Methods of Using Compositions Comprising Variants and Fusions of FGF19 Polypeptides for Treatment of Metabolic Disorders and Diseases

Abstract

The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21), and variants or fusions of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21) proteins and peptide sequences (and peptidomimetics), having one or more activities, such as glucose lowering activity, and methods for and uses in treatment of hyperglycemia and other disorders.

1 .- 74 . (canceled) 
     
     
         75 . A method of treating bile acid diarrhea (BAD) or progressive familial intrahepatic cholestasis (PFIC) in a subject, comprising administering to the subject an effective amount of a peptide, wherein the peptide comprises:
 a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO:121) or DASPH (SEQ ID NO:122); and   b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises
 (i) a first C-terminal region sequence comprising WGDPIRLRHLYTSG (amino acids 16 to 29 of SEQ ID NO:99 [FGF19]), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and 
 (ii) a second C-terminal region sequence comprising 
   
       
         
           
                 
               
                   PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYL 
                 
                     
                 
                   CMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPVSLSSAKQR 
                 
                     
                 
                   QLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFG 
                 
                     
                 
                   LVTGLEAVRSPSFEK (amino acid residues 30 to 194 of 
                 
                     
                 
                   SEQ ID NO: 99 [FGF19]). 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         76 . The method of  claim 75 , wherein the peptide comprises 
       
         
           
                 
               
                   (M69) 
                 
                   RDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAH 
                 
                     
                 
                   SLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIR 
                 
                     
                 
                   PDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPE 
                 
                     
                 
                   DLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK. 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         77 . The method of  claim 75 , wherein the peptide comprises 
       
         
           
                 
               
                   (M70) 
                 
                   MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA 
                 
                     
                 
                   HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI 
                 
                     
                 
                   RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEP 
                 
                     
                 
                   EDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK. 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         78 . The method of  claim 75 , wherein the peptide comprises 
       
         
           
                 
               
                   (M141) 
                 
                   DSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHS 
                 
                     
                 
                   LLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRP 
                 
                     
                 
                   DGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPED 
                 
                     
                 
                   LRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK. 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         79 . A method of treating bile acid diarrhea (BAD) or progressive familial intrahepatic cholestasis (PFIC), comprising administering to the subject a pharmaceutical composition comprising the peptide of  claim 75 , and a pharmaceutically acceptable carrier. 
     
     
         80 . A method of treating bile acid diarrhea (BAD) or progressive familial intrahepatic cholestasis (PFIC), comprising administering to the subject a pharmaceutical composition comprising the peptide of  claim 75 , a glucose lowering agent and a pharmaceutically acceptable carrier. 
     
     
         81 . A method of treating bile acid diarrhea (BAD) or progressive familial intrahepatic cholestasis (PFIC), comprising administering to the subject a nucleic acid molecule encoding the peptide of  claim 75 . 
     
     
         82 . The method of  claim 81 , wherein the nucleic acid molecule further comprises an expression control element in operable linkage that confers expression of the nucleic acid molecule encoding the peptide. 
     
     
         83 . A method of treating bile acid diarrhea (BAD) or progressive familial intrahepatic cholestasis (PFIC), comprising administering to the subject a vector comprising a nucleic acid molecule encoding the peptide of  claim 75 . 
     
     
         84 . The method of  claim 83 , wherein the vector comprises a viral vector. 
     
     
         85 . A peptide having an amino acid sequence comprising 
       
         
           
                 
               
                   (SEQ ID NO: 52) 
                 
                   RDSSPLLQWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL 
                 
                     
                 
                   LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPD 
                 
                     
                 
                   GYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDL 
                 
                     
                 
                   RGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK. 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         86 . A pharmaceutical composition, comprising the peptide of  claim 85 , and a pharmaceutically acceptable carrier. 
     
     
         87 . A transformed or host cell that expresses the peptide of  claim 85 . 
     
     
         88 . A nucleic acid molecule encoding a peptide having an amino acid sequence comprising 
       
         
           
                 
               
                   (SEQ ID NO: 52) 
                 
                   RDSSPLLQWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL 
                 
                     
                 
                   LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPD 
                 
                     
                 
                   GYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDL 
                 
                     
                 
                   RGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK.