Therapeutic uses of BPI protein products in BPI-deficient humans

Abstract

New therapeutic uses for BPI protein products that involve treatment of subjects with a BPI deficiency condition, including selective BPI deficiency, and newborns, including BPI-deficient newborns.

Description

[0001] This application is a continuation-in-part of U.S. application Ser. No. 09 / 285,124 filed Apr. 1, 1999, incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates generally to novel therapeutic uses of BPI protein products that involve treatment of BPI-deficient subjects. BACKGROUND OF THE INVENTION [0003] Newborns as a group are at increased risk for invasive bacterial infections and resulting sepsis. Although the majority of these infections in newborns are caused by gram-positive organisms, a variable but significant percentage of bacterial infections (about 20-40%) are due to gram-negative bacteria, particularly E. coli, Haemophilus influenzae, Klebsiella spp., and Enterobacter spp. In fact, it is the gram-negative infections that are, in some studies, associated with the highest mortality rate, which can be as high as about 40%. [Beck-Sague, C M et al., Pediatr Infect Dis J 13: 1110-116 (1994) and Stoll, B J et al., J Pediatr 129: 63-71 (...

AI Technical Summary

Benefits of technology

"The present invention provides new ways to use BPI protein products to treat people with a BPI deficiency, which makes them more susceptible to infections. The invention also covers the use of BPI protein products for newborns who are also deficient in BPI. The treatment can help alleviate the symptoms of BPI deficiency, reduce the severity or invasiveness of infections, and prevent sequelae. The use of BPI protein products can be combined with other known therapeutic agents. The invention also covers the manufacture of a medicine using BPI protein products for the treatment of humans with BPI deficiency and newborns with BPI deficiency."

Problems solved by technology

Newborns as a group are at increased risk for invasive bacterial infections and resulting sepsis.

These findings may explain the difficulty in mobilizing neutrophils to sites of bacterial infection but do not explain the decreased phagocytic and bactericidal activity of the neutrophils of newborns.

However, the major elements of the oxygen-independent antimicrobial arsenal of neutrophil primary granules, including BPI and the defensin peptides, have not been assessed in neonates.

Moreover, improved technology has led to increased survival rates for extremely ill full-term as well as premature neonates, which represent a growing population at high risk for bacterial infection.

Although the replacement of neutrophils by granulocyte transfusion in newborns with sepsis has apparently been beneficial in some studies [Cairo et al., Pediatrics 74: 887-92 (1984)] this potential therapy has been complicated by difficulty in obtaining histocompatible neutrophils and by transfusion reactions.

In susceptible gram-negative bacteria, BPI binding is thought to disrupt LPS structure, leading to activation of bacterial enzymes that degrade phospholipids and peptidoglycans, altering the permeability of the cell's outer membrane, and initiating events that ultimately lead to cell death.

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