Compositions comprising alternating 2'-modified nucleosides for use in gene modulation

• US 20050080246A1
• Filed: 06/03/2004
• Published: 04/14/2005
• Est. Priority Date: 11/05/2002
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Bhat, Balkrishen, Allerson, Charles, Griffey, Richard H., Swayze, Eric E., Baker, Brenda F., Manoharan, Muthiah, Eldrup, Anne B.
• Granted Patent: US 9,150,605 B2
• Time in Patent Office: Days
• US Class Current: 536/23.100
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/343 having patterns, e.g. ==--==--==--
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance

Abstract

The present invention provides compositions comprising at least one oligomeric compound comprising an alternating motif and further include a region that is complementary to a nucleic acid target. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In preferred embodiments the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. The present invention also provides methods for modulating gene expression.

Claims

1. An oligomeric compound comprising:

a plurality of nucleosides linked together in a sequence;

said sequence comprising at least nucleosides of a first type (F) and nucleosides of a second type (S);

said first and said second types of nucleosides differing in at least one aspect from one another in that they have different 2′

-substituent groups; and

when said 2′

-substituent groups of said first and said second types of nucleosides are other than H or OH then said oligomeric compound includes at least two nucleosides of said first type and at least one nucleoside of said second type wherein said nucleosides of said first type and said nucleosides of said second type are located with respect to one another such that said sequence includes at least one FSF motif;

or

when the 2′

-substituent group of one of said first or said second type of nucleoside is H or OH then said oligomeric compound includes at least three nucleosides of said first type and at least three nucleosides of said second type and said nucleosides of said first type and said nucleosides of said second type are located with respect to one another such that said sequence includes at least one FSFSFS motif.

2. The oligomeric compound of claim 1 having at least one portion that is complementary to and capable of hybridizing to a selected nucleic acid target.

3. The oligomeric compound of claim 1 wherein said plurality of nucleosides further includes at least one nucleoside of a third type (T), said third type of nucleoside including a 2′

-substituent group and wherein said 2′

-substituent group of said third type nucleoside is different from the 2′

-substituent group of either of said first and said second type of nucleosides.

4. The oligomeric compound of claim 1 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₂CH₂—

O—

CH₃, —

OC₁-C₁₂alkyl, —

O—

CH₂—

CH₂—

CH₂—

NH₂, —

O—

(CH₂)₂—

O—

N(R₁)₂, —

O—

CH₂C(═

O)—

N(R₁)₂,—

O—

(CH₂)₂—

O—

(CH₂)₂—

N(R₁)₂, —

O—

CH₂—

CH₂—

CH₂—

NHR₁, —

N₃, —

O—

CH₂—

CH═

CH₂, —

NHCOR₁, —

NH₂, —

NHR₁, —

N(R₁)₂, —

SH, —

SR₁, —

N(H)OH, —

N(H)OR₁, —

N(R₁)OH, —

N(R₁)OR₁ or —

O—

CH₂—

N(H)—

C(═

NR₁)[N(R₁)₂];

wherein each R₁ is, independently, H, C₁-C₁₂ alkyl, a protecting group or substituted or unsubstituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl wherein the substituent groups are selected from halogen, hydroxyl, amino, azido, cyano, haloalkyl, alkenyl, alkoxy, thioalkoxy, haloalkoxy or aryl; and

wherein said oligomeric compound includes said FSF motif.

5. The oligomeric compound of claim 1 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₃, —

O—

CH₂CH₂—

O—

CH₃, —

O—

CH₂—

CH═

CH₂, N₃, NH₂, NHOH, —

O—

(CH₂)₂—

O—

N(R₁)₂, —

O—

CH₂C(O)—

N(R₁)₂, —

O—

CH₂—

CH₂—

CH₂—

NH₂, —

O—

(CH₂)₂—

O—

(CH₂)₂—

N(R₁)₂ or —

O—

CH₂—

N(H)—

C(═

NR₁)[N(R₁)₂];

wherein each R₁ is, independently, H, C₁-C₁₂ alkyl, a protecting group or substituted or unsubstituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl wherein the substituent groups are selected from halogen, hydroxyl, amino, azido, cyano, haloalkyl, alkenyl, alkoxy, thioalkoxy, haloalkoxy or aryl; and

wherein said oligomeric compound includes said FSF motif.

