CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE

• US 20140343123A1
• Filed: 05/01/2014
• Published: 11/20/2014
• Est. Priority Date: 05/01/2013
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Prakash, Thazha P., Seth, Punit P., Swayze, Eric E.
• Granted Patent: US 9,127,276 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/31 of the backbone
• 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 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 : having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 : Conjugate
• CPC Class Codes: C12N 2310/3511 : intercalating or cleaving agent
• CPC Class Codes: C12N 2310/3513 : Protein; Peptide
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3525 : MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/353 : linked to the nucleic acid via an atom other than carbon
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12Y 301/03048 : Protein-tyrosine-phosphatase (3.1.3.48)

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

Claims

1. A compound having the formula (XXVI):

2. The compound of claim 1, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

3. The compound of claim 1 or 2, wherein the linker does not comprise a pyrrolidine.

4. The compound of any of claim 1 or 2, wherein the linker has the formula:

5. The compound of any of claims 1 to 4, wherein T₂ has the formula:

6. The compound of any of claims 1 to 5, wherein T₂ has the formula:

7. The compound of any of claims 1 to 6, wherein T₂ or T₃ is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

8. The compound of claim 7, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

9. The compound of claim 8, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among:

a 2′

-MOE nucleoside, a 2′

-OMe nucleoside, a 2′

-F nucleoside, a (4′

-CH₂—

O-2′

) bicyclic nucleoside, a (4′

-(CH₂)₂—

O-2′

) bicyclic nucleoside, a (4′

-C(CH₃)H—

O-2′

) bicyclic nucleoside; and

a morpholino.

10. The compound of any of claims 7 to 9, wherein the modified oligonucleotide has a gapmer sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

11. The compound of claim 10, wherein each 5′

-region nucleoside is a modified nucleoside;

each 3′

-region nucleoside is a modified nucleoside; and

each central region nucleoside is an unmodified deoxynucleoside.

12. The compound of any of claims 10 to 11, wherein the 5′

-region consists of 2-5 linked 5′

-region nucleosides;

the 3′

-region consists of 2-5 linked 3′

-region nucleosides; and

the central region consists of 8-10 central region nucleosides.

13. The compound of any of claims 7 to 12, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

14. The compound of any of claims 7 to 13, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

15. The compound of any of claims 7 to 14, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

16. The compound of any of claims 7 to 15, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′

-end of the modified oligonucleotide.

17. The compound of any of claims 7 to 15, wherein the modified oligonucleotide is attached to the remainder of the compound at the 3′

-end of the modified oligonucleotide.

18. The compound of any of claims 7 to 17, wherein the modified oligonucleotide is an antisense oligonucleotide.

19. The compound of claim any of claims 7 to 18, wherein the modified oligonucleotide is single-stranded.

20. The compound of any of claims 7 to 18, wherein the modified oligonucleotide is double-stranded.

21. The compound of any of claims 7 to 20, wherein the modified oligonucleotide activates the RISC pathway.

22. The compound of any of claims 7 to 20, wherein the modified oligonucleotide is an RNase H based antisense compound.

23. The compound of any of claims 7 to 20, wherein the modified oligonucleotide alters splicing of a target pre-mRNA.

24. The compound of any of claims 18 to 22, wherein the modified oligonucleotide is complementary to a target nucleic acid.

25. The compound of claim 24, wherein the target nucleic acid is selected from among:

pre-mRNA, micro-RNA, or long non-coding RNA.

26. The compound of any of claims 18 to 25, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

27. The compound of any of claims 18 to 25, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

28. The compound of any of claims 18 to 25, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

29. A method of administering the compound of any of claims 1 to 28 to an animal.

30. A method of treating a metabolic disorder comprising administering the compound of any of claims 1 to 28 to a subject in need thereof.

31. A method of treating a cardiovascular disorder comprising administering the compound of any of claims 1 to 28 to a subject in need thereof.

267. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence at least 80% identical to any of the nucleobase sequences recited in SEQ ID NOs. 17 to 159.

268. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

269. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

270. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

271. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobase of any of the sequences recited in SEQ ID NOs. 17 to 159.

272. The compound of any of claims 1-28, 32-59, 63-90, 94-121, 125-152, or 234-263, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence selected from among the sequences recited in SEQ ID NOs. 17 to 159.

