Method of treatment of hemorrhagic disease using a factor VIIa/tissue factor inhibitor
View Patent ↗The present invention provides methods of treating hemorrhagic fevers where selective inhibitors of fVIIa/TF are used as a treatment for hemorrhagic fevers and have therapeutic effects which include ameliorating and/or preventing coagulopathy and inflammatory responses. These inhibitors include certain proteins which are part of a family termed Nematode-Extracted Anticoagulant Proteins (“NAPs”). Other inhibitors include Tissue Factor Pathway Inhibitor (“TFPI”) and TFPI analogs.
1. A method of treating a mammal having a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“NAP”) having Factor VIIa/tissue factor inhibitory activity (“fVIIa/TF”), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence: Cys-A1-Cys-A2-Cys-A3-Cys-A4-Cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-Cys-A10, wherein
(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;
(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;
(c) A3 is an amino acid sequence of 3 amino acid residues;
(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;
(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;
(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;
(g) A7 is an amino acid;
(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;
(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and
(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.
2. A method according to claim 1 wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.
3. A method according to claim 2 wherein said virus is from the family Filoviridae.
4. A method according to claim 3 wherein said NAP is AcaNAPc2 (SEQ ID NO:3) and said virus is Marburg virus.
5. A method according to claim 3 wherein said NAP is AcaNAPc2/proline (SEQ ID NO: 4) and said virus is Marburg virus.
6. A method of treating a coagulopathy in a mammal with a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“NAP”) having Factor VIIa/tissue factor inhibitory activity (“fVIIa/TF”), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence: Cys-A1-Cys-A2-Cys-A3-Cys-A4-Cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-Cys-A10, wherein
(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;
(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;
(c) A3 is an amino acid sequence of 3 amino acid residues;
(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;
(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;
(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;
(g) A7 is an amino acid;
(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;
(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and
(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.
7. A method according to claim 6 wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.
8. A method according to claim 7 wherein said virus is from the family Filoviridae.
9. A method according to claim 8 wherein said NAP is AcaNAPc2 (SEQ ID NO:3) and said virus is Marburg virus.
10. A method according to claim 8 wherein said NAP is AcaNAPc2/proline (SEQ ID NO:4) and said virus is Marburg virus.
11. A method of treating an inflammatory response in a mammal with a viral hemorrhagic fever which comprises administering to said mammal an effective amount of a Nematode-Extracted Anticoagulant Protein (“NAP”) having Factor VIIa/tissue factor inhibitory activity (“fVIIa/TF”), wherein said NAP comprises one or more NAP domains, wherein each NAP domain includes the sequence: Cys-A1-Cys-A2-Cys-A3-Cys-A4-cys-A5-Cys-A6-Cys-A7-Cys-A8-Cys-A9-cys-A10, wherein
(a) A1 is an amino acid sequence of 7 to 8 amino acid residues;
(b) A2 is an amino acid sequence of 3 to 5 amino acid residues;
(c) A3 is an amino acid sequence of 3 amino acid residues;
(d) A4 is an amino acid sequence of 6 to 19 amino acid residues;
(e) A5 is an amino acid sequence of 3 to 4 amino acid residues;
(f) A6 is an amino acid sequence of 3 to 5 amino acid residues;
(g) A7 is an amino acid;
(h) A8 is an amino acid sequence of 11 to 12 amino acid residues;
(i) A9 is an amino acid sequence of 5 to 7 amino acid residues; and
(j) A10 is an amino acid sequence of 5 to 25 amino acid residues.
12. A method according to claim 11 , wherein said virus is selected from the group consisting of Filoviridae, Arenaviridae, Bunyaviridae and Flaviridae.
13. A method according to claim 12 wherein said virus is from the family Filoviridae.
14. A method according to claim 13 wherein said NAP is AcaNAPc2 (SEQ ID NO:3) and said virus is Marburg virus.
15. A method according to claim 13 wherein said NAP is AcaNAPc2/proline (SEQ ID NO:4) and said virus is Marburg virus.