Oligodeoxynucleotide intervention for prevention and treatment of sepsis

Abstract

A method for producing ODNs in bacterial or fungal cells in vivo for treatment of sepsis so that, when the ODNs reach and knock down their target genes, and thereby kill bacterial or fungal cells or inhibit their growth, the bacterial or fungal accumulation in the bloodstream is held constant or diminished and the sepsis syndrome is reduced or eliminated. The invention also contemplates of certain ODNs for use in treatment of sepsis.

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] The present application is a continuation-in-part of co-pending application Ser. No. 10 / 453,410, filed Jun. 3, 2003 and IDENTIFICATION OF NOVEL ANTIBACTERIAL AGENTS BY SCREENING THE SINGLE-STRANDED DNA EXPRESSION LIBRARY, and co-pending application Ser. No. 10 / 743,956, filed Dec. 23, 2003 and entitled OLIGODOXYNUCLEOTIDE (ODN) LIBRARIES, THEIR USE IN SCREENING FOR ANTIBACTERIAL AGENTS, AND CATALYTIC ODN SEQUENCE FOR USE AS AN ANTIBACTERIAL AGENT. Both of the applications listed in this paragraph are hereby incorporated into the specification of the present application in their entirety by this specific reference thereto.BACKGROUND OF THE INVENTION [0002] Severe sepsis and septic shock are life threatening complication of infections and the most common cause of death in intensive care units (Angus et al., 2001, Crit. Care Med., 29:1303-1310). Recent US and European surveys have estimated that severe sepsis accounts for 2-11% of all admiss...

AI Technical Summary

Benefits of technology

[0034] The present invention comprises a method for delivering the ODN-expressing plasmid constructions into host cells in vivo so that, when the ODNs are produced

Problems solved by technology

The incidence of this condition is rising due to the aging of the population and increasing numbers of immuno-compromised and critically ill patients.

However, a deficient immunologic defense may allow infection to become established.

Further, an excessive or poorly regulated response may harm the host through maladaptive release of indigenously generated inflammatory compounds.

Additionally, diabetic individuals or others who suffer from lymphedema, especially in the feet and legs, are at risk of infection from exogenous opportunistic pathogens normally present on the skin due to the growth potential afforded by the edematous medium or the lack of circulation.

Such infections may result in severe cellulitis or related sequelae that can lead to sepsis.

This uncontrolled cascade of inflammation and coagulation fuels the progression of sepsis, resulting in hypoxia, widespread ischemia, organ dysfunction, and ultimately death for a large number of patients.

However, despite some encouraging results from early studies, none of the anti-endotoxin strategies have been shown to be of benefit in large clinical trials.

However, anti-TNF or anti-IL-1 antibodies have yet to be demonstrated any beneficial effect in sepsis or septic shock (Abraham et al., 1998, Lancet, 351, 929-933).

While theoretical and experimental animal evidence exists supporting the use of large doses of corticosteroids in severe sepsis and septic shock, all randomized human studies found that corticosteroids do not prevent the development of septic shock, reverse the shock state, or improve mortality.

However, treatment with this drug results in relatively modest improvements in patient mortality, and at the price of a slight increase in bleeding events (Id.).

Unfortunately, numerous classes of antibiotics have become less effective as a result of the rapid emergence of antibiotic resistance by many common bacterial pathogens such as S. aureus, Streptococcus pneumoniae and Enterococcus faecalis (Nicolaou & Boddy, 2001, Scientific American, p.56-61).

Although these approaches make a significant contribution to fighting against bacterial infections, difficulty remains in meeting the increasing needs of the medical community.

However, antisense technology is not used extensively in prokaryotic systems.

On the other hand, sepsis represents an excessive innate immune response to microbial products, and many processes in the complex pathophysiology of sepsis are simultaneously over-activated.

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