32. A compound having the formula (XXXI):

33. The compound of claim 32, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

34. The compound of claim 32 or 33, wherein the linker does not comprise a pyrrolidine.

35. The compound of any of claims 32 to 34, wherein the linker is:

36. The compound of any of claims 32 to 35, wherein T₂ has the formula:

37. The compound of any of claims 32 to 36, wherein T₂ has the formula:

38. The compound of any of claims 32 to 37, wherein T₂ or T₃ is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

39. The compound of claim 38, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

40. The compound of claim 39, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among:

a 2′

-MOE nucleoside, a 2′

-OMe nucleoside, a 2′

-F nucleoside, a (4′

-CH₂—

O-2′

) bicyclic nucleoside, a (4′

-(CH₂)₂—

O-2′

) bicyclic nucleoside, a (4′

-C(CH₃)H—

O-2′

) bicyclic nucleoside; and

a morpholino.

41. The compound of any of claims 38 to 40, wherein the modified oligonucleotide has a gapmer sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

42. The compound of claim 41, wherein each 5′

-region nucleoside is a modified nucleoside;

each 3′

-region nucleoside is a modified nucleoside; and

each central region nucleoside is an unmodified deoxynucleoside.

43. The compound of any of claims 41 to 42, wherein the 5′

-region consists of 2-5 linked 5′

-region nucleosides;

the 3′

-region consists of 2-5 linked 3′

-region nucleosides; and

the central region consists of 8-10 central region nucleosides.

44. The compound of any of claims 38 to 43, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

45. The compound of any of claims 38 to 44, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

46. The compound of any of claims 38 to 45, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

47. The compound of any of claims 38 to 46, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′

-end of the modified oligonucleotide.

48. The compound of any of claims 38 to 46, wherein the modified oligonucleotide is attached to the remainder of the compound at the 3′

-end of the modified oligonucleotide.

49. The compound of any of claims 38 to 48, wherein the modified oligonucleotide is an antisense oligonucleotide.

50. The compound of claim any of claims 38 to 49, wherein the modified oligonucleotide is single-stranded.

51. The compound of any of claims 38 to 49, wherein the modified oligonucleotide is double-stranded.

52. The compound of any of claims 38 to 51, wherein the modified oligonucleotide activates the RISC pathway.

53. The compound of any of claims 38 to 51, wherein the modified oligonucleotide is an RNase H based antisense compound.

54. The compound of any of claims 38 to 51, wherein the modified oligonucleotide alters splicing of a target pre-mRNA.

55. The compound of any of claims 49 to 54, wherein the modified oligonucleotide is complementary to a target nucleic acid.

56. The compound of claim 55, wherein the target nucleic acid is selected from among:

pre-mRNA, micro-RNA, or long non-coding RNA.

57. The compound of any of claims 49 to 56, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

58. The compound of any of claims 49 to 56, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

59. The compound of any of claims 49 to 56, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

60. A method of administering the compound of any of claims 32 to 59 to an animal.

61. A method of treating a metabolic disorder comprising administering the compound of any of claims 32 to 59 to a subject in need thereof.

62. A method of treating a cardiovascular disorder comprising administering the compound of any of claims 32 to 59 to a subject in need thereof.

69. The compound of any of claims 63 to 58, wherein T₂ or T₃ is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

70. The compound of claim 69, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

71. The compound of claim 70, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among:

a 2′

-MOE nucleoside, a 2′

-OMe nucleoside, a 2′

-F nucleoside, a (4′

-CH₂—

O-2′

) bicyclic nucleoside, a (4′

-(CH₂)₂—

O-2′

) bicyclic nucleoside, a (4′

-C(CH₃)H—

O-2′

) bicyclic nucleoside; and

a morpholino.

72. The compound of any of claims 69 to 71, wherein the modified oligonucleotide has a gapmer sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

73. The compound of claim 72, wherein each 5′

-region nucleoside is a modified nucleoside;

each 3′

-region nucleoside is a modified nucleoside; and

each central region nucleoside is an unmodified deoxynucleoside.

74. The compound of any of claims 72 to 73, wherein the 5′

-region consists of 2-5 linked 5′

-region nucleosides;

the 3′

-region consists of 2-5 linked 3′

-region nucleosides; and

the central region consists of 8-10 central region nucleosides.

