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

[0015] The present invention provides novel therapeutic uses for BPI protein products that involve treatment of subjects, including humans, with a BPI deficiency condition, including a selective BPI deficiency. Another aspect of the invention provides treatment of newborns, including BPI-deficient newborns, with BPI protein products. The invention is based on the discovery that the neutrophils of newborns are selectively deficient in BPI, a protein that plays an important role in defending against infection, including gram-negative bacterial infection. Treatment of subjects with a BPI deficiency condition is expected to alleviate adverse effects associated with this BPI deficiency, including, for example, decreasing susceptibility to infections, reducing the severity or invasiveness of the infection(s), and preventing the sequelae of the infection(s).

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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