Modified iRNA agents

1. An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (I) is incorporated into at least one of said strands:

wherein:

X is N(CO)R 7 , NR 7 or CH 2 ;

Y is NR 8 , O, S, CR 9 R 10 , or absent;

Z is CR 11 R 12 or absent;

Each of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is, independently, H, OR a , OR b , (CH 2 ) n OR a , or (CH 2 ) n OR b , provided that at least one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is OR a or OR b and that at least one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is (CH 2 ) n OR a , or (CH 2 ) n OR b ;

Each of R 5 , R 6 , R 11 , and R 12 is, independently, H, C 1 -C 6 alkyl optionally substituted with 1-3 R 13 , or C(O)NHR 7 ; or R 5 and R 11 together are C 3 -C 8 cycloalkyl optionally substituted with R 14 ;

R 7 is R d ; or C 1 -C 20 alkyl substituted with NR c R d or NHC(O)R d ;

R 8 is C 1 -C 6 alkyl;

R 13 is hydroxy, C 1 -C 4 alkoxy, or halo;

R 14 is NR c R 7 ;

R a is H or

R b is H or

wherein the Strand in each occurrence is independently the first strand or second strand of the iRNA agent;

each of A and C is, independently, O or S; and

B is OH, O − , or

R c is H or C 1 -C 6 alkyl;

R d is H or a ligand; and

n is 1-4.

2. The iRNA agent of claim 1 , wherein X is N(CO)R 7 or NR 7 , Y is CR 9 R 10 , and Z is CR 11 R 12 .

3. The iRNA agent of claim 2 , wherein one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is OR a or OR b ; and one of R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is (CH 2 ) n OR a or (CH 2 ) n OR b .

4. The iRNA agent of claim 3 , wherein R 9 is OR a or OR b , and R 10 is (CH 2 ) n OR a or (CH 2 ) n OR b .

5. The iRNA agent of claim 3 , wherein R 3 is OR a or OR b , and R 4 is (CH 2 ) n OR a or (CH 2 ) n OR b .

6. The iRNA agent of claim 3 , wherein R 1 is OR a or OR b , and R 2 is (CH 2 ) n OR a or (CH 2 ) n OR b .

7. The iRNA agent of claim 3 , wherein R 9 is OR a or OR b , and R 3 is (CH 2 ) n OR a or (CH 2 ) n OR b .

8. The iRNA agent of claim 7 , wherein R 9 and R 3 are cis.

9. The iRNA agent of claim 7 , wherein R 9 and R 3 are trans.

10. The iRNA agent of claim 3 , wherein R 1 is OR a or OR b , and R 3 is (CH 2 ) n OR a or (CH 2 ) n OR b .

11. The iRNA agent of claim 10 , wherein R 1 and R 3 are cis.

12. The iRNA agent of claim 10 , wherein R 1 and R 3 are trans.

13. The iRNA agent of claim 1 , wherein X is N(CO)R 7 or NR 7 , Y is O, and Z is CR 11 R 12 .

14. The iRNA agent of claim 13 , wherein R 1 is OR a or OR b , and R 3 is (CH 2 ) n OR a or (CH 2 ) n OR b .

15. The iRNA agent of claim 14 , wherein R 1 and R 3 are cis.

16. The iRNA agent of claim 14 , wherein R 1 and R 3 are trans.

17. The iRNA agent of claim 1 , wherein X is N(CO)R 7 or NR 7 , Y is NR 8 , and Z is CR 11 R 12 .

18. The iRNA agent of claim 17 , wherein R 1 is OR a or OR b , and R 3 is (CH 2 ) n OR a or (CH 2 ) n OR b .

19. The iRNA agent of claim 18 , wherein R 1 and R 3 are cis.

20. The iRNA agent of claim 18 , wherein R 1 and R 3 are trans.

21. The iRNA agent of claim 1 , wherein X is CH 2 , Y is CR 9 R 10 , Z is CR 11 R 12 , and R 5 and R 11 together are C 3 -C 8 cycloalkyl optionally substituted with R 14 .