75. The compound of any of claims 69 to 74, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

76. The compound of any of claims 69 to 75, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

77. The compound of any of claims 69 to 76, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

78. The compound of any of claims 69 to 77, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′

-end of the modified oligonucleotide.

79. The compound of any of claims 69 to 77, wherein the modified oligonucleotide is attached to the remainder of the compound at the 3′

-end of the modified oligonucleotide.

80. The compound of any of claims 69 to 79, wherein the modified oligonucleotide is an antisense oligonucleotide.

81. The compound of claim any of claims 69 to 80, wherein the modified oligonucleotide is single-stranded.

82. The compound of any of claims 69 to 80, wherein the modified oligonucleotide is double-stranded.

83. The compound of any of claims 69 to 82, wherein the modified oligonucleotide activates the RISC pathway.

84. The compound of any of claims 69 to 82, wherein the modified oligonucleotide is an RNase H based antisense compound.

85. The compound of any of claims 69 to 82, wherein the modified oligonucleotide alters splicing of a target pre-mRNA.

86. The compound of any of claims 80 to 85, wherein the modified oligonucleotide is complementary to a target nucleic acid.

87. The compound of claim 86, wherein the target nucleic acid is selected from among:

pre-mRNA, micro-RNA, or long non-coding RNA.

88. The compound of any of claims 80 to 87, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

89. The compound of any of claims 80 to 87, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

90. The compound of any of claims 80 to 87, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

63. A compound having the formula (XXXII):

64. The compound of claim 63, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

65. The compound of claim 63 or 64, wherein the linker does not comprise a pyrrolidine.

66. The compound of any of claims 63 to 65, wherein the linker is:

67. The compound of any of claims 63 to 66, wherein T₂ has the formula:

68. The compound of any of claims 63 to 67, wherein T₂ has the formula:

91. A method of administering the compound of any of claims 63 to 90 to an animal.

92. A method of treating a metabolic disorder comprising administering the compound of any of claims 63 to 90 to a subject in need thereof.

93. A method of treating a cardiovascular disorder comprising administering the compound of any of claims 63 to 90 to a subject in need thereof.

94. A compound having the formula (XXXVIII):

95. The compound of claim 94, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

96. The compound of claim 94 or 95, wherein the linker does not comprise a pyrrolidine.

97. The compound of any of claims 94 to 96, wherein the linker is:

98. The compound of any of claims 94 to 97, wherein T₂ has the formula:

99. The compound of any of claims 94 to 98, wherein T₂ has the formula:

100. The compound of any of claims 94 to 99, wherein T₂ or T₃ is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

101. The compound of claim 100, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

102. The compound of claim 101, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among:

a 2′

-MOE nucleoside, a 2′

-OMe nucleoside, a 2′

-F nucleoside, a (4′

-CH₂—

O-2′

) bicyclic nucleoside, a (4′

-(CH₂)₂—

O-2′

) bicyclic nucleoside, a (4′

-C(CH₃)H—

O-2′

) bicyclic nucleoside; and

a morpholino.

103. The compound of any of claims 100 to 102, wherein the modified oligonucleotide has a gapmer sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

104. The compound of claim 103, wherein each 5′

-region nucleoside is a modified nucleoside;

each 3′

-region nucleoside is a modified nucleoside; and

each central region nucleoside is an unmodified deoxynucleoside.

105. The compound of any of claims 103 to 104, wherein the 5′

-region consists of 2-5 linked 5′

-region nucleosides;

the 3′

-region consists of 2-5 linked 3′

-region nucleosides; and

the central region consists of 8-10 central region nucleosides.

106. The compound of any of claims 101 to 105, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

107. The compound of any of claims 101 to 106, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

108. The compound of any of claims 101 to 107, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

109. The compound of any of claims 101 to 108, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′

-end of the modified oligonucleotide.

110. The compound of any of claims 101 to 108, wherein the modified oligonucleotide is attached to the remainder of the compound at the 3′

-end of the modified oligonucleotide.

111. The compound of any of claims 101 to 110, wherein the modified oligonucleotide is an antisense compound.

112. The compound of claim any of claims 101 to 110, wherein the modified oligonucleotide is single-stranded.

113. The compound of any of claims 101 to 110, wherein the modified oligonucleotide is double-stranded.

114. The compound of any of claims 101 to 113, wherein the modified oligonucleotide activates the RISC pathway.

115. The compound of any of claims 101 to 112, wherein the modified oligonucleotide is an RNase H based antisense compound.

