Protection from endotoxemia by adenoviral-mediated gene transfer of human bactericidal/permeability-increasing protein

Abstract

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 (Adh- BPI IntroductionSepsis is a heterogeneous condition with approximately 400 000 to 500 000 cases presented in the United States annually. 1,2 The mortality rate for all septic episodes is estimated between 30% to 50%, and approximately 70% of all septic episodes involve Gram-negative bacteria. 2,3 The Centers for Disease Control and Prevention has reported an increase in the incidence of sepsis over the last decade, which can be attributed to an increase in the number of patients at high risk for developing sepsis. 1 High-risk patients include those who are immunocompromised from HIV infection, undergoing cancer therapy, or on immunosuppressive drugs, and those undergoing invasive surgical procedures. These patients are at greater risk of exposure to bacteria, especially in the clinical setting. 4 The goal of sepsis management is to reduce or control the detrimental systemic inflammation responses to the infection using support therapies, while treatment therapies, such as antibiotics, attempt to eliminate the infection. 5 With the increase in incidence of both drug-resistant bacteria and immunocompromised septic patients, current aggressive therapies are ineffective or even detrimental, and new therapies must be developed to increase the survival of septic patients. 5-9 Moreover, it may be possible to prophylactically reduce the number of sepsis-induced mortalities by introducing a set of criteria to identify and treat high-risk individuals prior to surgery or cancer therapy.Various novel sepsis therapies currently under development or under evaluation in clinical trials include anticoagulant therapy, therapies directed at the neutralization of lipopolysaccharide (LPS), and cytokine therapies. Anticoagulant therapy aims to improve multiple organ failure by attenuating intravascular coagulation. 10 In this regard, the use of recombinant activated protein C has been shown to increase survival of patients. 10,11 However, activated protein C therapy addresses only one portion of the complex sepsis condition and does not address the important initial proinflammatory cytokine cascade elicited by LPS from Gram-negative bacteria. On the other hand, while therapies directed at the neutralization of proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF-␣), are promising in experimental models, they are largely ineffective in clinical trials. 12-17 The interleukin-10 (IL-10) cytokine therapy aiming to counter the expression and effect of TNF-␣ has also proved ineffective. 18 Such cytokine therapies are thus unlikely to be the best strategy. Seps...

Effect of Plasma Phospholipid Transfer Protein Deficiency on Lethal Endotoxemia in Mice

“…BPI, another PLTP-related protein that neutralizes LPS, is a potent inhibitor of CD14-dependent cell activation by endotoxins, has direct Gram-negative bacterial killing properties, and enhances bacterial phagocytosis (36,51). Although BPI is normally an intracellular factor that is produced and stored in neutrophils and is not detected in plasma under normal physiological conditions (52), the overexpression of circulating forms of BPI or BPI fragments in mice was shown to provide protection from lethal endotoxemia (53,54). In humans, the injection of recombinant BPI was found to be effective in decreasing morbidity and functional outcomes in children with severe meningococcemia but with no significant decrease in mortality (55).…”

The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

“…In brief summary, in a variety of animal models, recombinant human BPI (rBPI) and its amino-terminal derivate (rBPI 21 ), were protective against lethal and sub-lethal challenges with Gram-negative bacteria and endotoxin [11,[58][59][60][61]. Subsequent studies in humans, including in meningococcal sepsis, also showed a significant protective effect of BPI [12][13][14][15][61][62][63][64], although not yet sufficient to lead to an approved clinical application.…”

Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

“…8 Despite continuing progress in the development of antibiotics and other supportive care therapies, there is a lack of effective means of prevention of or therapy for sepsis. 8,9 Indeed, therapies directed at neutralizing LPS or proinflammatory cytokines can prevent the development of septic shock in animal models, but clinical trials of these therapies have in general failed to improve the outcome of patients with sepsis. 8,9 Therefore, there is great enthusiasm about the development of novel strategies for the treatment of sepsis.…”