Modified compounds and uses thereof
The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.
1. An oligomeric compound comprising a modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a 5′-region, a central region, and a 3′-region, wherein:
the 5′-region consists of 3 linked nucleosides, each comprising a 4′-to-2′ linked bicyclic sugar moiety;
the 3′ region consists of 3 linked nucleosides, each comprising a 4′-to-2′ linked bicyclic sugar moiety;
and the central region consists of 10 linked nucleosides, wherein the central region has the following formula:
(N d )(N x )(N d ) n
wherein N x is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety and each N d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety;
and n is 8.
2. The oligomeric compound of claim 1 , wherein each 4′-to-2′ linked bicyclic sugar moiety of each nucleoside of the 5′ region is independently selected from cEt, LNA, and ENA.
3. The oligomeric compound of claim 1 , wherein each 4′-to-2′ linked bicyclic sugar moiety of each nucleoside of the 3′ region is independently selected from cEt, LNA, and ENA.
4. The oligomeric compound of claim 1 , wherein each 4′-to-2′ linked bicyclic sugar moiety of each nucleoside of the 3′ region and the 5′ region is independently selected from cEt and LNA.
5. The oligomeric compound of claim 1 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
6. The oligomeric compound of claim 1 , wherein each internucleoside linkage is independently selected from phosphodiester and phosphorothioate internucleoside linkages.
7. The oligomeric compound of claim 1 , wherein at least one internucleoside linkage within the central region is a modified internucleoside linkage other than phosphorothioate and each remaining internucleoside linkage in the modified oligonucleotide is independently selected from phosphodiester and phosphorothioate internucleoside linkages.
8. The oligomeric compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to a target RNA.
9. The oligomeric compound of claim 8 , wherein the target RNA is a target mRNA or a target pre-mRNA.
10. The oligomeric compound of claim 8 , wherein the target RNA is expressed in the liver, in the central nervous system, and/or in muscle cells.
11. The oligomeric compound of claim 8 , wherein the target RNA is expressed in cancer cells.
12. The oligomeric compound of claim 8 , wherein the target RNA is selected from a MeCP2, DUX4, HDAC2, APP, Ataxin 1, Ataxin 2, Ataxin 3, Ataxin 6, Ataxin 7, C9ORF72, UBE3A, Prion, PMP22, Tau, LRRK2, LINGO2, GYS1, KCNT1, IRF8, Progranulin, or GFAP RNA.
13. The oligomeric compound of claim 7 , wherein the modified internucleoside linkage other than phosphorothioate is a methoxypropyl internucleoside linkage.
14. The oligomeric compound of claim 7 , wherein the central region contains exactly one modified internucleoside linkage other than phosphorothioate.
15. The oligomeric compound of claim 1 , comprising a conjugate group.
16. The oligomeric compound of claim 15 , wherein the conjugate group comprises GalNAc.
17. A method comprising administering the oligomeric compound of claim 1 to a subject.
18. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of the motif kkk-d-m-d(8)-kkk, wherein each k is a nucleoside comprising a cEt sugar moiety, wherein each d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety, and wherein m is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety.
19. The oligomeric compound of claim 18 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
20. The oligomeric compound of claim 18 , wherein each internucleoside linkage is independently selected from phosphodiester and phosphorothioate internucleoside linkages.
21. The oligomeric compound of claim 18 , comprising a conjugate group.
22. The oligomeric compound of claim 21 , wherein the conjugate group comprises GalNAc.
23. A method comprising administering the oligomeric compound of claim 18 to a subject.
24. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of the motiflll-d-m-d(8)-lll, wherein each 1 is a nucleoside comprising a β-D-LNA sugar moiety, wherein each d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety, and wherein m is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety.
25. The oligomeric compound of claim 24 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.
26. The oligomeric compound of claim 24 , wherein each internucleoside linkage is independently selected from phosphodiester and phosphorothioate internucleoside linkages.
27. The oligomeric compound of claim 24 , comprising a conjugate group.
28. The oligomeric compound of claim 27 , wherein the conjugate group comprises GalNAc.
29. A method comprising administering the oligomeric compound of claim 24 to a subject.