116. The compound of any of claims 101 to 112, wherein the modified oligonucleotide alters splicing of a target pre-mRNA.

117. The compound of any of claims 100 to 116, wherein the modified oligonucleotide is complementary to a target nucleic acid.

118. The compound of claim 117, wherein the target nucleic acid is selected from among:

pre-mRNA, micro-RNA, or long non-coding RNA.

119. The compound of any of claims 100 to 118, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

120. The compound of any of claims 100 to 118, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

121. The compound of any of claims 100 to 118, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

122. A method of administering the compound of any of claims 94 to 121 to an animal.

123. A method of treating a metabolic disorder comprising administering the compound of any of claims 94 to 121 to a subject in need thereof.

124. A method of treating a cardiovascular disorder comprising administering the compound of any of claims 94 to 121 to a subject in need thereof.

279. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence at least 80% identical to any of the nucleobase sequences recited in SEQ ID NOs. 17 to 159.

280. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

281. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

282. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

283. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobase of any of the sequences recited in SEQ ID NOs. 17 to 159.

284. The method of any of claims 29-31, 60-62, 91-93, 122-124, 153-224, 233, or 264-266, wherein the oligomeric compound, modified oligonucleotide, or antisense oligonucleotide has a nucleobase sequence selected from among the sequences recited in SEQ ID NOs. 17 to 159.

125. A compound having the formula (XL):

126. The compound of claim 125, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

127. The compound of claim 125 or 126, wherein the linker does not comprise a pyrrolidine.

128. The compound of any of claims 125 to 126, wherein the linker is:

129. The compound of any of claims 125 to 128, wherein T₂ has the formula:

130. The compound of any of claims 125 to 129, wherein T₂ has the formula:

131. The compound of any of claims 125 to 130, wherein T₂ or T₃ is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

132. The compound of claim 131, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

133. The compound of claim 132, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among:

a 2′

-MOE nucleoside, a 2′

-OMe nucleoside, a 2′

-F nucleoside, a (4′

-CH₂—

O-2′

) bicyclic nucleoside, a (4′

-(CH₂)₂—

O-2′

) bicyclic nucleoside, a (4′

-C(CH₃)H—

O-2′

) bicyclic nucleoside; and

a morpholino.

134. The compound of any of claims 131 to 133, wherein the modified oligonucleotide has a gapmer sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

135. The compound of claim 134, wherein each 5′

-region nucleoside is a modified nucleoside;

each 3′

-region nucleoside is a modified nucleoside; and

each central region nucleoside is an unmodified deoxynucleoside.

136. The compound of any of claims 134 to 135, wherein the 5′

-region consists of 2-5 linked 5′

-region nucleosides;

the 3′

-region consists of 2-5 linked 3′

-region nucleosides; and

the central region consists of 8-10 central region nucleosides.

137. The compound of any of claims 131 to 136, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

138. The compound of any of claims 131 to 137, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

139. The compound of any of claims 131 to 138, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

140. The compound of any of claims 131 to 139, wherein the modified oligonucleotide is attached to the remainder of the compound at the 5′

-end of the modified oligonucleotide.

141. The compound of any of claims 131 to 139, wherein the modified oligonucleotide is attached to the remainder of the compound at the 3′

-end of the modified oligonucleotide.

142. The compound of any of claims 131 to 141, wherein the modified oligonucleotide is an antisense oligonucleotide.

143. The compound of claim any of claims 131 to 142, wherein the modified oligonucleotide is single-stranded.

144. The compound of any of claims 131 to 142, wherein the modified oligonucleotide is double-stranded.

145. The compound of any of claims 131 to 144, wherein the modified oligonucleotide activates the RISC pathway.

146. The compound of any of claims 131 to 144, wherein the modified oligonucleotide is an RNase H based antisense compound.

147. The compound of any of claims 131 to 144, wherein the modified oligonucleotide alters splicing of a target pre-mRNA.

148. The compound of any of claims 131 to 147, wherein the modified oligonucleotide is complementary to a target nucleic acid.

