Conjugated antisense compounds and their use
The present disclosure provides duplexes comprising a first oligomeric compound and a second oligomeric compound wherein the second oligomeric compound comprises a conjugate group. In certain embodiments, the duplex modulates the amount or activity of a target nucleic acid in extra hepatic tissues and/or extra hepatic cells. In certain embodiments, the duplex modulates the amount or activity of a target nucleic acid in hepatic tissues and/or hepatic cells.
1. A method of reducing the expression of DMPK in skeletal muscle and cardiac muscle, comprising administering to a subject a duplex comprising a first oligomeric compound and a second oligomeric compound wherein
the first oligomeric compound comprises a first modified oligonucleotide consisting of 10-30 linked nucleosides; and
the second oligomeric compound comprises a second modified oligonucleotide consisting of 10-30 linked nucleosides and a conjugate group;
wherein the conjugate group comprises a conjugate moiety and a conjugate linker,
wherein the conjugate moiety is cholesterol; and wherein the conjugate linker comprises at least one cleavable moiety; and
wherein the nucleobase sequence of the first oligomeric compound is complementary to the nucleobase sequence of the second oligomeric compound and to a DMPK mRNA.
2. The method of claim 1 , wherein the first modified oligonucleotide comprises at least one modified nucleoside.
3. The method of claim 2 , wherein the first modified oligonucleotide comprises a least one modified nucleoside comprising a modified sugar moiety.
4. The method of claim 3 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
5. The method of claim 4 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 —; and —O—CH(CH 3 )—.
6. The method of claim 2 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.
7. The method of claim 6 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety comprising a 2′-MOE or 2′-O-Methyl modified sugar moiety.
8. A method of reducing the expression of DMPK in skeletal muscle and cardiac muscle, comprising administering to a subject a duplex comprising a first oligomeric compound and a second oligomeric compound wherein
the first oligomeric compound comprises a first modified oligonucleotide consisting of 10-30 linked nucleosides; and
the second oligomeric compound comprises a second modified oligonucleotide consisting of 10-30 linked nucleosides and a conjugate group;
wherein the conjugate group comprises a conjugate moiety and a conjugate linker,
wherein the conjugate moiety is tocopherol; and wherein the conjugate linker comprises at least one cleavable moiety; and
wherein the nucleobase sequence of the first oligomeric compound is complementary to the nucleobase sequence of the second oligomeric compound and to a DMPK mRNA.
9. The method of claim 8 , wherein the first modified oligonucleotide comprises at least one modified nucleoside.
10. The method of claim 9 , wherein the first modified oligonucleotide comprises a least one modified nucleoside comprising a modified sugar moiety.
11. The method of claim 10 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
12. The method of claim 11 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 —; and —O—CH(CH 3 )—.
13. The method of claim 9 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.
14. The method of claim 13 , wherein the first modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety comprising a 2′-MOE or 2′-O-Methyl modified sugar moiety.
15. The method of claim 1 , wherein the first modified oligonucleotide has a sugar motif consisting of:
a 5′-region consisting of 1-5 linked 5′-nucleosides;
a central region consisting of 6-10 linked central region nucleosides; and
a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein
each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety.
16. The method of claim 8 , wherein the first modified oligonucleotide has a sugar motif consisting of:
a 5′-region consisting of 1-5 linked 5′-nucleosides;
a central region consisting of 6-10 linked central region nucleosides; and
a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein
each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety.