FGF-9 Variants and Methods of Use Thereof

Abstract

A method of treating an individual (i) having abnormal bone; or (ii) afflicted with a disease or disorder related to normal or abnormal FGF receptors or a skeletal disorder; or (iii) having dysplasic bone. The method includes administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a fibroblast growth factor 9 (FGF-9) variant comprising at least one amino acid substitution in the beta 8-beta 9 loop, wherein said FGF-9 variant incorporates one of the amino acid sequences set forth in SEQ ID NO: 11, 13, 14, 15, 16 or 17.

What is claimed is: 
     
         1 . A method of treating an individual that (i) has abnormal bone; or (ii) is afflicted with a disease or disorder related to normal or abnormal FGF receptors or a skeletal disorder; or (iii) has dysplasic bone, which method comprises administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a fibroblast growth factor 9 (FGF-9) variant comprising at least one amino acid substitution in the beta 8-beta 9 loop, wherein the FGF-9 variant is an antagonist; wherein the FGF-9 variant reduces proliferation of target cells having at least one FGF receptor subtype compared to the corresponding wild type FGF-9; wherein the FGF-9 variant has enhanced receptor specificity for the at least one receptor subtype compared to the corresponding wild type FGF-9 by decreasing the biological activity mediated by at least one receptor subtype while retaining the activity mediated through another receptor subtype; wherein the FGF-9 variant further comprises a truncation at the N-terminus, or at the C-terminus, or at both termini; and wherein the FGF-9 variant comprises an amino acid sequence selected from one of the sequences forth in SEQ ID NO: 11, 13, 14, 15, 16 and 17. 
     
     
         2 . The method according to  claim 1 , for treating an individual having an abnormal bone or a dysplasic bone. 
     
     
         3 . The method according to  claim 1 , for treating an individual having an abnormal bone by increasing the size of a bone growth plate in said abnormal bone. 
     
     
         4 . The method according to  claim 1 , for treating an individual having a dysplasic bone. 
     
     
         5 . The method according to  claim 1 , wherein the FGF-9 variant comprises the amino acid sequence set forth in SEQ ID NO: 11 or 13. 
     
     
         6 . The method according to  claim 1 , wherein the FGF-9 variant comprises the amino acid sequence set forth in SEQ ID NOS: 14 or 15. 
     
     
         7 . The method according to  claim 1 , wherein the FGF-9 variant is linked to a bioactive agent. 
     
     
         8 . The method according to  claim 7 , wherein the bioactive agent is CNP(1-22). 
     
     
         9 . The method according to  claim 8 , wherein the FGF-9 variant comprises the amino acid sequence set forth in SEQ ID NOS: 16 or 17. 
     
     
         10 . The method according to  claim 1 , wherein the method is used for elongating said abnormal bone. 
     
     
         11 . The method according to  claim 1 , wherein the FGF-9 variant is an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 13, 14, 15, 16 and 17.