Therapeutic medicine for cystic fibrosis

Details Therapeutic medicine for cystic fibrosis Therapeutic medicine for cystic fibrosis

1994-10-20

1996-12-10

Wityshyn, Michael G.

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Transferases

435193, A61K 3845

Patent

active

055828256

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a therapeutic medicine for cystic fibrosis.


BACKGROUND ART

In the white population, an inherited gene-defective disease known as cystic fibrosis is encountered with a frequency of 1/1000-2000. This disease is caused by the defect of a gene coding for cystic fibrosis transmembrane conductance regulator (CFTR) protein and in the event of bacterial infection to the respiratory organ with mucoid forms of Pseudomonas aeruginosa,. Mucous substances collect in the lungs to cause an obstruction of airways leading to premature death. Though antibiotics and digestive enzymes are currently in use for the treatment of this disease, adequate therapeutic responses remain to be achieved as yet.
Recently (Richard C. Hubbard, et al.) have reported that symptomatic improvements in cystic fibrosis may be expected if the DNA contained in said mucus is lysed with a DNase [The New England Journal of Medicine 326, 812-815, 1992]. However, the DNase is little capable of lysing the mucus produced by bacteria of the genus Pseudomonas so that no sufficient efficacy can be expected.
Meanwhile, it is not deniable that the action of antibiotics and digestive enzymes on Pseudomonas aeruginosa is compromised by the alginate which these microorganisms themselves produce.


DISCLOSURE OF INVENTION

The inventors of this invention did a great deal of research to develop a therapeutically effective drug for cystic fibrosis. In the course of their exploration, the inventors discovered that the mucous substance secreted by strains of Pseudomonas aeruginosa isolated from the lungs of patients with cystic fibrosis contained not only DNA but also alginate in an amount several-fold as great as the amount of DNA. Inspired by the thought that should this alginate be somehow decomposed the morbidity of cystic fibrosis could be cured, the inventors did further research and have found that a certain alginate lyase is effective for the treatment of cystic fibrosis.
The object of this invention is to provide a drug suited for the therapy of cystic fibrosis.
In accordance with this invention there is provided a therapeutic medicine for cystic fibrosis which comprises an alginate lyase capable of lysing the alginate produced by microorganisms of the genus Pseudomonas as an active ingredient.
The alginate lyase that can be used as the active ingredient of the therapeutic medicine of this invention is not restricted insofar as it is able to lyse the alginate produced by microorganisms of the genus Pseudomonas. The preferred species of the-alginate lyase for the purposes of this invention include the alginate lyase having an N-terminal amino acid sequence corresponding to SEQ ID NO: 1 presented hereinafter and having the following physicochemical properties (hereinafter referred to as Al-I lyase) and the alginate lyase having an N-terminal amino acid sequence corresponding to SEQ ID NO: 2, which also appears hereinafter, and having the following physicochemical properties (hereinafter referred to as Al-III lyase), among others. non-reducing end C.sub.4 -C.sub.5 double bond and ultimately to 4-deoxy-5-ketouronic acid. bacterial origin non-reducing end C.sub.4 -C.sub.5 double bond and ultimately to 4-deoxy-5-ketouronic acid. bacterial orgin.
The above physicochemical properties are now described in detail. It should be understood that the physicochemical properties of Al-I lyase and Al-III lyase were determined using the purified enzyme samples prepared in Reference Examples 1 and 2 which are presented hereinafter.
The activity of each alginate lyase was assayed according to the principle that the saccharides having a non-reducing end C.sub.4 -C.sub.5 double bond as produced on lysis of alginate cause a specific increase in absorbance at 235 nm.
Specifically, the enzymatic activity was determined as follows. First, 1.0 ml of a 0.2% aqueous solution of the alginate, 0.5 ml of 200 mM Tris-HCl buffer (pH 7.0) and 0.1 ml of the enzyme solution were mixed together and after the mixture was diluted with 0.4 ml of water to

REFERENCES:
Brown et al., Applied and Environmental Microbiology 57(6): 1870-1872 (Jun. 1991).
Wicker-Bockelmann et al., Zbi Bakt Hyg A 266: 379-389 (1987).
Gacesa et al, Infection. Antibiot. Chemother. 42:67-71 (1989).
Hubbard et al, The New Enland Journal of Medicine, 326:812-815 (1992).
Eftekhar and Schiller, Current Microbiology, 29:37-42 (1994).

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