6. The oligomeric compound of claim 1 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₂CH₂—

O—

CH₃, —

O—

CH₃, —

O—

CH₂—

CH═

CH₂ or —

O—

CH₂—

CH—

CH₂—

NH(R_j) where R_j is H or C₁-C₁₀ alkyl.

7. The oligomeric compound of claim 1 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₃ or —

O—

CH₂CH₂—

O—

CH₃.

8. The oligomeric compound of claim 1 wherein said plurality of nucleosides further includes at least one nucleoside of a third type (T), said third type of nucleoside including a 2′

-substituent group that is different from the 2′

-substituent groups of either of said first or said second type of nucleosides.

9. The oligomeric compound of claim 8 wherein said 2′

-substituent group of said third type of nucleoside is H or OH.

10. The oligomeric compound of claim 1 wherein the 2′

-substituent group of one of said first or said second type of nucleosides is H or OH and said oligomeric compound includes said FSFSFS motif.

11. The oligomeric compound of claim 1 wherein each of said linked nucleosides is linked by a phosphodiester internucleoside linking group.

12. The oligomeric compound of claim 1 wherein each of said linked nucleosides is linked by a phosphorothioate internucleoside linking group.

13. The oligomeric compound of claim 1 wherein each of said linked nucleosides is, independently, linked by a phophosphodiester or a phosphorothioate internucleoside linking group.

14. The oligomeric compound of claim 1 wherein each of said linked nucleosides is independently linked by an internucleoside linking group wherein said internucleoside linking groups are independently selected from the group consisting of phosphodiester, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl phosphonate, alkyl phosphonate, 5′

-alkylene phosphonate, chiral phosphonate, phosphinate, phosphoramidate, 3′

-amino phosphoramidate, aminoalkylphosphoramidate, thionophosphoramiidate, thionoalkylphosphonate, thionoalkylphosphotriester, selenophosphate and boranophosphate.phosphodiester and phosphorothioate.

15. The oligomeric compound of claim 1 comprising at least one motif selected from F(SF)_n(S)_nn where n is from 2 to about 20 and nn is 0 or 1.

16. The oligomeric compound of claim 15 comprising at least two motifs independently selected from F(SF)_n(S)_nn where n is from 1 to about 20 and nn is 0 or 1.

17. The oligomeric compound of claim 16 comprising two motifs independently selected from F(SF)_n(S)_nn where n is from 1 to about 20 and nn is 0 or 1, said two motifs further separated by a region comprising a sequence of nucleosides.

18. The oligomeric compound of claim 17 comprising a sequence of nucleosides joined together such that one of said motifs is located at the 5′

-end of said sequence of nucleosides and the other of said motifs is located at the 3′

-end of said sequence of nucleosides and said motifs being separated by from about 6 to about 20 nucleosides.

19. The oligomeric compound of claim 1 having the formula X₁—

Y—

X₂;

wherein

Y is a region of from about 6 to about 18 linked nucleosides; and

each of X₁ and X₂ is, independently, a plurality of linked nucleosides having the formula F(SF)_n(S)_nn where n is from 1 to about 20 and nn is 0 or 1.

20. The oligomeric compound of claim 19 wherein each of X₁ and X₂ is, independently, FSFS, FSFSF, FSFSFS, FSFSFSF or FSFSFSFS.

21. The oligomeric compound of claim 20 wherein Y is from about 5 to about 12 linked nucleosides.

22. The oligomeric compound of claim 19 wherein each of said linked nucleosides is linked by a phosphodiester internucleoside linkage.

23. The oligomeric compound of claim 19 wherein each of said linked nucleosides is linked by a phosphorothioate internucleoside linkage.

24. The oligomeric compound of claim 19 wherein each of said linked nucleosides is, independently, linked by a phophosphodiester or a phosphorothioate internucleoside linkage.

