Methods, Compounds, and Compositions For Treatment and Prophylaxis in the Respiratory Tract

Abstract

The present invention provides a method of reducing the quanitity of mucus in the respiratory tract of a subject with elevated levels of mucus in said respiratory tract. The method includes administering to the subject a compound or composition containing a therapeutically effective amount of a fusion protein comprising a sialidase or an active portion thereof and an anchoring domain. The therapeutically effective amount comprises an amount of the fusion protein that results in a reduction of the quanitity of mucus in the respiratory tract after administration of the compound or composition when compared to the quantity of mucus present prior to administration of the compound or composition.

1 . A method of reducing the quantity or level of mucus or preventing an increase in the quantity or level of mucus in a respiratory tract of a subject, the method comprising:
 administering to the subject a compound or composition comprising a therapeutically effective amount of a fusion protein, wherein   the fusion protein comprises at least one catalytic domain of a sialidase, wherein the catalytic domain of the sialidase comprises the sequence of amino acids extending from amino acid 274 to amino acid 666 of SEQ ID NO:12, inclusive, and at least one anchoring domain, wherein the anchoring domain is a glycosaminoglycan (GAG) binding domain of human amphiregulin comprising the amino acid sequence of SEQ ID NO:7; and   the therapeutically effective amount comprises an amount of the fusion protein that results in a reduction of the quantity of mucus in the respiratory tract after administration of the compound or composition when compared to the quantity of mucus present prior to administration of the compound or composition.   
     
     
         2 . The method of  claim 1 , wherein the composition further comprises one or more additional compounds. 
     
     
         3 . The method of  claim 2 , wherein the one or more additional compounds comprises MgSO 4  or an analog thereof 
     
     
         4 . The method of  claim 2 , wherein the one or more additional compounds comprises CaCl 2  or an analog thereof. 
     
     
         5 . The method of  claim 2 , wherein the one or more additional compounds comprises Histidine or an analog thereof 
     
     
         6 . The method of  claim 2 , wherein the one or more additional compounds comprises Histidine-HCl or an analog thereof. 
     
     
         7 . The method of  claim 2 , wherein the one or more additional compounds comprises Trehalose or an analog thereof 
     
     
         8 . The method of  claim 2 , wherein the one or more additional compounds comprises MgSO 4 , CaCl 2 , Histidine, Histine-HCl and Trehalose. 
     
     
         9 . The method of  claim 1 , wherein the compound or composition is formulated as a spray. 
     
     
         10 . The method of  claim 1 , wherein the compound or composition is formulated as an inhalant. 
     
     
         11 . The method of  claim 1 , wherein the compound or composition is formulated as a solution for injection. 
     
     
         12 . The method of  claim 1 , wherein the compound or composition is formulated as a cream, salve, gel, or ointment. 
     
     
         13 . The method of  claim 1 , wherein the compound or composition is formulated as a pill, tablet, lozenge, suspension, or solution that can be administered orally. 
     
     
         14 . The method of  claim 1 , wherein said administration is by use of a nasal spray. 
     
     
         15 . The method of  claim 1 , wherein said administration is by use of an inhaler. 
     
     
         16 . The method of  claim 1 , wherein said administration is performed from once to four times a day. 
     
     
         17 .- 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the subject has one or more of the following conditions: chronic obstructive pulmonary disease (COPD), bronchitis, bronchiectasis, cystic fibrosis (CF), vasculitis, mucus plugging, Wegener's granulomatosis, pneumonia, tuberculosis, cancer involving the lungs or the respiratory tract, Kartagener syndrome, Young's syndrome, chronic sinopulmonary infection, alpha 1-antitrypsin deficiency, primary immunodeficiency, acquired immune deficiency syndrome, opportunistic infection, an infectious state, a post infectious state, common cold, exercise induced hypersecretion of mucus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, respiratory infection, respiratory obstruction, inhalation or aspiration of a toxic gas, pulmonary aspiration, or alcoholism. 
     
