Inhibitors of neuroligin 4 - neurexin 1-beta protein-protein interaction for treatment of liver disorders

Abstract

Provided is a method for treating, attenuating and/or preventing progression of a liver disorder in a subject, the method including administering a therapeutically effective amount of an agent capable of interfering with, inhibiting and/or preventing neuroligin 4 (NLGn4)-Neurexin 1-beta (Nrx1b) protein-protein interaction. Also provided are compositions including the agent.

1 .- 21 . (canceled) 
     
     
         22 . A composition comprising a therapeutically effective amount of an agent capable of interfering with, inhibiting and/or preventing neuroligin 4 (NLGn4)-Neurexin 1β (Nrx1b) protein-protein interaction and a pharmaceutically acceptable carrier wherein the therapeutic agent comprises an anti-NLGn4 antibody, or a fragment, derivative or analog thereof, comprising at least the antigen binding portion thereof. 
     
     
         23 . The composition of  claim 22 , wherein the anti-NLGn4 antibody is capable of binding specifically to amino acids 359-364 of the human NLGN4 protein. 
     
     
         24 . The composition of  claim 22 , wherein the anti-NLGn4 antibody is capable of binding to an epitope within a sequence selected from the group of: residues 261-270 of the human NLGn4, as set forth in SEQ ID NO: 3 (SLLTLSHYSE); residues 265-275, as set forth in SEQ ID NO: 5 (LSHYSEGLFQK), of the human NLGn4; and residues 461-470 of the human NLGn4, as set forth in SEQ ID NO: 4 (AQYGSPTYFY). 
     
     
         25 . A method of treating, attenuating and/or preventing progression of a liver disorder, comprising administering a therapeutically effective amount of an agent capable of interfering with, inhibiting and/or preventing neuroligin 4 (NLGn4)-Neurexin 1β (Nrx1b) protein-protein interaction and a pharmaceutically acceptable carrier, thereby treating, attenuating and/or preventing progression of a liver disorder. 
     
     
         26 . The method of  claim 25 , wherein the agent comprises recombinant soluble NLGn4 (rsNLGn4); wherein the rsNLGn4 comprises the extracellular domain of NLGn4 or a fragment, derivative or analog thereof. 
     
     
         27 . The method of  claim 26 , wherein the extracellular domain of NLGn4 consists of SEQ ID NO: 7; or wherein the rsNLGn4 consists of SEQ ID NO: 7, or a fragment, derivative or analog thereof; or wherein the rsNLGn4 competes with endogenous NLGn4 for binding to Nrx1b; or wherein the rsNLGn4 is devoid of the intracellular domain and/or the transmembrane domain of NLGn4. 
     
     
         28 . The method of  claim 25 , wherein the agent comprises recombinant soluble Nrx1b (rsNrx1b); wherein the rsNrx1b comprises the extracellular domain of Nrx1b or a fragment, derivative or analog thereof capable of binding the NLGn4. 
     
     
         29 . The method of  claim 28 , wherein the extracellular domain of Nrx1b consists of SEQ ID NO: 10; wherein the rsNrx1b consists of SEQ ID NO: 10, or a fragment, derivative or analog thereof; wherein the rsNrx1b competes with endogenous Nrx1b for binding to NLGn4; or wherein the rsNrx1b is devoid of the intracellular domain and/or the transmembrane domain of Nrx1b. 
     
     
         30 . The method of  claim 25 , wherein NLGn4 is encoded by the sequence set forth in SEQ ID NO: 1. 
     
     
         31 . The method of  claim 25 , wherein Nrx1b is encoded by the sequence set forth in SEQ ID NO: 6. 
     
     
         32 . The method of  claim 25 , the agent comprises a fusion protein comprising the Fc portion of an immunoglobulin molecule and SEQ ID NO: 7 or a fragment thereof. 
     
     
         33 . The method of  claim 25 , wherein the agent comprises a fusion protein comprising the Fc portion of an immunoglobulin molecule and SEQ ID NO: 10 or a fragment thereof. 
     
     
         34 . The method of  claim 25 , wherein the therapeutic agent comprises an anti-NLGn4 antibody, or a fragment, derivative or analog thereof, comprising at least the antigen-binding portion thereof; wherein the anti-NLGn4 antibody is capable of binding specifically to an interaction domain of human NLGn4. 
     
     
         35 . The method of  claim 34 , wherein the anti-NLGn4 antibody is capable of binding specifically to amino acids 359-364 of the human NLGN4 protein. 
     
     
         36 . The method of  claim 34 , wherein the anti-NLGn4 antibody is capable of binding to an epitope within a sequence selected from the group of: residues 261-270 of the human NLGn4, as set forth in SEQ ID NO: 3 (SLLTLSHYSE); residues 265-275, as set forth in SEQ ID NO: 5 (LSHYSEGLFQK), of the human NLGn4; and residues 461-470 of the human NLGn4, as set forth in SEQ ID NO: 4 (AQYGSPTYFY). 
     
     
         37 . The method of  claim 25 , wherein the liver disorder is selected from the group consisting of: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis, liver adenoma, insulin hypersensitivity, liver cancer and any combination thereof. 
     
     
         38 . The method of  claim 37 , wherein the liver disorder is NAFLD. 
     
     
         39 . The composition of  claim 37 , wherein the liver disorder is hepatocellular carcinoma.