Conductance of improperly folded proteins through the secretory pathway and related methods for treating disease

Abstract

This invention provides the methodology and agents for treating any disease or clinical condition which is at least partly the result of endoplasmic reticulum-associated retention of proteins. Thus, the methods and agents of the present invention provide for the release of normally retained proteins from the endoplasmic reticulum. The present invention is particularly useful for treating any disease or clinical condition which is at least partly the result of endoplasmic reticulum-associated retention or degradation of mis-assembled or mis-folded proteins.

1 . A method of preventing, treating, or alleviating symptoms of any disease or clinical condition, which condition is at least partly the result of endoplasmic reticulum-associated retention or degradation of mis-assembled or mis-folded proteins, the method comprising steps of: 
 identifying an individual at risk of or suffering from a condition that is at least partly the result of endoplasmic reticulum-associated retention or degradation of mis-assembled or mis-folded proteins; and    administering a composition comprising curcumin, a curcumin related compound, or an analog or derivative of curcumin to the individual so that the disease or clinical condition is treated, prevented, or its symptoms relieved.    
     
     
         2 . The method of  claim 1 , wherein the condition is cystic fibrosis.  
     
     
         3 . The method of  claim 1 , wherein the condition is rhinosinusitis.  
     
     
         4 . The method of  claim 1 , wherein the condition is selected from the group consisting of: chronic obstructive pulmonary disease, paroxysmal nocturnal hemoglobinuria, familial hypercholesterolemia, Tay-Sachs disease, viral diseases, neoplastic diseases, hereditary myeloperoxidase deficiency, congenital insulin resistance, nephrogenic diabetes insipidus, hemochromatosis, Gitelman's Syndrome, and cystinuria.  
     
     
         5 . The method of  claim 1 , wherein the proteins are glycoproteins.  
     
     
         6 . The method of  claim 1 , wherein some or all of the proteins are misfolded or misassembled.  
     
     
         7 . The method of  claim 1 , wherein the agent is administered as an aerosol.  
     
     
         8 . The method of  claim 1 , wherein the agent is administered intranasally.  
     
     
         9 . The method of  claim 1 , wherein the composition comprises a curcumin related compound.  
     
     
         10 . The method of  claim 1 , wherein the composition comprises a 1,7-diaryl-1,6-heptadiene -3,5-dione.  
     
     
         11 . The method of  claim 1 , wherein the composition comprises a curcumin related compound, analog, or derivative having an OH group at the 4 position of each phenyl ring.  
     
     
         12 . The method of  claim 1 , wherein the composition comprises curcumin, a curcumin related compound, analog, or derivative synthesized in vitro.  
     
     
         13 . The method of  claim 1 , wherein the composition decreases or inhibits activity of the endoplasmic reticulum Ca 2+  ATPase.  
     
     
         14 . The method of  claim 1 , wherein the composition lowers the concentration of Ca 2+  within the ER.  
     
     
         15 . The method of  claim 1 , wherein the composition causes release of proteins from the endoplasmic reticulum.  
     
     
         16 . The method of  claim 1 , wherein the composition causes release of mutant CFTR from the endoplasmic reticulum.  
     
     
         17 . A method of releasing a mis-assembled or mis-folded protein from the endoplasmic reticulum of a cell comprising the step of administering the composition of  claim 1 , thereby lowering the concentration of Ca ++  in the endoplasmic reticulum.  
     
     
         18 . A method of increasing the permeability of the apical surfaces of airway epithelial cells to a chloride ion comprising the step of administering the composition of  claim 1 , thereby increasing the permeability of the apical surfaces of airway epithelial cells to a chloride ion.  
     
     
         19 . A composition comprising an siRNA targeted to a transcript encoding a molecule selected from the group consising of: UDP glucose:glycoprotein glycosyl transferase, calnexin or endoplasmic reticulum Ca ++  ATPase, or a chaperone involved in retention of a misfolded or misassembled protein in the endoplasmic reticulum.  
     
     
         20 . The composition of  claim 19 , wherein the the siRNA comprises a base-paired region approximately 19 nucleotides long.  
     
     
         21 . The composition of  claim 19 , wherein the siRNA comprises a single RNA strand with a self-complementary region.  
     
     
         22 . The composition of  claim 19 , the siRNA comprises two complementary RNA strands.  
     
     
         23 . The composition of  claim 19 , wherein the siRNA comprises a region that is precisely complementary with a region of the target transcript.  
     
     
         24 . A method of releasing a mis-assembled or mis-folded protein from the endoplasmic reticulum of a cell comprising the step of administering the composition of  claim 19 , thereby lowering the concentration of Ca ++  in the endoplasmic reticulum.  
     
     
         25 . A method of increasing the permeability of the apical surfaces of airway epithelial cells to a chloride ion comprising the step of administering the composition of  claim 19 , thereby increasing the permeability of the apical surfaces of airway epithelial cells to a chloride ion.  
     
     
         26 . The siRNA composition of  claim 19 , the composition comprising a vector that directs synthesis of siRNA.  
     
     
         27 . The vector of  claim 26 , wherein the vector is a vector suitable for gene therapy applications.  
     
     
         28 . A cell engineered or manipulated to contain an siRNA targeted to a transcript encoding a molecule selected from the group consising of: UDP glucose:glycoprotein glycosyl transferase, calnexin or endoplasmic reticulum Ca ++  ATPase, or a chaperone involved in retention of a misfolded or misassembled protein in the endoplasmic reticulum.  
     
     
         29 . A method of preventing, treating, or alleviating symptoms of any disease or clinical condition, which condition is at least partly the result of endoplasmic reticulum-associated retention or degradation of mis-assembled or mis-folded proteins, the method comprising steps of: 
 identifying an individual at risk of or suffering from a condition that is at least partly the result of endoplasmic reticulum-associated retention or degradation of mis-assembled or mis-folded proteins; and    administering the composition of  claim 19 , the vector of  claim 27 , or the cell of  claim 28 , to the individual.    
     
     
         30 . The method of  claim 29 , wherein the condition is cystic fibrosis.  
     
     
         31 . The method of  claim 29 , wherein the condition is selected from the group consisting of: rhinosinusitis, chronic obstructive pulmonary disease, paroxysmal nocturnal hemoglobinuria, familial hypercholesterolemia, Tay-Sachs disease, viral diseases, neoplastic diseases, hereditary myeloperoxidase deficiency, congenital insulin resistance, nephrogenic diabetes insipidus, hemochromatosis, Gitelman's Syndrome, and cystinuria.  
     
     
         32 . The method of  claim 29 , wherein the composition is administered as an aerosol.  
     
     
         33 . A composition comprising a nebulized or aerosolized formulation of curcumin, a curcumin related compound, or an analog or derivative of curcumin.  
     
     
         34 . The composition of  claim 33 , wherein the composition comprises a curcumin related compound.  
     
     
         35 . The composition of  claim 33 , wherein the composition comprises a 1,7-diaryl-1,6-heptadiene -3,5-dione.  
     
     
         36 . The composition of  claim 33 , wherein the composition comprises a curcumin related compound, analog, or derivative having an OH group at the 4 position of each phenyl ring.