25. The oligomeric compound of claim 19 wherein the linked nucleosides selected from F(SF)_n(S)_nn are linked by phosphodiester internucleoside linkages, the linked nucleosides comprising the Y region are linked by phosphorothioate internucleoside linkages and each of the F(SF)_n(S)_nn motifs are independently linked to the ends of the Y region by a phosphodiester or phosphorothioate internucleoside linkage.

26. The oligomeric compound of claim 19 wherein the linked nucleosides selected from F(SF)_n(S)_nn are linked by phosphorothioate internucleoside linkages, the linked nucleosides comprising the Y region are linked by phosphodiester internucleoside linkages and each of the F(SF)_n(S)_nn motifs are independently linked to the ends of the Y region by a phosphodiester or phosphorothioate internucleoside linkage.

27. The oligomeric compound of claim 1 having about 8 to about 80 nucleobases.

28. The oligomeric compound of claim 1 having about 10 to about 50 nucleobases.

29. The oligomeric compound of claim 1 having about 12 to about 30 nucleobases.

30. The oligomeric compound of claim 1 having about 12 to about 24 nucleobases.

31. The oligomeric compound of claim 1 having about 19 to about 23 nucleobases.

32. The oligomeric compound of claim 1 further comprising at least one conjugate group.

33. The oligomeric compound of claim 1 further comprising at least one terminal cap moiety.

34. The oligomeric compound of claim 33 wherein said terminal cap moiety is attached to one or both of the 3′

-terminal and 5′

-terminal ends of said oligomeric compound.

35. The oligomeric compound of claim 34 wherein said terminal cap moiety is an inverted deoxy abasic moiety.

101. A composition comprising the oligomeric compound of claim 1 having complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein, said protein comprising at least a portion of a RNA-induced silencing complex (RISC).

102. The composition of claim 101 wherein said oligomeric compound is an antisense oligomeric compound.

105. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 1.

36. A composition comprising a first oligomeric compound and a second oligomeric compound, wherein:

at least a portion of said first oligomeric compound is capable of hybridizing with at least a portion of said second oligomeric compound;

at least a portion of said first oligomeric compound is complementary to and capable of hybridizing to a selected nucleic acid target;

at least one of said first and said second oligomeric compounds comprises at least nucleosides of a first type (F) and nucleosides of a second type (S);

said first and said second types of nucleosides differing in at least one aspect from one another in that they have different 2′

-substituent groups; and

when said 2′

-substituent groups of said first and said second types of nucleosides are other than H or OH then at least one of said first and said second oligomeric compounds includes at least two nucleosides of said first type and at least one nucleoside of said second type wherein said nucleosides of said first type and said nucleosides of said second type are located with respect to one another such that said first or second oligomeric compound includes at least one FSF motif;

or

when the 2′

-substituent group of one of said first or said second type of nucleoside is H or OH then at least one of said first and said second oligomeric compounds includes at least three nucleosides of said first type and at least three nucleosides of said second type and said nucleosides of said first type and said nucleosides of said second type are located with respect to one another such that at least one of said first and said second oligomeric compounds includes at least one FSFSFS motif.

37. The composition of claim 36 wherein the 2′

-substituent groups of said first and said second types of nucleosides are other than H and OH further comprising at least one of said first and said second oligomeric compounds having at least two of said nucleosides of said first type (F) and at least two of said nucleosides of said second (S) type wherein said nucleosides of said first and said second types are alternating to give at least one of said first and said second oligomeric compounds having at least one FSFS motif.

38. The composition of claim 36 wherein the 2′

-substituent groups of said first and said second types of nucleosides are other than H and OH further comprising at least one of said first and said second oligomeric compounds having at least two of said nucleosides of said first type (F) and at least three of said nucleosides of said second (S) type wherein said nucleosides of said first and said second types are alternating to give at least one of said first and said second oligomeric compounds having at least one FSFSF motif.

39. The composition of claim 36 wherein at least one of said first and said second oligomeric compounds comprise only nucleosides of said first type and said second type and wherein said nucleosides of said first and said second types are alternating throughout the entire sequence of said oligomeric compound.

