Combination therapy for treating protein deficiency disorders

Abstract

This application provides methods of improving protein replacement therapy by combining protein replacement therapy with active site-specific chaperones (ASSC) to increase the stability and efficiency of the protein being administered. The application further provides stable compositions comprising the purified protein and an ASSC, and methods of treatment by administering the compositions.

1 . A method of extending the half-life and prolonging the activity in vivo of a purified protein in an individual who has been administered the protein in a pharmaceutically acceptable carrier, which method comprises contacting the protein with an effective amount of an active site-specific chaperone in a pharmaceutically acceptable carrier.  
   
   
       2 . The method of  claim 1 , wherein the protein is co-administered with the active site-specific chaperone.  
   
   
       3 . The method of  claim 1 , wherein the protein is an enzyme and the active site-specific chaperone is a reversible competitive inhibitor of the enzyme.  
   
   
       4 . The method of  claim 3 , wherein the enzyme is associated with a lysosomal storage disorder.  
   
   
       5 . The method of  claim 4 , wherein the enzyme is α-galactosidase A.  
   
   
       6 . The method of  claim 4 , wherein the enzyme is β-glucocerebrosidase.  
   
   
       7 . The method of  claim 5 , wherein the reversible competitive inhibitor is a compound of the following formula:  
     
       
         
         
             
             
         
       
       wherein R 0  represents H or a C 1 -C 12  alkyl chain;  
       R 1  and R 1 ′ independently represent H, OH, a 1-4 carbon alkyl, alkoxy or hydroxyalkyl group;  
       R 2  and R 2 ′ independently represent H, OH or a C 1 -C 12  alkyl group  
       R 4  and R 4 ′ independently represent H or OH; and  
       R 7  represents H or OH.  
     
   
   
       8 . The method of  claim 5 , wherein the reversible competitive inhibitor is a compound selected from the group consisting of 1-deoxygalactonojirimycin, α-allo-homonojirimycin, α-galacto-homonojirimycin, α-1-C-butyl-deoxynojirimycin, calystegine A 3 , calystegine B 2 , N-methyl-calystegine A 3 , and N-methyl-calystegine B 2 .  
   
   
       9 . The method of  claim 8 , wherein the reversible competitive inhibitor is 1-deoxygalactonojirimycin.  
   
   
       10 . The method of  claim 6  wherein the reversible competitive inhibitor is a compound of the following formula:  
     
       
         
         
             
             
         
       
       wherein R 0  represents H or a C 1 -C 12  alkyl chain;  
       R 0 ′ represents H, a straight chain or branched saturated carbon chain containing 1-12 carbon atoms, optionally substituted with a phenyl, hydroxyl or cyclohexyl group;  
       R 1  and R 1 ′ independently represent H, OH, a 1-4 carbon alkyl, alkoxy or hydroxyalkyl group; and  
       R 2  and R 2 ′ independently represent H, OH or a C 1 -C 12  alkyl group.  
     
   
   
       11 . The method of  claim 6 , wherein the reversible competitive inhibitor is a compound selected from the group consisting of isofagomine, N-dodecyl-isofagomine, N-nonyl-isofagomine, N-dodecyl-deoxynojirimycin, calystegine A 3 , calystegine B 2 , calystegine B 3  and calystegine C 1 .  
   
   
       12 . The method of  claim 11 , wherein the reversible competitive inhibitor is isofagomine.  
   
   
       13 . The method of  claim 11 , wherein the reversible competitive inhibitor is N-dodecyl-isofagomine.  
   
   
       14 . A method for improving treatment of an individual who has a disorder characterized by a protein deficiency and who is being administered a purified replacement protein, comprising co-administering to the individual an effective amount of an active site-specific chaperone for the replacement protein.  
   
   
       15 . The method of  claim 14 , wherein the protein is an enzyme.  
   
   
       16 . The method of  claim 15 , wherein the disorder is Fabry disease and the replacement protein is α-galactosidase A, and the active site-specific chaperone is selected from the group consisting of 1-deoxygalactonojirimycin, α-allo-homonojirimycin, α-galacto-homonojirimycin, α-1-C-butyl-deoxynojirimycin, calystegine A 3 , calystegine B 2 , N-methyl-calystegine A 3 , and N-methyl-calystegine B 2 .  
   
   
       17 . The method of  claim 16  wherein the active site-specific chaperone is 1-deoxygalactonojirimycin.  
   
   
       18 . The method of  claim 15 , wherein the disorder is Gaucher disease and the replacement protein is β-glucocerebrosidase and the active site-specific chaperone is selected from the group consisting of isofagomine, N-dodecyl-isofagomine, N-nonyl-isofagomine, N-dodecyl-deoxynojirimycin, calystegine A 3 , calystegine B 2 , calystegine B 3  and calystegine C 1 .  
   
   
       19 . The method of  claim 10  wherein the active site-specific chaperone is isofagomine.  
   
   
       20 . The method of  claim 15 , wherein the disorder is Pompe disease and the replacement protein is α-glucosidase, and the active site-specific chaperone is 1-deoxynojirimycin.