Methods for modulating factor 12 expression
View Patent ↗Disclosed herein are methods for decreasing Factor 12 and treating or preventing thromboembolic conditions in an individual in need thereof. Examples of disease conditions that can be ameliorated with the administration of antisense compounds targeted to Factor 12 include thrombosis, embolism, and thromboembolism, such as, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and mesenteric thrombosis. Methods for inhibiting Factor 12 can also be used as a prophylactic treatment to prevent individuals at risk for thrombosis and embolism.
1. A method of treating an animal having a thromboembolic condition or at risk for developing a thromboembolic condition comprising administering to the animal a therapeutically effective amount of a compound comprising an oligonucleotide consisting of 12-25 linked nucleosides targeted to a Factor 12 nucleic acid, wherein the oligonucleotide has a nucleobase sequence that is at least 90% complementary to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 as measured over the entirety of the oligonucleotide, wherein said compound does not significantly increase bleeding risk in the animal.
2. The method of claim 1 , wherein the thromboembolic condition is any of deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, mesenteric thrombosis, or a combination thereof.
3. The method of claim 1 , wherein the animal is a human.
4. The method of claim 2 , wherein the administering inhibits thrombus and clot formation.
5. The method of claim 2 , wherein the administering prolongs aPTT.
6. The method of claim 2 , wherein the administering does not prolong PT.
7. The method of claim 2 , wherein the administering prolongs aPTT and does not prolong PT.
8. The method of claim 2 , wherein the administering decreases Platelet Factor 4 (PF-4).
9. The method of claim 2 , wherein the administering increases time for thrombus formation.
10. The method of claim 1 , wherein the oligonucleotide has a nucleobase sequence that is 100% complementary to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 as measured over the entirety of the oligonucleotide.
11. The method of claim 1 , wherein the oligonucleotide comprises at least one modified internucleoside linkage.
12. The method of claim 11 , wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
13. The method of claim 12 , wherein at least one nucleoside of the oligonucleotide comprises a modified sugar.
14. The method of claim 13 , wherein the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl modified sugar.
15. The method of claim 14 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge.
16. The method of claim 14 , wherein at least one nucleoside of the oligonucleotide comprises a modified nucleobase.
17. The method of claim 16 , wherein the modified nucleobase is a 5-methylcytosine.
18. The method of claim 1 , wherein the oligonucleotide comprises:
a gap segment consisting of linked deoxy nucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
19. The method of claim 18 , wherein the oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each cytosine in the oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage.
20. The method of claim 19 , wherein the oligonucleotide consists of 20 linked nucleosides.
21. The method of claim 1 , wherein said compound is a single-stranded oligonucleotide.