Mutated factor x polypeptides and uses thereof for the treatment of haemophilia

Abstract

The present invention relates to mutated factor (FX) polypeptides and uses thereof for the treatment of haemophilia. In particular, the present invention relates to a mutated factor X (FX) polypeptide wherein the heavy chain comprises at least one mutation selected from the group consisting of: the mutation which consists of the substitution of the glutamic acid residue (E) at position 215 by a glutamine residue (Q), an asparagine residue (N), a serine residue (S), an alanine residue (A), or a tyrosine residue (Y); the mutation which consists of the substitution of the glutamic acid residue (E) at position 216 by a glutamine residue (Q); and the mutation which consists of the substitution of the glutamic acid residue (E) at position 218 by a glutamine residue (Q);

1 - 9 . (canceled) 
     
     
         10 . A nucleic acid molecule which encodes for a mutated factor X (FX) polypeptide comprising the amino acid sequence of SEQ ID NO. 1 from the amino acid residue at position 235 to the amino acid residue at position 488 of SEQ ID NO: 1, wherein the heavy chain comprises at least one mutation selected from the group consisting of:
 a mutation comprising substitution of a glutamic acid residue (E) at position 255 by a glutamine residue (Q), a serine residue (S), an alanine residue (A), or a tyrosine residue (Y);   a mutation comprising substitution of a glutamic acid residue (E) at position 256 by a glutamine residue (Q); and   a mutation comprising substitution of a glutamic acid residue (E) at position 258 by a glutamine residue (Q).   
     
     
         11 . A vector which comprises the nucleic acid molecule of  claim 10 . 
     
     
         12 . A host cell which is transformed with the nucleic acid molecule of  claim 10  or a vector comprising the nucleic acid. 
     
     
         13 . (canceled) 
     
     
         14 . A method of treating haemophilia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a mutated factor X (FX) polypeptide comprising the amino acid sequence of SEQ ID NO. 1 from the amino acid residue at position 235 to the amino acid residue at position 488 of SEQ ID NO: 1, wherein the heavy chain comprises at least one mutation selected from the group consisting of:
 a mutation comprising substitution of a glutamic acid residue (E) at position 255 by a glutamine residue (Q), a serine residue (S), an alanine residue (A), or a tyrosine residue (Y);   a mutation comprising substitution of a glutamic acid residue (E) at position 256 by a glutamine residue (Q); and   a mutation comprising substitution of a glutamic acid residue (E) at position 258 by a glutamine residue (Q),   
       or a nucleic acid molecule encoding the mutated factor X (FX) polypeptide. 
     
     
         15 . A pharmaceutical composition which comprises the nucleic acid molecule of  claim 10 . 
     
     
         16 . The method of  claim 14 , wherein the nucleic acid molecule is present in a vector. 
     
     
         17 . The method of  claim 14 , wherein the nucleic acid molecule is not present in a vector. 
     
     
         18 . The nucleic acid of  claim 10  wherein the at least one mutation is a glutamine residue at position 255, 256, or 289. 
     
     
         19 . The nucleic acid of  claim 10  wherein the mutated FX polypeptide comprises an activation peptide and where a fibrinopeptide A is inserted between the activation peptide and the heavy chain. 
     
     
         20 . A pharmaceutical composition which comprises the nucleic acid molecule of  claim 18 . 
     
     
         21 . A pharmaceutical composition which comprises the nucleic acid molecule of  claim 19 .