149. The compound of claim 148, wherein the target nucleic acid is selected from among:

pre-mRNA, micro-RNA, or long non-coding RNA.

150. The compound of any of claims 131 to 149, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

151. The compound of any of claims 131 to 149, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

152. The compound of any of claims 131 to 149, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

153. A method of administering the compound of any of claims 125 to 152 to an animal.

154. A method of treating a metabolic disorder comprising administering the compound of any of claims 125 to 152 to a subject in need thereof.

155. A method of treating a cardiovascular disorder comprising administering the compound of any of claims 125 to 152 to a subject in need thereof.

156. A method comprising administering a conjugated antisense compound to an animal, wherein the conjugated antisense compound comprises a modified oligonucleotide having a gapmer sugar motif and a conjugate comprising a GalNAc.

158. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

159. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

160. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

161. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

162. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

163. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

164. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

165. The method of claim 156 or 157, wherein the conjugate comprises the following structure:

166. The method of claim 156 or 157, wherein the conjugate has a branching group selected from the following structures:

167. The method of claim 156 or 157, wherein the conjugate has a linker selected from the following structures:

168. The method of any of claim 156 or 167, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

169. The method of claim 168, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

170. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

171. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 2 phosphodiester internucleoside linkages.

172. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 3 phosphodiester internucleoside linkages.

173. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 4 phosphodiester internucleoside linkages.

174. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.

175. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 6 phosphodiester internucleoside linkages.

176. The method of claim 168 or 169, wherein the modified oligonucleotide comprises at least 7 phosphodiester internucleoside linkages.

177. The method of any of claim 168 or 176, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

179. The method of any of claims 168 to 178, wherein modified oligonucleotide is at least 80% complementary to a target nucleic acid.

180. The method of any of claims 168 to 178, wherein modified oligonucleotide is at least 85% complementary to a target nucleic acid.

181. The method of any of claims 168 to 178, wherein modified oligonucleotide is at least 90% complementary to a target nucleic acid.

182. The method of any of claims 168 to 178, wherein modified oligonucleotide is 100% complementary to a target nucleic acid.

183. The method of any of claims 168 to 182, wherein the target nucleic acid is expressed in the liver.

184. The method of any of claims 168 to 183, wherein the target nucleic acid is expressed in hepatocytes.

185. The method of any of claims 168 to 184, wherein the target nucleic encodes a protein selected from among:

Androgen Receptor, Apolipoprotein (a), Apolipoprotein B, Apolipoprotein C-III, C-Reactive Protein, eIF-4E, Factor VII, Factor XI, Glucocorticoid Receptor, Glucagon Receptor, Protein Tyrosine Phosphatase 1B, STAT3, and Transthyretin.

264. The method of any of claims 156-224, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides.

265. The method of any of claims 156-224, wherein the modified oligonucleotide consists of 18 to 22 linked nucleosides.

266. The method of any of claims 156-224, wherein the modified oligonucleotide consists of 16 to 20 linked nucleosides.

291. The method of any of claims 156-224 or 279-284 wherein the conjugate comprises a cleavable moiety.

292. The method of claim 291, wherein the cleavable moiety comprises a cleavable nucleoside.

293. The method of claim 291, wherein the cleavable moiety does not comprise a cleavable nucleoside.

294. The method of claim 291, wherein the cleavable moiety is an ester bond.

295. The method of any of claims 291-294, wherein the cleavable moiety attaches directly to the oligonucleotide.

296. The method of any of claims 291-295, wherein cleavage of the cleavable moiety in an animal results in the oligonucleotide, with no portion of the conjugate remaining.

157. A method of reducing the amount or activity of a target nucleic acid in a cell in an animal comprising administering to the animal a conjugated antisense compound comprising a modified oligonucleotide and a conjugate, wherein the modified oligonucleotide has a gapmer sugar motif and the conjugate comprises a GalNAc;

and thereby reducing the amount or activity of the target nucleic acid in the cell in the animal.

178. The method of claim 178, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

186. A method of modulating splicing of a pre-mRNA target nucleic acid in a cell comprising contacting the cell with a conjugated antisense compound, wherein the conjugated antisense compound comprises a modified oligonucleotide and a conjugate;

and wherein the conjugate comprises a GalNac; and

thereby modulating splicing of the pre-mRNA target nucleic acid in the cell.

