Modulation of prekallikrein (PKK) expression
Disclosed herein are antisense compounds and methods for decreasing PKK mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate PKK-associated diseases, disorders, and conditions.
1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 27427-27466 of SEQ ID NO: 10, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 10 as measured over the entirety of the modified oligonucleotide, wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
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.
2. The compound of claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.
3. The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
4. The compound of claim 3 , wherein the modified nucleobase is a 5-methylcytosine.
5. The compound of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
6. The compound of claim 5 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The compound of claim 1 , wherein each of the modified sugars have the same modification.
8. The compound of claim 1 , wherein at least one of the modified sugars has a different modification.
9. The compound of claim 1 , wherein at least one modified sugar is a bicyclic sugar.
10. The compound of claim 9 , wherein the bicyclic sugar is selected from among cEt, LNA, and ENA.
11. The compound of claim 1 , wherein at least one nucleoside comprising a modified sugar is a 2′-substituted nucleoside.
12. The compound of claim 11 , wherein the substituent at the 2′ position of the 2′-substituted nucleoside is selected from among: 2′-OCH 3 , 2′-F, and 2′-O-methoxyethyl.
13. The compound of claim 1 , wherein the modified oligonucleotide consists of 16, 17, 18, 19, or 20 linked nucleosides.
14. A compound consisting of a modified oligonucleotide according to the following formula: Tes Ges mCes Aes Aes Gds Tds mCds Tds mCds Tds Tds Gds Gds mCds Aes Aes Aes mCes Ae, wherein,
A=an adenine,
mC=a 5-methylcytosine
G=a guanine,
T=a thymine,
e=a 2′-O-methoxyethyl modified nucleoside,
d=a 2′-deoxynucleoside, and
s=a phosphorothioate internucleoside linkage.
15. A composition comprising the modified oligonucleotide of claim 14 , and a pharmaceutically acceptable carrier or diluent.
16. A method comprising administering to an animal having or at risk for developing a PKK associated disease, disorder, or condition a therapeutically effective amount of the composition according to claim 15 .
17. The method of claim 16 , wherein the PKK associated disease, disorder, or condition is any of hereditary angioedema (HAE), edema, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infraction, stroke, or infarct.
18. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 567, 568, 569, 570, 571, 572, 573, 574, or 575.
19. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
20. The compound of claim 2 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
21. The compound of claim 3 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
22. The compound of claim 4 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
23. The compound of claim 5 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
24. The compound of claim 6 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
25. The compound of claim 7 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
26. The compound of claim 11 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
27. The compound of claim 12 , wherein the nucleobase sequence of the modified oligonucleotide consists of SEQ ID NO: 570.
28. The composition of claim 15 , wherein the modified oligonucleotide is a salt.
29. The composition of claim 28 , wherein the modified oligonucleotide is a sodium salt.