22. The iRNA agent of claim 21 , wherein R 3 is OR a or OR b ; R 6 is C(O)NHR 7 ; and R 9 is (CH 2 ) n OR a or (CH 2 ) n OR b .

23. The iRNA agent of claim 22 , wherein R 1 and R 3 are trans.

24. The iRNA agent of claim 21 , wherein R 3 is OR a or OR b ; R 6 is C 1 -C 6 alkyl; and R 9 is (CH 2 ) n OR a or (CH 2 ) n OR b .

25. The iRNA agent of claim 24 , wherein R 1 and R 3 are trans.

26. The iRNA agent of claim 24 , wherein R 5 and R 11 together are C 3 cycloalkyl substituted with R 14 .

27. The iRNA agent of claim 24 , wherein R 5 and R 11 together are C 4 cycloalkyl substituted with R 14 .

28. The iRNA agent of claim 1 , wherein R d is chosen from the group of a folic acid radical; a cholesterol radical; a carbohydrate radical; a vitamin A radical; a vitamin E radical; a vitamin K radical.

29. The iRNA agent of claim 28 , wherein R d is a cholesterol radical.

30. The iRNA agent of claim 1 , wherein R d is a steroid radical, which is optionally tethered to at least one carbohydrate radical.

31. The iRNA agent of claim 1 , wherein at least one of said strands leads to the cleavage of a complementary target sequence via a RISC-dependent mechanism.

32. The iRNA agent of claim 1 , wherein A is O in each occurrence.

33. The iRNA agent of claim 1 , wherein A is S in at least one occurrence.

34. The iRNA agent of claim 1 , wherein formula (I) is incorporated into a sense strand.

35. The iRNA agent of claim 34 , wherein formula (I) is incorporated into the 3′ end of the sense strand.

36. The iRNA agent of claim 1 , wherein formula (I) is incorporated into an antisense strand.

37. The iRNA agent of claim 36 , wherein formula (I) is incorporated into the 3′ end of the antisense strand.

38. A kit comprising an iRNA agent of claim 1 , a sterile container in which the iRNA agent is enclosed, and instructions for use.

39. The iRNA agent of claim 1 , wherein the iRNA is 21 nucleotides in length and there is a duplex region of about 19 pairs.

40. The iRNA agent of claim 1 , wherein the iRNA agent includes a duplex region between 17 and 23 pairs in length.

41. An iRNA agent delivery module of formula Y:

wherein:

A is an iRNA agent;

W and Z are independently NH, O, or S;

X and Y are independently S, Se, BH 3 − , C 1 -C 6 alkyl, C 6 -C 10 aryl, H, O, O − , alkoxy, or amino;

R 1 and R 3 are each, independently, hydrogen or C 1 -C 100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl;

R 2 is hydrogen or C 1 -C 100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl; or, when n is 1, R 2 may be taken together with R 4 or R 6 to form a ring of 5-12 atoms;

R 4 is hydrogen or C 1 -C 100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl; or, when n is 1, R 4 may be taken together with R 2 or R 5 to form a ring of 5-12 atoms;

R 5 is hydrogen or C 1 -C 100 alkyl optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl; or, when n is 1, R 5 may be taken together with R 4 to form a ring of 5-12 atoms;

R 6 is hydrogen or C 1 -C 100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl, or, when n is 1, R 6 may be taken together with R 2 to form a ring of 6-10 atoms;

R 7 is hydrogen, C 1 -C 100 alkyl, or C(O)(CH 2 ) q C(O)NHR 9 ;

R 9 is hydrogen, C 1 -C 100 alkyl, C 6 -C 10 aryl, or a solid support agent;

n and q are each independently 1-100; and

T is hydrogen or a functional group selected from the group consisting of a steroid, a carbohydrate, a fluorophore, an isotopically labelled moiety, a protein binding agent, a RGD peptide or a mimetic thereof, a folate, a vitamin B12, a biotin, a bisphosphonate, a polyglutamate, a polyaspartate, a multivalent mannose, a lactose, a galactose, a N-acetyl-galactosamine, a monoclonal antibody, a glycoprotein, a lectin, a melanotropin, a thyrotropin, and a combination thereof.

