Mutated fibroblast growth factor (fgf) 1 and methods of use

Abstract

The present disclosure provides FGF1 mutant proteins, such as those having an N-terminal deletion, point mutation(s), or combinations thereof, which can reduce blood glucose in a mammal. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1c-binding protein, a β-Klotho-binding protein and a FGFR1c-binding protein, a C-terminal region from FGF19 or FGF21. In some examples, mutant FGF1 proteins have reduced mitogenic activity. Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. Methods of using the disclosed molecules to reduce blood glucose levels are also provided.

We claim: 
     
         1 . An isolated mutated mature fibroblast growth factor (FGF) 1 protein comprising:
 at least 90% sequence identity to the protein sequence of SEQ ID NO: 213, and comprising a C117V and K118V mutation.   
     
     
         2 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises at least 95% sequence identity to the protein sequence of SEQ ID NO: 213, and comprises a C117V and K118V mutation. 
     
     
         3 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises at least 96% sequence identity to the protein sequence of SEQ ID NO: 213, and comprises a C117V and K118V mutation. 
     
     
         4 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises at least 97% sequence identity to the protein sequence of SEQ ID NO: 213, and comprises a C117V and K118V mutation. 
     
     
         5 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises at least 98% sequence identity to the protein sequence of SEQ ID NO: 213, and comprises a C117V and K118V mutation. 
     
     
         6 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises at least 99% sequence identity to the protein sequence of SEQ ID NO: 213, and comprises a C117V and K118V mutation. 
     
     
         7 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein comprises the protein sequence of SEQ ID NO: 213. 
     
     
         8 . The isolated mutated mature FGF1 protein of  claim 1 , wherein the protein consists of the protein sequence of SEQ ID NO: 213. 
     
     
         9 . A method of reducing blood glucose in a mammal, comprising:
 administering to the subject a therapeutically effective amount of the isolated mutated mature FGF1 protein of  claim 1 , thereby reducing blood glucose in the mammal.   
     
     
         10 . The method of  claim 9 , wherein the administering is subcutaneous, intraperitoneal, intramuscular, or intravenous. 
     
     
         11 . The method of  claim 9 , wherein the amount of mutated mature FGF1 protein administered is at least 0.5 mg/kg. 
     
     
         12 . The method of  claim 9 , wherein the method further comprises administering an additional therapeutic compound. 
     
     
         13 . The method of  claim 12 , wherein the additional therapeutic compound is an alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor, meglitinide, sulfonylurea, or a peroxisome proliferator-activated receptor (PPAR)-gamma agonist. 
     
     
         14 . The method of  claim 13 , wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar. 
     
     
         15 . The method of  claim 14 , wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone. 
     
     
         16 . The method of  claim 9 , wherein the mammal is a human. 
     
     
         17 . The method of  claim 9 , wherein the mutated mature FGF1 protein has less mitogenic activity than a native mature FGF1 protein.