Short oligomer antagonist compounds for the modulation of target mRNA
View Patent ↗The invention provides LNA gapmer oligomers of between 10-20 nucleobases in length, which have a total of 1-3 phosphodiester internucleoside linkages. Such oligomers have been found to have superior bioavailability and have also been found to selectively accumulate in kidney cells.
1. An oligomer 10-14 nucleobase units in length, wherein the nucleobase sequence of said oligomer comprises the formula (5′-3′), AB-C, wherein:
region A (5′ region) comprises 1-3 contiguous locked nucleic acid (LNA) nucleobase units;
region B (central domain) comprises 7-9 contiguous nucleobase units and is capable of recruiting RNase H when formed in a duplex with a complementary RNA molecule; and
region C (3′ region) comprises 1-3 contiguous locked nucleic acid (LNA) nucleobase units;
and wherein 1, 2 or 3 internucleoside linkages adjacent to an LNA unit in region A, region C, or in each of regions A and C are phosphodiester linkages; and wherein the remaining internucleoside linkages are phosphorothioate linkages.
2. The oligomer according to claim 1 , wherein region A comprises a phosphodiester linkage between two LNA units.
3. The oligomer according to claim 1 , wherein region C comprises a phosphodiester linkage between two LNA units.
4. The oligomer according to claim 1 , wherein the number of nucleobases in regions A, B, and C (A-B-C) is selected from the group consisting of: 1-8-2, 2-8-1, 2-8-2, 3-8-3, 2-8-3, and 3-8-2.
5. A conjugate comprising the oligomer of claim 1 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said oligomer.
6. A pharmaceutical composition comprising the oligomer of claim 1 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
7. The oligomer of claim 1 , wherein said nucleobase sequence further comprises one or two DNA units (region D), wherein said region D precedes region A.
8. A pharmaceutical composition comprising the conjugate of claim 5 and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
9. The oligomer of claim 1 , wherein a phosphodiester linkage is present between a LNA unit located at the 3′ terminus of region A and the nucleobase unit located at the 5′ terminus of region B.
10. The oligomer of claim 1 wherein a phosphodiester linkage is present between a LNA unit located at the 5′ terminus of region C and the nucleobase unit located at the 3′ terminus of region B.
11. The oligomer according to claim 1 , wherein region B consists of nucleobase units selected from the group consisting of DNA units, alpha-L-Oxy LNA units and mixtures thereof.
12. The oligomer according to claim 1 , wherein region B consists of DNA units.
13. The oligomer according to claim 4 , wherein the number of nucleobases in regions A, B, and C (A-B-C) is 3-8-3.
14. A method for reducing the cellular concentration of an mRNA in a mammalian cell comprising contacting the oligomer of claim 1 with the mammalian cell, wherein said mammalian cell comprises an mRNA species having a nucleobase sequence complementary to said oligomer.
15. The method of claim 14 , wherein the cell is a kidney cell.
16. A method for reducing the cellular concentration of an mRNA in a mammalian cell comprising contacting the conjugate of claim 5 with the mammalian cell, wherein said mammalian cell comprises an mRNA species having a nucleobase sequence complementary to the oligomer of the conjugate.
17. The method of claim 16 , wherein the cell is a kidney cell.