Therapeutic compositions

1. An iRNA agent comprising a sense strand and an antisense strand, wherein the antisense strand and/or the sense strand comprise two or more different modifications, wherein at least one modification is an L sugar modification, and the other modifications are selected from the following group:

(a) backbone;

(b) 2′-O alkyl;

(c) 2′-5′ linkages

(d) LNAs, HNAs and/or CeNAs;

(e) nucleobase; and

(f) cationic groups and/or Zwitterionic groups;

wherein the modifications occur 1-6 nucleotides from either end of the strand, and wherein the first four terminal pairs at the 5′ end of the antisense comprises at least two A:U groups.

2. The iRNA agent of claim 1 , wherein the L sugar modification is a L-ribose or L-arabinose modification.

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

4. The iRNA agent of claim 2 , wherein at least one of the modifications occurs 1-3 nucleotides from the 3′-end of the antisense strand or the sense strand, or 1-3 nucleotides from either end of the sense strand.

5. The iRNA agent of claim 1 , wherein at least one of the modifications is a 2′-5′ linkage, and wherein the 2′-5′ linkage occurs 1-3 nucleotides from the 3′-end of the antisense strand or the sense strand, or 1-3 nucleotides from either end of the sense strand.

6. The iRNA agent of claim 1 , wherein at least one of the modifications is a 2′-O alkyl modification, and wherein the 2′-O alkyl modification occurs 1-6 nucleotides from the 3′ end and/or the 5′-end of the antisense strand and/or the sense strand.

7. The iRNA agent of claim 6 , wherein the 2′-O alkyl modification is a 2′-OMe modification.

8. The iRNA agent of claim 1 , wherein the iRNA agent is a double stranded iRNA agent comprising a duplex portion of 15-30 nucleotide pairs in length.

9. The iRNA agent of claim 8 , wherein the iRNA agent comprises at least one 3′ overhang of 1-5 nucleotides in length.

10. An iRNA agent comprising a sense strand and an antisense strand, wherein the antisense strand and/or the sense strand comprises at least one 2′-O alkyl modification and at least one L sugar modification, and optionally one or more 2′-5′ linkages modifications.

11. The iRNA agent of claim 10 , wherein the modifications occur 1-6 nucleotides from either end of the antisense strand or the sense strand.

12. The iRNA agent of claim 10 , wherein the L sugar modification is an L-ribose or L-arabinose modification.

13. The iRNA agent of claim 12 , wherein the L-ribose and L-arabinose modifications comprise a 2′-H, a 2′-OH or a 2′-OMe.

14. The iRNA agent of claim 12 , wherein the modifications occur at the 3′-end of the antisense strand and/or the sense strand.

15. The iRNA agent of claim 11 , wherein the iRNA agent comprises at least one 2′-OMe modification, at least one L sugar modification, and at least one 2′-5′ linkage modification.

16. A method of increasing nuclease resistance of a duplex comprising an antisense strand and a sense strand, by incorporating two or more different modifications positioned 1-6 nucleotides from either end of the antisense strand and/or the sense strands, wherein at least one modification is an L sugar modification, and the other modifications are selected from the following group:

(a) backbone;

(b) 2′-O alkyl;

(c) 2′-5′ linkages

(d) LNAs, HNAs and/or CeNAs;

(e) nucleobase; and

(f) cationic groups and/or Zwitterionic groups;

wherein the first four terminal pairs at the 5′ end of the antisense comprise at least two A:U groups.

17. The method of claim 16 , wherein the L sugar modification comprises a 2′-H, a 2′-OH or a 2′-OMe.

18. The method of claim 17 , wherein at least one of the modifications occurs 1-3 nucleotides from the 3′-end of the antisense strand or the sense strand, or 1-3 nucleotides from either end of the sense strand.

19. The method of claim 16 , wherein at least one of the modifications is a 2′-5′ linkage, and wherein the 2′-5′ linkage occurs 1-3 nucleotides from the 3′-end of the antisense strand or the sense strand, or 1-3 nucleotides from either end of the sense strand.

20. The method of claim 16 , wherein at least one of the modifications is a 2′-O alkyl modification, and wherein the 2′-O alkyl modification occurs 1-6 nucleotides from the 3′ end and/or the 5′-end of the antisense strand and/or the sense strand.

21. The method of claim 16 , wherein the iRNA agent is a double stranded iRNA agent comprising a duplex portion of 15-30 nucleotide pairs in length.

22. The iRNA agent of claim 21 , wherein the iRNA agent comprises at least one 3′ overhang of 1-5 nucleotides in length.

23. A method of increasing nuclease resistance of a duplex by incorporating at least one 2′-O alkyl modification and at least one L sugar modification and optionally one or more 2′-5′ linkages to an iRNA agent, wherein the modifications occur at the 3′ end and/or the 5′ end of either strand or 1-6 nucleotides from either end of the strand.

24. The method of claim 23 , wherein the L sugar modification is an L-ribose or L-arabinose modification.

25. The method of claim 23 , wherein the L-ribose and L-arabinose modifications further comprise a 2′-H, a 2′-OH or a 2′-OMe.

26. The method of claim 25 , wherein at least one modification occurs at the 3′-end of the antisense strand and/or the sense strand.