Truncated VWF
The present invention relates to novel truncated fragments of von Willebrand factor (VWF) and the use of such fragments and nucleic acids encoding such fragments in the treatment of von Willebrand disease (VWD) and haemophilia.
1. A von Willebrand factor (vWF) polypeptide lacking amino acid residues 1875-2720 (D4-C6 domains) of the full length vWF protein (SEQ ID NO: 1) comprising:
(a) the amino acid sequence consisting of SEQ ID NO: 3, or
(b) an amino acid sequence with at least 70% sequence identity to SEQ ID NO: 3;
wherein the amino acid sequence retains the CK domain (SEQ ID NO: 31) or a CK domain (SEQ ID NO: 31) with up to ten amino acid deletions.
2. The polypeptide according to claim 1 , wherein the polypeptide is fused to a heterologous peptide, polypeptide or protein.
3. A method of treating von Willebrand disease or haemophilia in a subject comprising administering to the subject the polypeptide according to claim 1 .
4. A pharmaceutical composition comprising a polypeptide according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients.
5. A pharmaceutical composition according to claim 4 , further comprising at least one second therapeutically active agent.
6. A pharmaceutical composition according to claim 5 , wherein said therapeutically active agent is factor VIII, desmopressin, or an antifibrinolytic agent.
7. A pharmaceutical composition according to claim 6 wherein the antifibrinolytic agent is tranexamic acid.
8. A method for the treatment of von Willebrand disease or haemophilia comprising administering to a subject in need thereof a pharmaceutical composition according to claim 4 .
9. A nucleic acid comprising a nucleotide sequence encoding a polypeptide according to claim 1 .
10. The nucleic acid according to claim 9 , wherein the nucleotide sequence lacks nucleotides 5623 to 8160 of SEQ ID NO: 2.
11. The nucleic acid according to claim 9 , wherein the nucleotide sequence comprises or consists of the cDNA sequence of SEQ ID NO: 4, or a sequence having at least 70% identity thereto.
12. A method of treating von Willebrand disease or haemophilia in a subject comprising administering to the subject the nucleic acid according to claim 9 .
13. A pharmaceutical composition comprising a nucleic acid according to claim 9 and one or more pharmaceutically acceptable carriers, diluents or excipients.
14. A construct comprising the nucleic acid according to claim 9 .
15. A method for the treatment of von Willebrand disease or haemophilia comprising administering to a subject in need thereof a construct according to claim 14 .
16. A vector comprising a nucleic acid according to claim 9 .
17. A method for the treatment of von Willebrand disease or haemophilia comprising administering to a subject in need thereof a vector according to claim 16 .
18. A cell comprising a nucleic acid according to claim 9 .
19. A method for the treatment of von Willebrand disease or haemophilia comprising administering to a subject in need thereof a cell according to claim 18 .