     
         23 . The method of  claim 1 , wherein the fusion protein has the sequence set forth in SEQ ID NO:21. 
     
     
         24 . A method of reducing the quantity of mucus in the respiratory tract of a subject with elevated levels of mucus in said respiratory tract, comprising:
 administering to the subject a compound or composition comprising a therapeutically effective amount of a peptide comprising a sialidase or an active portion thereof and, optionally, an anchoring domain, wherein   the therapeutically effective amount comprises an amount of the peptide that results in a reduction of the quanitity of mucus in the respiratory tract after administration of the compound or composition when compared to the quantity of mucus present prior to administration of the compound or composition.   
     
     
         25 .- 51 . (canceled) 
     
     
         52 . A method of limiting an increase in the quantity of mucus in the respiratory tract of a subject above a baseline level of mucus in said subject's respiratory tract, comprising:
 administering to the subject a compound or composition comprising a therapeutically effective amount of a fusion protein, wherein   the fusion protein comprises at least one catalytic domain of a sialidase, wherein the catalytic domain of the sialidase comprises the sequence of amino acids extending from amino acid 274 to amino acid 666 of SEQ ID NO:12, inclusive, and at least one anchoring domain, wherein the anchoring domain is a glycosaminoglycan (GAG) binding domain of human amphiregulin comprising the amino acid sequence of SEQ ID NO:7; and   the therapeutically effective amount comprises an amount of the fusion protein that limits an increase in the quantity of mucus in the respiratory tract of said subject above a baseline level after administration of the compound or composition.   
     
     
         53 .- 74 . (canceled) 
     
     
         75 . A method of limiting an increase in the quantity of mucus in the respiratory tract of a subject above a baseline level of mucus in said subject's respiratory tract, comprising:
 administering to the subject a compound or composition containing a therapeutically effective amount of a peptide comprising a sialidase or an active portion thereof and, optionally, an anchoring domain, wherein   the therapeutically effective amount comprises an amount of the peptide that limits an increase in the quanitity of mucus in the respiratory tract of said subject above a baseline level after administration of the compound or composition.   
     
     
         76 .- 112 . (canceled) 
     
     
         113 . A method, comprising:
 (a) administering a collection of compounds or compositions comprising sialidase(s) and/or catalytically active portion(s) thereof to an animal model of asthma;   (b) quantitating the level of mucus in the lung of the animal;   (c) comparing the level measured in (b) with the level of mucus in the lung of the animal prior to administering the collection of compounds or compositions; and   (d) identifying or selecting a compound or composition that reduces the level of mucus relative to the level of mucus in the absence of the compound or composition.   
     
     
         114 . A method, comprising:
 (a) administering a compound or composition comprising a sialidase and/or a catalytically active portion thereof to an animal model of asthma;   (b) quantitating the level of mucus in the lung of the animal;   (c) comparing the level measured in (b) with the level of mucus in the lung of the animal prior to administering the collection of compounds or compositions; and   (d) identifying whether the compound or composition reduces the level of mucus relative to the level of mucus in the absence of the compound or composition.   
     
     
         115 . A method of assessing whether a compound or composition comprising a sialidase and/or catalytically active portion thereof reduces the quantity of mucus in the respiratory tract of a subject, comprising:
 (a) contacting the muscarinic receptors of an animal subject with a compound or composition comprising a sialidase and/or a catalytically active portion thereof;   (b) administering a muscarinic receptor agonist to the subject;   (c) quantitating the airway resistance in the subject;   (d) comparing the airway resistance level measured in (c) with the airway resistance in the absence of contact with the compound or composition;   (e) identifying whether the compound or composition reduces the airway resistance relative to the airway resistance in the absence of contact with the compound or composition; and   (f) if the compound or composition reduces the airway resistance as determined in (e), assessing the compound or composition as one that reduces the quantity of mucus in the respiratory tract of the subject.