Poly oligomer compound with biocleavable conjugates
The invention relates to the field of oligonucleotide therapeutics, and in particular to poly oligo oligonucleotides conjugates where two or more antisense oligonucleotides are covalently linked by physiologically labile linkers, and to a biocleavable functional group such as a conjugate group.
1. An oligomeric compound comprising
a. a first region of a contiguous sequence of 7-26 phosphorothioate linked nucleosides (A);
b. a second region of a contiguous sequence of 7-26 phosphorothioate linked nucleosides (A′);
c. 1-5 phosphodiester linked DNA nucleotides (B) which covalently links region A and A′; and
d. a conjugate moiety (C) covalently linked to region A or A′ by 1 5 phosphodiester linked DNA nucleotides;
wherein the conjugate moiety comprises a trivalent GalNAc cluster.
2. The oligomeric compound according to claim 1 , wherein the first region (A) and second region (A′) are positioned 5′ and 3′ respectively to (B).
3. The oligomeric compound according to claim 1 wherein the contiguous sequence of nucleobases of A and A′ the first and the second region are identical.
4. The oligomeric compound according to claim 1 wherein the contiguous sequence of nucleobases of A and A′ are different.
5. The oligomeric compound according to claim 1 wherein the first and the second regions are targeted to the same nucleic acid target.
6. The oligomeric compound according to claim 1 wherein A and A′ are targeted to different independent nucleic acid targets.
7. The oligomeric compound according to claim 1 wherein A and A′ each comprise at least one LNA nucleoside.
8. The oligomeric compound according to claim 1 wherein A and A′ are LNA gapmers.
9. The oligomeric compound according to claim 1 wherein the first and/or second region target mRNA targets.
10. The oligomeric compound according to claim 1 wherein A and/or A′ target microRNA targets.
11. The oligomeric compound according to claim 1 wherein A and/or A′ are mixmer or totalmer oligomers.
12. The oligomeric compound according to claim 1 wherein A and A′ are 10-16 nucleotides in length.
13. The oligomeric compound according to claim 1 wherein A and A′ are 8-10 nucleotides in length.
14. The oligomeric compound according to claim 1 , wherein at least one or both of A and A′ target a microRNA selected from the group consisting of microRNA ID NO 40-976.
15. The oligomeric compound according to claim 1 wherein A is complementary to human ApoB-100 mRNA nucleotide sequence and/or wherein A′ is complementary to human mtGPAT mRNA nucleotide sequence.
16. The oligomeric compound according to claim 1 , the second region (A′) and first region (A) are positioned 5′ and 3′ respectively to (B).
17. The oligomeric compound according to claim 1 , wherein A is positioned 3′ of A′.
18. A pharmaceutical composition comprising the oligomeric compound according to claim 1 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.