Use of neuregulin-4 for treatment of inflammatory bowel disease and necrotizing enterocolitis

Abstract

The invention provides methods, pharmaceutical compositions and kits for treating, inhibiting and/or reducing the severity of inflammatory bowel disease and necrotizing enterocolitis in a subject in need thereof by administering an effective amount of a composition comprising an activator of ErbB4.

1 - 22 . (canceled) 
     
     
         23 . A method for screening for an activator of ErbB4 comprising:
 (i) contacting the ErbB4 in a ErbB4 positive cells with a molecule of interest, and   (ii) determining whether the contact results in increased phosphorylation of ErbB4, an increase in phosphorylation of ErbB4 being indicative that the molecule of interest is an activator of ErbB4.   
     
     
         24 . The method of  claim 23 , wherein the ErbB4 activator is selected from the group consisting of a small molecule, a polypeptide, a peptide, an antibody or a fragment thereof and a nucleic acid molecule. 
     
     
         25 . The method of  claim 23 , wherein the activator does not phosphorylate ErbB1 (EGFR), ErbB2, and ErbB3. 
     
     
         26 . The method of  claim 23 , wherein determining phosphorylation comprises phospho-specific immunoassay of ErbB4. 
     
     
         27 . The method of  claim 23 , wherein the ErbB4 positive cell is a colonic epithelial cell or a paneth cell. 
     
     
         28 . The method of  claim 23 , wherein the increase in phosphorylation by the molecule of interest is at least the same as the level of phosphorylation of ErbB4 in the presence of Neuregulin-4. 
     
     
         29 . A screening method according to  claim 23 , which comprises separately contacting each of a plurality of samples to be tested. 
     
     
         30 . The screening method of  claim 29 , wherein the plurality of samples comprises more than about 10 4  samples. 
     
     
         31 . The screening method of  claim 29 , wherein the plurality of samples comprises more than about 5×10 4  samples. 
     
     
         32 . A method for treating, inhibiting or reducing the severity of a disease in a subject in need thereof comprising:
 providing a composition comprising an activator of ErbB4; and   administering a therapeutically effective amount of the composition to the subject so as to treat the disease,   wherein the activator of ErbB4 activates ErbB4 and does not activate ErbB1, ErbB2 and ErbB3.   
     
     
         33 . The method of  claim 32 , wherein the disease is any one or more of inflammatory bowel disease, inflammation-associated death of small intestinal and colonic epithelial cells, necrotizing enterocolitis, or combination thereof. 
     
     
         34 . The method of  claim 32 , wherein the ErbB4 activator is Neuregulin-4 or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         35 . A pharmaceutical composition comprising an activator of ErbB4 and a pharmaceutically acceptable carrier. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the ErbB4 activator is Neuregulin-4 or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein Neuregulin-4 is administered orally. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the composition is administered by gavage. 
     
     
         39 . A kit for the treatment of inflammatory bowel disease, inhibition of inflammatory bowel disease, treatment of necrotizing enterocolitis and/or inhibition of necrotizing enterocolitis in a subject in need thereof, comprising:
 (i) a composition comprising an ErbB4 activator; and   (ii) instructions for use of the composition for the treatment of inflammatory bowel disease, inhibition of inflammatory bowel disease, treatment of necrotizing enterocolitis and/or inhibition of necrotizing enterocolitis.   
     
     
         40 . The kit of  claim 39 , wherein the ErbB4 activator is Neuregulin-4 or a pharmaceutical equivalent, analog, derivative or a salt thereof. 
     
     
         41 . The kit of  claim 40 , wherein the composition is administered orally by gavage.