Modified serpins for the treatment of bleeding disorders
This invention relates pro-coagulant serpin molecules engineered by modification of the P4, P2, P1 and/or P1′ residues within the reactive center loop (RCL) to display increased specificity for anticoagulant proteases. These modified serpin molecules may be useful in therapy, for example as pro-coagulants for the treatment of bleeding.
1. A serpin comprising the amino acid sequence of residues 25-418 of SEQ ID NO: 12.
2. A pharmaceutical composition comprising the serpin according to claim 1 and a pharmaceutically acceptable excipient.
3. A method of treatment of bleeding or promotion of hemostasis comprising administering the serpin according to claim 1 to an individual in need thereof.
4. A method according to claim 3 , wherein the individual has a bleeding disorder.
5. A method according to claim 4 , wherein the bleeding disorder is hemophilia.
6. A method according to claim 3 wherein the individual is a trauma patient.
7. A serpin comprising the amino acid sequence of residues 25-418 of SEQ ID NO: 12 with residue E25 substituted for S.
8. A pharmaceutical composition comprising the serpin according to claim 7 and a pharmaceutically acceptable excipient.
9. A method of treatment of bleeding or promotion of hemostasis comprising administering the serpin according to claim 7 to an individual in need thereof.
10. A method according to claim 9 , wherein the individual has a bleeding disorder.
11. A method according to claim 10 , wherein the bleeding disorder is hemophilia.
12. A method according to claim 9 wherein the individual is a trauma patient.
13. A serpin comprising the amino acid sequence of residues 25-418 of SEQ ID NO: 12 with residue C256 substituted for S.
14. A pharmaceutical composition comprising the serpin according to claim 13 and a pharmaceutically acceptable excipient.
15. A method of treatment of bleeding or promotion of hemostasis comprising administering the serpin according to claim 13 to an individual in need thereof.
16. A method according to claim 15 , wherein the individual has a bleeding disorder.
17. A method according to claim 16 , wherein the bleeding disorder is hemophilia.
18. A method according to claim 15 wherein the individual is a trauma patient.
19. A serpin comprising the amino acid sequence of residues 25-418 of SEQ ID NO: 12 with residue C256 substituted for S and residue E25 substituted for S.
20. A pharmaceutical composition comprising the serpin according to claim 19 and a pharmaceutically acceptable excipient.
21. A method of treatment of bleeding or promotion of hemostasis comprising administering the serpin according to claim 20 to an individual in need thereof.
22. A method according to claim 21 , wherein the individual has a bleeding disorder.
23. A method according to claim 22 , wherein the bleeding disorder is hemophilia.
24. A method according to claim 21 wherein the individual is a trauma patient.