interleukin, IL • long terminal repeat, LTR • phosphate-buffered saline, PBS

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