40. The composition of claim 39 wherein both of said first and said second oligomeric compounds comprise only nucleosides of said first type and said second type and wherein said nucleosides of said first and said second types are alternating throughout the entire sequence of both of said oligomeric compounds.

41. The composition of claim 40 wherein said nucleosides of said first and said second types have 2′

-substituent groups other than H and OH.

42. The composition of claim 36 further comprising nucleosides of a third type (T) wherein said nucleosides of said third type are different from said nucleosides of said first and said second type.

43. The composition of claim 42 wherein said nucleosides of said third type have 2′

-H or 2′

-OH substituent groups.

44. The composition of claim 36 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₂CH₂—

O—

CH₃, —

OC₁-C₁₂ alkyl, —

O—

CH₂—

CH₂—

CH₂—

NH₂, —

O—

(CH₂)₂—

O—

N(R₁)₂, —

O—

CH₂C(═

O)—

N(R₁)₂, —

O—

(CH₂)₂—

O—

(CH₂)₂—

N(R₁)₂, —

O—

CH₂—

CH₂—

CH₂—

NHR₁, —

N₃, —

O—

CH₂—

CH═

CH₂, —

NHCOR₁, —

NH₂, —

NHR₁, —

N(R₁)₂, —

SH, —

SR₁, —

N(H)OH, —

N(H)OR₁, —

N(R₁)OH, —

N(R₁)OR₁ or —

O—

CH₂—

N(H)—

C(═

NR₁)[N(R₁)₂; and

wherein each R₁is, independently, H, C₁-C₁₂ alkyl, a protecting group or substituted or unsubstituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl wherein the substituent groups are selected from halogen, hydroxyl, amino, azido, cyano, haloalkyl, alkenyl, alkoxy, thioalkoxy, haloalkoxy or aryl.

45. The composition of claim 36 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₃, —

O—

CH₂CH₂—

O—

CH₃, —

O—

CH₂—

CH═

CH₂, N₃, NH₂, NHOH, —

O—

(CH₂)₂, —

O—

N(R₁)₂, —

O—

CH₂—

CH₂—

CH₂—

NH₂, —

O—

(CH₂)₂—

O—

(CH₂)₂—

N(R₁)₂ or —

O—

CH₂—

N(H)—

C(═

NR₁)[N(R₁)₂];

wherein each R₁ is, independently, H, C₁-C₁₂ alkyl, a protecting group or substituted or unsubstituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl wherein the substituent groups are selected from halogen, hydroxyl, amino, azido, cyano, haloalkyl, alkenyl, alkoxy, thioalkoxy, haloalkoxy or aryl; and

wherein said oligomeric compound includes said FSF motif.

46. composition of claim 36 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₂CH₂—

O—

CH₃, —

O—

CH₃, —

O—

CH₂—

CH═

CH₂ or —

O—

CH₂—

CH—

CH₂—

NH(R_j) where R_j is H or C₁-C₁₀ alkyl.

47. composition of claim 36 wherein the 2′

-substituent groups of said first type of nucleosides and said second type nucleosides are, independently, —

F, —

O—

CH₃ or —

O—

CH₂CH₂—

O—

CH₃.

48. The composition of claim 36 wherein the 2′

-substituent groups of said first type of nucleosides and said second type of nucleosides are independently selected as —

F or —

O—

CH₃.

49. The composition of claim 36 wherein each of said nucleosides of said first and said second type have 3′

-endo conformational geometry.

50. The composition of claim 36 wherein said first type of nucleosides are 2′

-OH nucleosides.

51. The composition of claim 36 wherein said first type of nucleosides are 2′

-H nucleosides.

52. The composition of claim 36 wherein said second type of nucleosides are 2′

-fluoro nucleosides.

53. The composition of claim 36 wherein said second type of nucleosides are 2′

-O—

CH₃ nucleosides.

54. The composition of claim 36 wherein said first type of nucleosides are 2′

-fluoro nucleosides and said second type of nucleosides are 2′

-O—

CH₃ nucleosides.

