REVERSIR™ compounds

1. A modified oligonucleotide consisting of 6 to 20 linked nucleotides and having a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of antisense strand of a siRNA, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strand hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand, wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are: (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end; or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).

2. The modified oligonucleotide of claim 1 , consisting of 8-15 linked nucleotides.

3. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide having at least 90% complementary to the antisense strand.

4. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide is substantially complementary to nucleotides 2-16 of the antisense stand.

5. The modified oligonucleotide of claim 1 , comprising at least one modified internucleotide linkage.

6. The modified oligonucleotide of claim 1 , comprising at least one modified internucleotide linkage and at least one unmodified internucleotide linkage.

7. The modified oligonucleotide of claim 6 , comprising an unmodified internucleotide linkage between the 3′-terminus nucleoside and the penultimate nucleoside.

8. The modified oligonucleotide of claim 1 , comprising at least one modified nucleobase.

9. The modified oligonucleotide of claim 1 , comprising at least one modified sugar.

10. The modified oligonucleotide of claim 9 , wherein said at least one modified sugar is a bicyclic sugar.

11. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least one nucleotide wherein 2′ position of furnaosyl is connected to the 4′ position by a linker selected independently from —[C(R1)(R2)] n -, —[C(R1)(R2)] n -O—, —[C(R1)(R2)] n -N(R1)-, —[C(R1)(R2)] n -N(R1)-O—, —[C(R1R2)] n -O—N(R1)-, —C(R1)=C(R2)-O—, —C(R1)=N—, —C(R1)=N—O—, —C(═NR1)-, —C(═NR1)-O—, —C(═O)—, —C(═O)O—, —C(═S)—, —C(═S)O—, —C(═S)S—, —O—, —Si(R1)2-, —S(═O) x — and —N(R1)-,

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R1 and R2 is, independently, H, a protecting group, hydroxyl, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl(C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)2-J1), or sulfoxyl (S(═O)-J1); and

each J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group.

12. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide is conjugated with a ligand.

13. The modified oligonucleotide of claim 12 , wherein the ligand is of structure:

14. The modified oligonucleotide of claim 12 , wherein the ligand is conjugated to 3′-terminus of the modified oligonucleotide.

15. The modified oligonucleotide of claim 1 , wherein the siRNA is targeted to an mRNA, a pre-mRNA, a micro-RNA a pre-micro-RNA.

16. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are: (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end; or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).

17. The modified oligonucleotide of claim 16 , wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside at position 1, counting from the 3′-end.

18. The modified oligonucleotide of claim 1 , wherein the modified oligonucleotide is at least 8 nucleotides shorter than the antisense strand.

19. A method of inhibiting the activity of a siRNA in a cell comprising contacting the cell with a modified oligonucleotide, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence; and,

the modified oligonucleotide consists of 6 to 25 linked nucleotides and has a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand,

wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and

wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are: (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end; or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).

20. The method of claim 19 , wherein the modified oligonucleotide is at least 8 nucleotides shorter than the antisense strand.

21. A method of treating a subject comprising:

administering to the subject a siRNA, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence;

monitoring the subject for siRNA activity;

if the siRNA activity becomes higher than desired, administering a modified oligonucleotide to the subject, wherein the modified oligonucleotide consists of 6 to 25 linked nucleotides and having a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide is at least 4 nucleotides shorter than the antisense strand, wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end, and wherein the modified oligonucleotide comprises at least 2 locked nucleic acid (LNA) modifications, and two of the LNA modifications in the modified oligonucleotide are: (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end; or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).

22. The method of claim 21 , wherein the modified oligonucleotide is at least 8 nucleotides shorter than the antisense strand.

23. A method of inhibiting the activity of a siRNA in a cell comprising contacting the cell with a modified oligonucleotide, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense and antisense strands hybridize to form a duplex structure comprising from 14 to 30 basepairs, wherein the antisense strand is complementary to at least a part of a target sequence, wherein the modified oligonucleotide consists of 6 to 25 linked nucleotides and has a nucleobase sequence substantially complementary to positions 2-10, counting from 5′-end of the antisense strand of the siRNA, wherein the modified oligonucleotide comprises only 2, 3, 4 or 5 locked nucleic acid (LNA) modifications, and wherein two of the LNA modifications in the modified oligonucleotide are: (i) at position 2, counting from 3′-end, and at position 1, counting from 5′-end; or (ii) at position 2, counting from 3′-end, and at position 2, counting from 5′-end).

24. The method of claim 23 , wherein the modified oligonucleotide comprises a 2′-deoxy nucleoside only at position 1, counting from the 3′-end.

25. The method of claim 23 , wherein the modified oligonucleotide is at least 8 nucleotides shorter than the antisense strand.