NOVEL SIRNA STRUCTURES

1 . A compound having a structure set forth below:

5′    (N) x -Z 3′

(antisense strand)

3′ Z′-(N′) y   5′

(sense strand)

wherein each of N and N′ is a nucleotide selected from an unmodified ribonucleotide, a modified ribonucleotide, an unmodified deoxyribonucleotide and a modified deoxyribonucleotide;

wherein each of (N) x and (N′) y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;

wherein each of x and y is an integer between 19 and 23;

wherein each of Z and Z′ may be present or absent, but if present is 1-5 consecutive nucleotides covalently attached at the 3′ terminus of the strand in which it is present;

wherein the sequence of (N)x is complementary to the sequence of (N′)y;

wherein the sequence of (N′)y is present within the mRNA of a target gene;

wherein at least one of (N)x or (N′)y comprises a modification selected from the group consisting of internucleotide modification and an L-nucleotide;

and wherein the internucleotide modification is 5′-2′ bridge or an alpha phosphate modification selected from the group consisting of thiophosphate and triester.

2 . The compound according to claim 1 wherein x=y=19 and the alpha phosphate modification is present in any one of the motifs selected from the group consisting of

a) an internucleotide modification between nucleotides at positions 1-19 of (N′)y;

b) an internucleotide modification between nucleotides at positions 1-19 of (N)x;

c) an internucleotide modification between nucleotides at positions 9-11 of (N′)y and positions 1-9 and 11-19 of (N)x;

d) an internucleotide modification between nucleotides at positions 1-2, 3-4, 5-6, 7-8, 12-13, 14-15, 16-17 and 18-19 of (N′)y and positions 2-3, 4-5, 6-7, 8-9 11-12, 13-14, 15-16 and 17-18 of (N)x;

e) an internucleotide modification between nucleotides at positions 1-2, 3-4, 5-6, 7-8, 14-15, 16-17 and 18-19 of (N′)y and positions 2-3, 4-5, 6-7, 13-14, 15-16 and 17-18 of (N)x;

f) an internucleotide modification between nucleotides at positions 1-2, 3-4, 16-17 and 18-19 of the (N′)y and 2-3, 4-5, 15-16 and 17-18 of the antisense strand;

g) an internucleotide modification between nucleotides at positions 1-2, 3-4, 16-17 and 18-19 of (N′)y and 2-3 and 17-18 of (N)x;

h) an internucleotide modification between nucleotides at positions 2-3 and 17-18 of (N′)y and 1-2, 3-4, 16-17 and 18-19 of (N)x;

i) an internucleotide modification between nucleotides at positions 1-2, 6-7, 13-14 and 18-19 of (N′)y and 5-6 and 14-15 of (N)x;

j) an internucleotide modification between nucleotides at positions 6-7 and 13-14 of (N′)y and 1-2, 5-6, 14-15 and 18-19 of (N)x;

k) an internucleotide modification between nucleotides at positions 1-2, 4-5, 6-7, 13-14, 15-16 and 18-19 of (N′)y and 5-6, 7-8, 12-13 and 14-15 of (N)x; and

l) an internucleotide modification between nucleotides at positions 4-5, 6-7, 13-14 and 15-16 of the (N′)y and 1-2, 5-6, 7-8, 12-13, 14-15 and 18-19 of (N)x.

3 . The compound according to claim 1 wherein the alpha phosphate modification is a thiophosphate.

4 . The compound according to claim 1 wherein the internucleotide linkage modification is a 5′-2′ bridge.

5 . The compound according to claim 1 wherein one of (N)x and (N′)y comprise one or more L-nucleotide.

6 . The compound according to claim 1 wherein x=y=19 and which has any one of the following motifs selected from the group consisting of:

a) an L-nucleotide at each of positions 1-19 of the (N′)y;

b) an L-nucleotide at each of positions 1-19 of the (N)x;

c) an L-nucleotide at each of positions 9-11 of the (N′)y and at each of positions 1-9 and 11-19 of (N)x;

d) an L-nucleotide at each of positions 1-8, and 12-19 of the (N′)y and each of positions 2-9 and 11-18 of (N)x;

e) an L-nucleotide at each of positions 1-8 and 14-19 of (N′)y and each of positions 2-7 and 13-18 of (N)x;

f) an L-nucleotide at each of positions 1-4 and 16-19 of the (N′)y and each of positions 2-5 and 15-18 of (N)x;

g) an L-nucleotide at each of positions 1-4, 16-19 of (N′)y and each of positions 2-3 and 17-18 of (N)x;

h) an L-nucleotide at each of positions 2-3 and 17-18 of (N′)y and each of positions 1-4 and 16-19 of (N)x;

i) an L-nucleotide at each of positions 1-2, 6-7, 13-14 and 18-19 of (N′)y and each of positions 5-6 and 14-15 of (N)x;

j) an L-nucleotide at each of positions 6-7 and 13-14 of (N′)y and each of positions 1-2, 5-6, 14-15 and 18-19 of (N)x;

k) an L-nucleotide at each of positions 1-2, 4-7, 13-16 and 18-19 of (N′)y and each of 5-8, 12-15 of (N)x; and

l) an L-nucleotide at each of positions 4-7 and 13-16 of (N′)y and each of positions 1-2, 5-8, 12-15 and 18-19 of (N)x.

7 . The compound of claim 1 wherein x=y.

8 . The compound of claim 7 wherein x=y=19 or x=y=23.

9 . The compound of claim 1 wherein each of Z and Z′ is absent.

10 . The compound of claim 1 wherein at least one of (N)x and (N′)y further comprises one or more modified nucleotides.

11 . The compound of claim 10 wherein the modified nucleotide is selected from the group consisting of DNA, LNA, PNA and arabinoside.

12 . The compound of claim 10 wherein the modified nucleotide comprises a sugar modifications.

13 . The compound of claim 12 wherein the sugar modification is selected from the group consisting of 2′ fluoro, 2′O allyl, 2′ amine and 2′ alkoxy.

14 . The compound according to claim 13 wherein the 2′ alkoxy is 2′O-methyl.

15 . The compound of claim 1 further comprising one or more terminal modifications.

16 . The compound of claim 15 wherein the terminal modification is selected from the group consisting of a nucleotide, a di-nucleotide, an oligonucleotide a lipid, a peptide, a sugar, and an amine.

17 . A siRNA produced by cleavage of the compound of claim 1 .

18 . The siRNA of claim 17 wherein the cleavage is nuclease cleavage.

19 . A pharmaceutical composition comprising at least one compound of claims 1 .