55. The composition of claim 36 wherein said first oligomeric compound further comprises a 5′

-phosphate group.

56. The composition of claim 36 wherein said second oligomeric compound further comprises a 5′

-phosphate group.

57. The composition of claim 36 wherein each of said first and said second oligomeric compounds independently, comprise a 5′

-phosphate group.

58. The composition of claim 36 wherein said first oligomeric compound comprises a 3′

-terminal OH group.

59. The composition of claim 36 wherein the nucleosides of each of said first and said second oligomeric compounds are linked by phosphodiester internucleoside linking groups.

60. The composition of claim 36 wherein the nucleosides of each of said first and said second oligomeric compounds are linked by phosphorothioate internucleoside linking groups.

61. The composition of claim 36 wherein the nucleosides of one said first and said second oligomeric compound are linked by phosphorothioate internucleoside linking groups and the nucleosides of the other of said first and said second oligomeric compound are linked by phosphodiester internucleoside linking groups.

62. The composition of claim 36 wherein the nucleosides of said first oligomeric compound are linked by phosphorothioate internucleoside linking groups and the nucleosides of said second oligomeric compound are linked by phosphodiester internucleoside linking groups.

63. The composition of claim 36 wherein each of the nucleosides of said first and said second oligomeric compound are independently linked by phosphorothioate or phosphodiester internucleoside linking groups.

64. The composition of claim 36 wherein each of the nucleosides of said first and said second oligomeric compound are independently linked by an internucleoside linking group selected from the group consisting of phosphodiester, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl phosphonate, alkyl phosphonate, 5′

-alkylene phosphonate, chiral phosphonate, phosphinate, phosphoramidate, 3′

-amino phosphoramidate, aminoalkylphosphoramidate, thionophosphoramidate, thionoalkylphosphonate, thionoalkylphosphotriester, selenophosphate and boranophosphate.

65. The composition of claim 36 wherein each of said first and said second oligomeric compounds comprise only said first and said second type nucleosides and wherein said first and said second type nucleosides are alternating in both of said first and said second oligomeric compounds.

66. The composition of claim 65 wherein said first oligomeric compound has first type nucleosides starting at its 5′

-terminus and wherein the first type nucleosides of said first and said second oligomeric compounds align with each other when the first and second oligomeric compounds are hybridized.

67. The composition of claim 65 wherein said first type nucleosides comprise 2′

-F or 2′

-O—

CH₃ groups.

68. The composition of claim 65 wherein said first type nucleosides comprises one of 2′

-F or 2′

-O—

CH₃ groups and the second type nucleosides comprise the other of 2′

-F or 2′

-O—

CH₃ groups.

69. The composition of claim 65 wherein said first oligomeric compound has first type nucleosides starting at its 5′

-terminus wherein said first type nucleosides of said first oligomeric compound and said second type nucleosides of said second oligomeric compound align with each other when said first and said second oligomeric compounds are hybridized.

70. The composition of claim 68 wherein said first type nucleosides comprise 2′

-F or 2′

-O—

CH₃ groups.

71. The composition of claim 65 wherein said first type nucleosides comprises one of 2′

-F or 2′

-O—

CH₃ groups and the second type nucleosides comprise the other of 2′

-F or 2′

-O—

CH₃ groups.

72. The composition of claim 65 wherein the nucleosides of said first oligomeric compound are linked with phosphorothioate internucleoside linking groups.

73. The composition of claim 71 wherein the nucleosides of said second oligomeric compound are linked with phosphodiester internucleoside linking groups.

74. The composition of claim 36 further comprising at least one conjugate group.

75. The composition of claim 36 wherein at least one of said first and said second oligomeric compounds further comprises at least one conjugate group attached at the 3′

-end, the 5′

-end or both the 3′

-end and the 5′

-end.

76. The composition of claim 36 wherein at least one of said first and said second oligomeric compounds further comprises at least one terminal cap moiety attached at the 3′

-end, the 5′

-end or both the 3′

-end and the 5′

-end.

