TREATMENT OF MUCUS HYPERSECRETION
A polypeptide and a nucleic acid encoding the polypeptide are described. The polypeptide includes a cytotoxic toxin, a targeting domain that selectively binds to a target cell that is a mucus-secreting cell and a translocating domain that translocates the cytotoxic toxin into the target cell. A nucleic acid encoding the polypeptide is also described. Also described is a pharmaceutical composition for topical administration to a patient suffering from mucus hypersecretion which includes the polypeptide and a formulation component selected from the group consisting of an excipient, an adjuvant and a propellant. Methods of treating hypersecretion of mucus, chronic obstructive pulmonary disease (COPD) or asthma are also described. These methods include administering to a patient in need thereof a therapeutically effective amount of the polypeptide.
1 . A polypeptide comprising:
(a) a cytotoxic toxin;
(b) a targeting domain that selectively binds to a target cell that is a mucus-secreting cell; and
(c) a translocating domain that translocates the cytotoxic toxin into the target cell.
2 . A polypeptide according to claim 1 , wherein said mucus-secreting cell is selected from the group consisting of consisting of epithelial goblet cells; submucosal gland mucus-secreting; Clara cells; serous cells; sensory efferent C-fibres; non-adrenergic non-cholinergic neural system fibres; and combinations thereof.
3 . A polypeptide according to claim 1 , wherein the mucus-secreting cell is a serous cell.
4 . A polypeptide according to claim 1 , wherein said targeting moiety is selected from the group consisting of epidermal growth factor (EGF), vascular endothelial growth factor, platelet-derived growth factor, keratinocyte growth factor, hepatocyte growth factor, transforming growth factor alpha, transforming growth factor beta.
5 . A polypeptide according to claim 1 , wherein the cytotoxic toxin is selected from the group consisting of bacterial cytotoxins, fungal cytotoxins, plant cytotoxins and animal cytotoxins.
6 . A polypeptide according to claim 1 , wherein the cytotoxin is selected from the group consisting of Helicobacter pylori VacA cytotoxin; Pseudomonas aeruginosa Exotoxin A (ETA); Bordatella pertussis Pertussis toxin (PT); Bordatella pertussis Adenylate cyclase toxin (CYA); E. coli Heat labile enterotoxin (LT); E. coli Shiga-like toxin A chain; Vibrio cholerae Cholera toxin; Staphylococcus aureus EDIN; Clostridial botulinum Exoenzyme C3; Corynebacterium diphtheriae Diphtheria toxin; Shigella dysenteriae Shiga-toxin A chain; Aspergillus giganteus α-sarcin; Naja oxiana Cytotoxin C1; Naja oxiana Cytotoxin C2; Russells viper Cytotoxic phospholipase A2; Iris hollandica IRIP type I ribosome inactivating protein; Iris hollandica Iris agglutinin b; Iris hollandica Iris agglutinin r; Cinnamomum camphora Cinnamomin type II ribosome inactivating protein; Ricinus communis Ricin A-chain; Abrus precatorius Abrin A-chain; Phytolacca Americana Pokeweed antiviral protein; Viscum album Mistletoe lectin A subunit; Saponaria officinalis Saporin 6; Triticum vulgaris Wheatgerm agglutinin A chain; Diathus caryophyllus Dianthin 30; Gelonium multiflorum Gelonin; and Tricosanthes kirilowii Trichosanthin.
7 . A nucleic acid encoding a polypeptide according to claim 1 .
8 . A pharmaceutical composition for topical administration to a patient suffering from mucus hypersecretion, comprising:
(i) a polypeptide according to claim 1 ; and
(ii) a formulation component selected from the group consisting of an excipient, an adjuvant and a propellant.
9 . A method of treating hypersecretion of mucus, comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide according to claim 1 ; wherein following said administration, hypersecretion of mucus is reduced.
10 . A method of treating chronic obstructive pulmonary disease (COPD), comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide according to claim 1 ; wherein following said administration, hypersecretion of mucus is reduced.
11 . A method of treating asthma, comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide according to claim 1 ; wherein following said administration, hypersecretion of mucus is reduced.
12 . A polypeptide according to claim 1 , wherein the target cell is:
(i) a cell that secretes mucins and/or aqueous components of mucus; and/or
(ii) a neuronal cell that controls or directs mucus secretion.