Modified oligonucleotides targeting SNPs

1. An siRNA molecule comprising:

a sense strand having complementarity to a target gene;

and an antisense strand having complementarity to the sense strand,

wherein the antisense strand comprises a nucleic acid comprising:

(a) a 5′ end and a 3′ end;

(b) a seed region that is complementary to a region of a gene comprising an allelic polymorphism;

(c) a single nucleotide polymorphism (SNP) position nucleotide at a position within the seed region, wherein the SNP position nucleotide is complementary to the allelic polymorphism;

(d) a mismatch (MM) position nucleotide that is a mismatch with a nucleotide in the gene; and

(e) at least one sugar-modified nucleotide (X) on either side of the SNP position nucleotide, wherein each X is located within four, three, or two nucleotides from the SNP position nucleotide; or

(f) at least one sugar-modified nucleotide (Y) on either side of the MM position nucleotide, wherein each Y is located within four, three or two nucleotides from the MM position nucleotide.

2. The siRNA molecule of claim 1 , wherein:

the sense strand has a length of from 13 nucleotides or nucleotide analogs to 17 nucleotides or nucleotide analogs.

3. The siRNA molecule of claim 1 , wherein the antisense strand has a length of from 18 nucleotides or nucleotide analogs to 22 nucleotides or nucleotide analogs.

4. The siRNA molecule of claim 1 , wherein the sense strand has a length of 15 nucleotides or nucleotide analogs and the antisense strand has a length of 20 nucleotides or nucleotide analogs.

5. The siRNA molecule of claim 1 , wherein the sense strand has a length of 16 nucleotides or nucleotide analogs and the antisense strand has a length of 20 nucleotides or nucleotide analogs.

6. A branched oligonucleotide comprising two or more siRNA molecules covalently bound to one another, wherein each siRNA molecule is, independently, an siRNA molecule of claim 1 .

7. The branched oligonucleotide of claim 6 , wherein the branched oligonucleotide comprises two siRNA molecules covalently bound to one another.

8. The branched oligonucleotide of claim 6 , wherein the siRNA molecules are covalently bound to one another by way of a linker.

9. A double-stranded nucleic acid comprising:

(a) a first strand of nucleotides comprising:

(i) a 5′ end and a 3′ end;

(ii) a seed region that is complementary to a region of a gene comprising an allelic polymorphism;

(iii) a single nucleotide polymorphism (SNP) position nucleotide at a position within the seed region, wherein the SNP position nucleotide is complementary to the allelic polymorphism;

(iv) a mismatch (MM) position nucleotide that is not complementary to a nucleotide in the gene; and

(v) at least one sugar-modified nucleotide located on either side of the SNP position nucleotide, on either side of the MM position nucleotide, or a combination thereof; wherein each sugar-modified nucleotide is located within four, three, or two nucleotides from the SNP position nucleotide or from the MM position nucleotide, respectively;

(b) a second strand of nucleotides that is complementary to the first strand of nucleotides.

10. The double-stranded nucleic acid of claim 9 , wherein:

the sugar-modified nucleotide comprises a modification selected from the group consisting of 2′-O-methyl(2′-OMe), 2′-fluoro (2′-F), 2′-ribo, 2′-deoxyribo, 2′-F-4′-thioarabino(2′-F-ANA), 2′-O-(2-methoxyethyl) (2′-MOE), 4′-S-RNA, locked nucleic acid (LNA), 4′-S-F-ANA, 2′-O-allyl, 2′-O-ethylamine, 2′-O-cyanoethyl-RNA(CNet-RNA), tricyclo-DNA, cyclohexenyl nucleic acid (CeNA), arabino nucleic acid (ANA), hexitol nucleic acid (HNA), and a combination thereof.

11. The double-stranded nucleic acid of claim 9 , wherein:

the sugar-modified nucleotide is positioned immediately 5′ to the SNP position nucleotide, immediately 3′ to the SNP position nucleotide, or a mixture thereof; or

the sugar-modified nucleotide is positioned immediately 5′ to the MM position nucleotide, immediately 3′ to the MM position nucleotide, or a mixture thereof.

12. The double-stranded nucleic acid of claim 9 , wherein the SNP position nucleotide is present from position 2 to position 6 from the 5′ end of the first strand of nucleotides.

13. The double-stranded nucleic acid of claim 9 , wherein:

the MM position nucleotide is located 2-11 nucleotides from the SNP position nucleotide of the first strand of nucleotides; or

the MM position nucleotide is located 2-6 nucleotides from the SNP position nucleotide of the first strand of nucleotides.

14. The double-stranded nucleic acid of claim 9 , wherein the sugar-modified nucleotides comprise identical nucleotide sugar modifications, different nucleotide sur modifications, or a mixture thereof.

15. The double-stranded nucleic acid of claim 9 , wherein:

the first strand has a length of from 13-17 nucleotides; or

the second strand has a length of from 18-22 nucleotides.

16. The double-stranded nucleic acid of claim 9 , wherein:

the first strand has a length of 15 nucleotides and the second strand has a length of 20 nucleotides; or

the first strand has a length of 16 nucleotides and the second strand has a length of 20 nucleotides.

17. The double-stranded nucleic acid of claim 9 , wherein the first strand has 3-7 more nucleotides than the second strand.

18. A branched oligonucleotide comprising two or more siRNA molecules covalently bound to one another, wherein each siRNA molecule comprises a double-stranded nucleic acid comprising:

(a) a first strand of nucleotides comprising:

(i) a 5′ end, a 3′ end;

(ii) a seed region that is complementary to a region of a gene comprising an allelic polymorphism;

(iii) a single nucleotide polymorphism (SNP) position nucleotide at a position within the seed region, wherein the SNP position nucleotide is complementary to the allelic polymorphism;

(iv) a mismatch (MM) position nucleotide that not complementary to a nucleotide in the gene; and

(v) at least one sur-modified nucleotide located on either side of the SNP position nucleotide, on either side of the MM position nucleotide, or a combination thereof; wherein each sugar-modified nucleotide is located within four, three, or two nucleotides from the SNP position nucleotide or from the MM position nucleotide, respectively;

(b) a second strand of nucleotides that is complementary to the first strand of nucleotides.

19. The branched oligonucleotide of claim 18 , wherein the branched oligonucleotide comprises two siRNA molecules covalently bound to one another.

20. The branched oligonucleotide of claim 18 , wherein the siRNA molecules are covalently bound to one another by way of a linker.