Methods and compounds for the treatment of mucus hypersecretion

Abstract

A method of treating mucus hypersecretion, the causative factor in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD, comprises administering a compound that inhibits exocytosis in mucus secreting cells or neurones that control or direct mucus secretion. Also described is a compound, for use in the treatment of hypersecretion of mucus, which inhibits mucus secretion by inhibiting mucus secretion by mucus secreting cells, and/or inhibiting neurotransmitter release from neuronal cells controlling or directing mucus secretion.

1 - 11 . (canceled) 
     
     
         12 . A single-chain fusion protein comprising:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain;   (b) a targeting domain comprising or consisting of a growth factor;   (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell; and   (d) a site for cleavage by a proteolytic enzyme.   
     
     
         13 . A fusion protein according to  claim 12 , wherein the growth factor is an epidermal growth factor (EGF). 
     
     
         14 . A fusion protein according to  claim 12 , wherein the cleavage site has been introduced into the fusion protein. 
     
     
         15 . A fusion protein according to  claim 12 , wherein the cleavage site is selected from the group consisting of: IEGR; DDDDK; EXXYXQSG; LEVLFQGP; LVPRGS; HY; and YH. 
     
     
         16 . A fusion protein according to  claim 12 , wherein said cleavage site is not present in a native clostridial neurotoxin. 
     
     
         17 . A fusion protein according to  claim 12 , wherein said cleavage site is located between the L-chain or L-chain fragment and the translocating domain. 
     
     
         18 . A fusion protein according to  claim 12 , wherein the cleavage site is cleavable by a proteolytic enzyme selected from the group consisting of: factor Xa; enterokinase; TEV protease; precission; thrombin; and genenase. 
     
     
         19 . A nucleic acid encoding a fusion protein according to  claim 12 . 
     
     
         20 . A pharmaceutical composition for topical administration to a patient suffering from mucus hypersecretion, comprising:
 (i) a polypeptide in an amount effective to inhibit mucus hypersecretion, wherein the polypeptide comprises:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain; 
 (b) a targeting domain comprising or consisting of a growth factor; and 
 (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell; and 
   (ii) a formulation component selected from the group consisting of an excipient, an adjuvant and a propellant.   
     
     
         21 . A method of treating hypersecretion of mucus, comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide comprising:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain;   (b) a targeting domain comprising or consisting of a growth factor; and   (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell;   wherein following said administration, hypersecretion of mucus is reduced.   
     
     
         22 . A method of treating chronic obstructive pulmonary disease (COPD), comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide comprising:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain;   (b) a targeting domain comprising or consisting of a growth factor; and   (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell;   wherein following said administration, hypersecretion of mucus is reduced.   
     
     
         23 . A method of treating asthma, comprising administering to a patient in need thereof, a therapeutically effective amount of a polypeptide comprising:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain;   (b) a targeting domain comprising or consisting of a growth factor; and   (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell;   wherein following said administration, hypersecretion of mucus is reduced.   
     
     
         24 . A method for activating a single-chain fusion protein, comprising:
 (i) providing a single-chain fusion protein comprising:
 (a) a light chain (L-chain) or L-chain fragment of a clostridial neurotoxin, which L-chain or L-chain fragment includes the active proteolytic enzyme domain of the L-chain; 
 (b) a targeting domain comprising or consisting of a growth factor; 
 (c) a translocating domain that translocates the L-chain or L-chain fragment into the target cell; and 
 (d) a site for cleavage by a proteolytic enzyme; 
   (ii) contacting said single-chain fusion protein with a proteolytic enzyme that cleaves said site for cleavage; and   (iii) cleaving said single-chain fusion protein at said site for cleavage, and thereby providing a di-chain polypeptide wherein (a) and (c) are linked together by a disulphide bond.   
     
     
         25 . A method according to  claim 24 , wherein the proteolytic enzyme is selected from the group consisting of: factor Xa; enterokinase; TEV protease; precission; thrombin; and genenase. 
     
     
         26 . A method according to  claim 24 , wherein the cleavage site is selected from the group consisting of: IEGR; DDDK; EXXYXQSG; LEVLFQGP; LVPRGS; HY; and YH.