42. The iRNA agent delivery module of claim 41 , wherein A is an iRNA agent having a first strand and a second strand, wherein at least one subunit having a formula (I) is incorporated into at least one of said strands of the iRNA agent:

wherein:

X′ is N(CO)R 7′ , NR 7′ or CH 2 ;

Y′ is NR 8′ , O, S, CR 9′ R 10′ , or absent;

Z′ is CR 11′ R 12′ or absent;

Each of R 1′ , R 2′ , R 3′ , R 4′ , R 9′ , and R 10′ is, independently, H, OR a , OR b , (CH 2 ) n′ OR a or (CH 2 ) n′ OR b , provided that at least one of R 1′ , R 2′ , R 3′ , R 4′ , R 9′ , and R 10′ is OR a or OR b and that at least one of R 1′ , R 2′ , R 3′ , R 4′ , R 9′ , and R 10′ is (CH 2 ) n′ OR a , or (CH 2 ) n′ OR b ;

Each of R 5′ , R 6′ , R 11′ , and R 12′ is, independently, H, C 1 -C 6 alkyl optionally substituted with 1-3 R 13′ , or C(O)NHR 7′ ; or R 5′ and R 11′ together are C 3 -C 8 cycloalkyl optionally substituted with R 14′ ;

R 7 is R d ; or C 1 -C 20 alkyl substituted with NR c R d or NHC(O)R d ;

R 8′ is C 1 -C 6 alkyl;

R 13′ is hydroxy, C 1 -C 4 alkoxy, or halo;

R 14′ is NR c R 7 ;

R a is H or

R b is H or

wherein the Strand in each occurrence is independently the first strand or second strand of the iRNA agent;

each of A′ and C′ is, independently, O or S; and

B′ is OH, O − , or

R c is H or C 1 -C 6 alkyl;

R d is H or a ligand; and

n′ is 1-4.

43. The iRNA agent delivery module of claim 41 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each H.

44. The iRNA agent delivery module of claim 41 , wherein n is 1.

45. The iRNA agent delivery module of claim 41 , wherein T is a steroid, a carbohydrate, or a combination thereof.

46. The iRNA agent delivery module of claim 41 , wherein T is a cholesterol radical.

47. The iRNA agent delivery module of claim 41 , wherein T is a steroid radical, which is optionally tethered to at least one carbohydrate radical.

48. The iRNA agent of claim 1 , wherein R d is a ligand selected from the group consisting of a lipophile, a lipid, a steroid, a terpene, a vitamin, a carbohydrate, a protein, a protein binding agent, an integrin targeting molecule, polycationic, a peptide or peptide mimic, a polyamine, a dye, an intercalating agent, a cross-linker, a porphyrin, a polycyclic aromatic hydrocarbon, an artificial endonuclease, a lipophilic molecule, a glycerol or ester or ether thereof, a geranyloxyhexyl group, a hexadecylglycerol, a borneol, a menthol, a 1,3-propanediol, a heptadecyl group, a palmitic acid, a myristic acid, an O3-(oleoyl)lithocholic acid, an O3-(oleoyl)cholenic acid, a dimethoxytrityl, a phenoxazine, a peptide conjugate, an alkylating agent, a phosphate, an amino, a mercapto, a PEG, a MPEG, a [MPEG] 2 , an alkyl or substituted alkyl, a radio labeled marker, an enzyme, a hapten, a transport/absorption facilitator, a synthetic ribonuclease, a dinitrophenyl, a HRP, an AP, and a derivative and a combination thereof.