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Blood, 1 January 2004, Vol. 103, No. 1, pp. 93-99.
Prepublished online as a Blood First Edition Paper on September 22, 2003; DOI 10.1182/blood-2003-02-0660.
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GENE THERAPY
Protection from endotoxemia by adenoviral-mediated gene transfer of human bactericidal/permeability-increasing protein
Scott Alexander,
Jonathan Bramson,
Ronan Foley, and
Zhou Xing
From the Department of Pathology and Molecular Medicine, and Infectious Diseases Division, Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada.
Sepsis represents a growing concern in high-risk patients and there has been a lack of effective preventives and therapies. Bacterial/permeability increasing protein (BPI) is a human neutrophil granule-associated defense molecule specific for Gram-negative bacteria and their products. To develop a BPI-transgene–based prophylactic or therapeutic modality, we have developed a recombinant, replication-deficient adenoviral vector expressing full-length human BPI protein (AdhBPI). The expression of BPI is under control of a murine cytomegalovirus (CMV) promoter. Using in vitro and in vivo systems, AdhBPI-mediated gene transfer led to extracellular secretion of BPI protein, which effectively neutralized endotoxin (lipopolysaccharide [LPS]) and markedly reduced the production of proinflammatory cytokines tumor necrosis factor  (TNF-) and macrophage inflammatory protein 2 (MIP-2) by freshly isolated murine alveolar macrophages. By using a mouse model of nonlethal sepsis elicited with LPS, we demonstrated that in vivo gene transfer of BPI was able to markedly inhibit the effect of a large dose of LPS on cytokine responses when injected intraperitoneally. Furthermore, such in vivo BPI gene transfer also improved the survival of mice suffering from lethal septic shock elicited by intraperitoneal injection of D-galactosamine and LPS. Thus, our results suggest that human BPI gene transfer vector has the potential to be used as a therapeutic agent for septic conditions.
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