187. The method of claim 186, wherein the pre-mRNA target nucleic acid is expressed in a hepatocyte.

188. The method of claim 186 or 187, wherein the cell is in vitro.

189. The method of claim 186 or 187, wherein the cell is in vivo.

190. The method of claim 186 or 187, wherein the cell is in an animal.

191. The method of any of claim 186 or 190, wherein the modified oligonucleotide comprises at least one modified nucleoside.

192. The method of claim 191, wherein the modified oligonucleotide comprises at least one nucleoside comprising a 2′

-O(CH₂)₂OCH₃ modification.

193. The method of claim 191 or 192, wherein the modified oligonucleotide comprises at least on nucleoside comprising a 2′

-OCH₃ modification.

194. The method of any of claims 191 to 193, wherein the modified oligonucleotide comprises at least one bicyclic nucleoside.

195. The method of claim 194 comprising a (4′

-CH₂—

O-2′

) BNA nucleoside.

196. The method of claim 194 or 195 comprising a (4′

-(CH₂)₂—

O-2′

) BNA nucleoside.

197. The method of claim any of claims 194 to 196 (4′

-C(CH₃)H—

O-2′

) BNA nucleoside.

198. The method of any of claims 194 to 197 wherein each nucleoside of the modified oligonucleotide is a modified nucleoside.

199. The method of claim 198 wherein each modified nucleoside of the modified oligonucleotide comprises the same modification.

200. The method of claim 198 wherein at least two modified nucleosides of the modified oligonucleotide comprise modifications that are different from one another.

201. The method of any of claim 194 to 198 or 200 wherein at least one nucleoside of the modified oligonucleotide is an unmodified deoxynucleotide.

202. The method of any of claim 186 or 201, wherein the conjugate comprises the following structure:

203. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

204. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

205. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

206. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

207. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

208. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

209. The method of any of claims 186 to 201, wherein the conjugate comprises the following structure:

210. The method of any of claims 186 to 201, wherein the conjugate has a branching group selected from the following structures:

211. The method of any of claims 186 to 201, wherein the conjugate has a linker selected from the following structures:

212. The method of any of claims 186 to 211, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

213. The method of claim 212, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

214. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

215. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 2 phosphodiester internucleoside linkages.

216. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 3 phosphodiester internucleoside linkages.

217. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 4 phosphodiester internucleoside linkages.

218. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.

219. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 6 phosphodiester internucleoside linkages.

220. The method of any of claims 186 to 213, wherein the modified oligonucleotide comprises at least 7 phosphodiester internucleoside linkages.

221. The method of any of claims 186 to 220, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

222. The method of claim 212, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

223. The method of any of claims 186 to 222, wherein at least one nucleoside of the modified oligonucleotide is a morpholino nucleoside.

224. The method of any of claims 186 to 223, wherein each nucleoside of the modified oligonucleotide is a morpholino nucleoside.

225. A prodrug comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc and the antisense oligonucleotide is an RNAse H based antisense oligonucleotide.

226. The prodrug of claim 225, wherein the RNase H based antisense oligonucleotide is a gapmer.

227. The prodrug of claim 225 or 226, wherein the conjugate is attached to the antisense oligonucleotide at the 5′

-end of the antisense oligonucleotide.

229. The prodrug of any of claims 225-228, wherein in vivo metabolism of the prodrug results in the antisense oligonucleotide lacking the conjugate.

230. The prodrug of any of claims 225-228, wherein the prodrug is at least 5 times more potent in vivo than the antisense oligonucleotide lacking the conjugate.

231. The prodrug of any of claims 225-228, wherein the prodrug is at least 8 times more potent in vivo than the antisense oligonucleotide lacking the conjugate.

232. The prodrug of any of claims 225-228, wherein the prodrug is at least 10 times more potent in vivo than the antisense oligonucleotide lacking the conjugate.

233. A method comprising administering the prodrug of any of claims 225-232 to an animal

273. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence at least 80% identical to any of the nucleobase sequences recited in SEQ ID NOs. 17 to 159.

274. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

275. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

276. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the sequences recited in SEQ ID NOs. 17 to 159.

277. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobase of any of the sequences recited in SEQ ID NOs. 17 to 159.

