Modulators of PCSK9 expression
The present embodiments provide methods, compounds, and compositions useful for inhibiting PCSK9 expression, which may be useful for treating, preventing, or ameliorating a disease associated with PCSK9.
1. A compound according to the following formula (SEQ ID NO: 1016):
or a pharmaceutically acceptable salt thereof.
2. A compound or a pharmaceutically acceptable salt thereof, comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide is 16 linked nucleosides in length and has the nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 1016, wherein the modified oligonucleotide has
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of three linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage; wherein each cytosine is a 5-methylcytosine.
3. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a sodium salt.
4. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt.
5. A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. A compound consisting of a modified oligonucleotide, wherein the modified oligonucleotide is 16 linked nucleosides in length and consists of the sequence of SEQ ID NO: 1016, wherein the modified oligonucleotide consists
of a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of three linked nucleosides; and
a 3′ wing segment consisting of three linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.
7. The compound of claim 2 , wherein the pharmaceutically acceptable salt is a sodium salt.
8. The compound of claim 2 , wherein the pharmaceutically acceptable salt is a potassium salt.
9. A composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The compound of claim 2 , wherein the conjugate group is 5′-Trishexylamino-(THA)-C 6 GalNAC3 and is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.