Therapeutic compositions

1. An iRNA agent comprising a sense sequence and an antisense sequence, wherein the antisense strand and/or the sense strand comprises formula (8) or its L-nucleoside or 2′-5′ linkage isomer:

wherein:

X is O, S, Se, NR, or B(R) 3 ;

R is H, OH, or OMe;

Y is H, OH, N(R′) 2 , or SR″;

Z is H, OH, N(R′) 2 , or SR″;

R′ is H, Me, Et, or (CH 2 ) n OH;

n is 2-6; and

R″ is a C 1 -C 10 alkyl group.

2. The iRNA agent of claim 1 , wherein Y is H, OH, or N(R′) 2 ; and Z is H, OH, or N(R′) 2 .

3. The iRNA agent of claim 2 , wherein the iRNA agent is a double-stranded iRNA agent comprising a duplex portion of 15-30 nucleotides pairs in length.

4. The iRNA agent of claim 3 , wherein the iRNA agent is a double-stranded iRNA agent comprising a duplex portion of 19 to 21 nucleotides pairs in length.

5. The iRNA agent of claim 4 , wherein the iRNA agent comprises at least one 3′ overhang of 1-5 nucleotides in length.

6. The iRNA agent of claim 2 , further comprising at least one modification, wherein the modification is selected from the group consisting of 2′-O-alkyl, 2′-5′ linkages, L sugars, and combinations thereof.

7. The iRNA agent of claim 6 , wherein at least one of the modifications occurs 1-6 nucleotides from either end of the strand.

8. The iRNA agent of claim 6 , wherein at least one modification is an L sugar modification, and wherein the L sugar modification is an L-ribose or L-arabinose modification.

9. The iRNA agent of claim 8 , wherein the L-ribose and L-arabinose modifications comprise a 2′-H, a 2′-OH or a 2′-OMe.

10. A method of increasing the nuclease resistance of an iRNA duplex, comprising the step of:

incorporating into the antisense strand and/or the sense strands of the duplex a compound of formula (8) or its L-nucleoside or 2′-5′ linkage isomer:

wherein:

X is O, S, Se, NR, or B(R) 3 ;

R is H, OH, or OMe;

Y is H, OH, N(R′) 2 , or SR″;

Z is H, OH, N(R′) 2 , or SR″;

R′ is H, Me, Et, or (CH 2 ) n OH;

n is 2-6; and

R″ is a C 1 -C 10 alkyl group.

11. The method of claim 10 , wherein Y is H, OH, or N(R′) 2 ; and Z is H, OH, or N(R′) 2 .

12. The method of claim 11 , wherein the duplex is a double-stranded iRNA agent comprising a duplex portion of 15-30 nucleotide pairs in length.

13. The method of claim 12 , wherein the duplex is a double-stranded iRNA agent comprising a duplex portion of 19 to 21 nucleotide pairs in length.

14. The method of claim 11 , wherein the iRNA agent comprises at least one 3′ overhang of 1-5 nucleotides in length.