Compositions and methods for the treatment of sjörgren's syndrome

Abstract

This invention provides a method of inducing a lacrimal acinar cell in a tissue to degrade a secretory vesicle and its content protein or proteins from the trans-Golgi network (TGN) by contacting the cells with an effective amount of an agent that induces autophagy. Also provided is a method for treating a mammal suffering from defective trans-Golgi network-secretory vesicle (TGN-SV) sorting by administering to the mammal an effective amount of an agent that induces autophagy in the tissue having the defective TGN-SV.

1 . A method of inducing a lacrimal acinar cell in a tissue to degrade a secretory vesicle and its content protein or proteins from the trans-Golgi network (TGN) comprising contacting the cell with an effective amount of one or more of verapamil, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto that induces autophagy, thereby inducing the cell to degrade the secretary vesicle and its content protein or proteins from the trans-Golgi network, with the proviso that the cell is not associated with Graft versus Host Disease. 
     
     
         2 . A method of inhibiting the missorting of a secretory protein or proteins by inducing a lacrimal acinar cell in a tissue to degrade a secretory vesicle and its content protein or proteins from the trans-Golgi network (TGN) comprising contacting the cell with an effective amount of one or more of verapamil, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto that induces autophagy, thereby inhibiting the missorting of secretory proteins from the trans-Golgi network, with the proviso that the cell is not associated with Graft versus Host Disease. 
     
     
         3 . The method of  claim 1  or  2 , wherein the contacting is in vitro or in vivo. 
     
     
         4 . A method of treating a mammal suffering from one or more conditions selected from defective degradation of a secretory vesicle in a lacrimal cell and its content proteins or proteins, an inflammatory autoimmune lacrimal gland disease, or primary or secondary Sjögren's Syndrome (SjS) comprising administering to the mammal an effective amount of one or more of verapamil, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8 or a polypeptide having at elast 90% sequence identity thereto, thereby treating the mammal. 
     
     
         5 . A method for treating a mammal suffering from defective trans-Golgi network-secretory vesicle (TGN-SV) sorting, comprising administering to the mammal an effective amount of one or more of verapamil, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8, thereby treating the mammal, with the proviso that the mammal is not suffering from Graft versus Host Disease. 
     
     
         6 . The method of  claim 5 , wherein the defective TGN-SV sorting is the result of the mammal suffering from inflammatory autoimmune lacrimal gland disease, or Sjögren's Syndrome (SjS). 
     
     
         7 . The method of any one of  claims 4 - 6 , wherein the mammal is a murine, a simian, a leporid, or a human patient. 
     
     
         8 . The method of any of  claims 4 - 6 , wherein the treatment comprises reducing the symptoms of dry eye and/or tear loss. 
     
     
         9 . The method of any of  claims 4 - 6 , wherein the agent is administered locally or systemically. 
     
     
         10 . (canceled) 
     
     
         11 . A method of inducing a lacrimal acinar cell in a tissue to degrade a secretory vesicle and its content protein or proteins from the trans-Golgi network (TGN) consisting essentially of contacting the cell with an effective amount of an agent of the group of rapamycin, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto, thereby inducting the cell to degrade the secretary vesicle and its content protein or proteins from the trans-Golgi network. 
     
     
         12 . A method of inhibiting the missorting of a secretory protein or proteins by inducing a lacrimal acinar cell in a tissue to degrade a secretory vesicle and its content protein or proteins from the trans-Golgi network (TGN) consisting essentially of contacting the cell with an effective amount of an agent of the group of rapamycin, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto; an amino acid sequence comprising on or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto, thereby inhibiting the missorting of a secretory proteins from the trans-Golgi network. 
     
     
         13 . The method of  claim 11  or  12 , wherein the contacting is in vitro or in vivo. 
     
     
         14 . A method of treating a mammal suffering from one or more condition selected from defective degradation of a secretory vesicle in a lacrimal cell and its content proteins or proteins, an inflammatory autoimmune lacrimal gland disease, or primary or secondary Sjögren's Syndrome (SjS) consisting essentially of administering to the mammal an effective amount of one or more of rapamycin, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an amino acid sequence comprising one or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto that induces autophagy, thereby treating the mammal. 
     
     
         15 . A method for treating a mammal suffering from defective trans-Golgi network-secretory vesicle (TGN-SV) sorting, consisting essentially of administering to the mammal an effective amount of one or more of rapamycin, clonidine, a region of the death effector domain (DED) of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an alpha-helix region of a DED of vFLIP or cFLIP or a polypeptide having at least 90% sequence identity thereto that induces autophagy; an amino acid sequence comprising on or more of SEQ ID NOs. 1 to 8 or a polypeptide having at least 90% sequence identity thereto that induces autophagy, thereby treating the mammal. 
     
     
         16 . The method of  claim 15 , wherein the defective TGN-SV sorting is the result of the mammal suffering from inflammatory autoimmune lacrimal gland disease or Sjögren's Syndrome (SjS). 
     
     
         17 . The method of any one of  claims 14 - 16 , wherein the mammal is a murine, a simian, a leporid, or a human patient. 
     
     
         18 . The method of any of  claims 14 - 16 , wherein the treatment comprises reducing the symptoms of dry eye and/or tear loss. 
     
     
         19 . The method of any of  claims 14 - 16 , wherein the agent is administered locally or systemically.