77. The composition of claim 76 wherein said terminal cap moiety is an inverted deoxy abasic moiety.

78. The composition of claim 76 wherein one of said first and second oligomeric compounds is a sense strand and wherein said sense strand comprises a terminal cap moiety at one or both of the 3′

-terminal and the 5′

-terminal ends.

79. The composition of claim 78 wherein said terminal cap moiety is an inverted deoxy abasic moiety.

80. The composition of claim 36 wherein said first and said second oligomeric compounds are a complementary pair of siRNA oligonucleotides.

81. The composition of claim 36 wherein at least one of said first or second oligomeric compounds comprise at least one motif selected from F(SF)_n(S)_nn where n is from 2 to about 20 and nn is 0 or 1.

82. The composition of claim 81 wherein at least one of said first or second oligomeric compounds comprises at least two motifs independently selected from F(SF)_n(S)_nn where n is from 2 to about 20 and nn is 0 or 1.

83. The composition of claim 82 wherein said two motifs are separated by a region comprising a sequence of nucleosides.

84. The composition of claim 83 wherein one of said two motifs are located at the 5′

-end of one of said first or second oligomeric compounds and the second of said two motifs is located at the 3′

-end of the same oligomeric compound and wherein from about 6 to about 20 nucleosides are located between said motifs.

85. The composition of claim 84 wherein said first or second oligomeric compound having said motifs has the formula:

X₃—

Y₂—

X₄;

wherein

Y₂ is a region of from about 6 to about 18 linked nucleosides;

each of X₃ and X₄ is, independently, a plurality of linked nucleosides having the formula F(SF)_n(S)_nn where n is from 2 to about 20 and nn is 0 or 1; and

nn is from 1 to about 3.

86. The composition of claim 85 wherein each of X₃ and X₄ is, independently, FSFS, FSFSF, FSFSFS, FSFSFSF or FSFSFSFS.

87. The composition of claim 86 wherein Y₂ is from about 5 to about 12 linked nucleosides.

88. The composition of claim 85 wherein each of said linked nucleosides is linked by a phosphodiester internucleoside linkage.

89. The composition of claim 85 wherein each of said linked nucleosides is linked by a phosphorothioate internucleoside linkage.

90. The composition of claim 85 wherein each of said linked nucleosides is, independently, linked by a phosphodiester or a phosphorothioate internucleoside linkage.

91. The composition of claim 85 wherein the linked nucleosides selected from F(SF)_n(S)_nn are linked by phosphodiester internucleoside linkages, the linked nucleosides comprising the Y region are linked by phosphorothioate internucleoside linkages and each of the F(SF)_n(S)_nn motifs are independently linked to the ends of the Y region by a phosphodiester or phosphorothioate internucleoside linkage.

92. The composition of claim 85 wherein the linked nucleosides selected from F(SF)_n(S)_nn are linked by phosphorothioate internucleoside linkages, the linked nucleosides comprising the Y region are linked by phosphodiester internucleoside linkages and each of the F(SF)_n(S)_nn motifs are independently linked to the ends of the Y region by a phosphodiester or phosphorothioate internucleoside linkage.

93. The composition of claim 36 wherein said first and said second oligomeric compounds are an antisense/sense pair of oligonucleotides.

94. The oligomeric compound of claim 36 wherein each of said first and second oligomeric compounds has about 8 to about 80 nucleobases.

95. The oligomeric compound of claim 36 wherein each of said first and second oligomeric compounds has about 10 to about 50 nucleobases.

96. The oligomeric compound of claim 36 wherein each of said first and second oligomeric compounds has about 12 to about 30 nucleobases.

97. The oligomeric compound of claim 36 wherein each of said first and second oligomeric compounds has about 12 to about 24 nucleobases.

98. The composition of claim 36 wherein each of said first and second oligomeric compounds has from about 19 to about 23 nucleobases.

99. The composition of claim 36 wherein said first oligomeric compound is an antisense oligonucleotide.

100. The composition of claim 36 wherein said second oligomeric compound is a sense oligonucleotide.

103. A composition comprising the composition of claim 36 and at least one protein, said protein comprising at least a portion of a RNA-induced silencing complex (RISC).

104. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with a composition of claim 36.