278. The prodrug of any of claims 225-232, wherein the antisense oligonucleotide has a nucleobase sequence selected from among the sequences recited in SEQ ID NOs. 17 to 159.

228. A prodrug comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc and the antisense oligonucleotide is an antisense oligonucleotide that alters splicing of a pre-mRNA.

234. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, wherein the antisense oligonucleotide has a gapmer sugar motif, and wherein the nucleobase sequence of the antisense oligonucleotide is not 100% complementary to a target nucleic acid selected from among:

mouse Raf Kinase C, mouse Fas receptor, or human Phosphatase and Tensin Homolog (PTEN).

235. The compound of claim 234, wherein the conjugate is attached to the 5′

-end of the antisense oligonucleotide.

236. The compound of any of claim 234 or 235, wherein the internucleoside linkages of the antisense oligonucleotide comprise at least one phosphodiester linkage and at least one phosphorothioate linkage.

237. The compound of any of claims 234-236, wherein the conjugate group does not comprise cholane.

238. The compound of any of claims 234-237, wherein the branching group comprises a quaternary carbon or an amino acid.

258. The compound of any of claims 234-257, wherein the conjugate comprises exactly one GalNAc ligand.

259. The compound of any of claims 234-257, wherein the conjugate comprises exactly two GalNAc ligands.

260. The compound of any of claims 234-257, wherein the conjugate comprises exactly three GalNAc ligands.

261. The compound of any of claims 234-260, wherein the antisense oligonucleotide consists of 10 to 30 linked nucleosides.

262. The compound of any of claims 234-260, wherein the antisense oligonucleotide consists of 18 to 22 linked nucleosides.

263. The compound of any of claims 234-260, wherein the antisense oligonucleotide consists of 16 to 20 linked nucleosides.

285. The compound of any of claims 234-263 or 267-272 wherein the conjugate comprises a cleavable moiety.

286. The compound of claim 285, wherein the cleavable moiety comprises a cleavable nucleoside.

287. The compound of claim 285, wherein the cleavable moiety does not comprise a cleavable nucleoside.

288. The compound of claim 285, wherein the cleavable moiety is an ester bond.

289. The compound of any of claims 285-288, wherein the cleavable moiety attaches directly to the oligonucleotide.

290. The compound of any of claims 285-289, wherein cleavage of the cleavable moiety in an animal results in the oligonucleotide, with no portion of the conjugate remaining

239. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, wherein the antisense oligonucleotide has a gapmer sugar motif, and wherein the nucleobase sequence of the antisense oligonucleotide is complementary to a target nucleic acid which may be modulated for the treatment of a metabolic or cardiovascular disorder.

240. The compound of claim 239, wherein the conjugate is attached to the 5′

-end of the antisense oligonucleotide.

241. The compound of any of claim 239 or 240, wherein the internucleoside linkages of the antisense oligonucleotide comprise at least one phosphodiester linkage and at least one phosphorothioate linkage.

242. The compound of any of claims 239-241, wherein the conjugate group does not comprise cholane.

243. The compound of any of claims 239-242, wherein the branching group comprises a quaternary carbon or an amino acid.

244. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, and wherein the antisense oligonucleotide comprises at least one phosphodiester linkage and at least one phosphorothioate linkage.

245. The compound of claim 244, wherein the conjugate is attached to the 5′

-end of the antisense oligonucleotide.

246. The compound of any of claim 244 or 245, wherein the antisense oligonucleotide has a gapmer sugar motif

247. The compound of any of claims 255-246, wherein the conjugate group does not comprise cholane.

248. The compound of any of claims 244-247, wherein the branching group comprises a quaternary carbon or an amino acid.

249. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, wherein the conjugate group does not comprise cholane;

and wherein the antisense oligonucleotide has a gapmer sugar motif

250. The compound of claim 249, wherein the conjugate is attached to the 5′

-end of the antisense oligonucleotide.

251. The compound of any of claim 249 or 250, wherein the internucleoside linkages of the antisense oligonucleotide comprise at least one phosphodiester linkage and at least one phosphorothioate linkage.

252. The compound of any of claims 249-251, wherein the branching group comprises a quaternary carbon or an amino acid.

253. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, wherein the antisense oligonucleotide has a gapmer sugar motif, and wherein the branching group comprises a quaternary carbon or an amino acid.

254. The compound of claim 253, wherein the conjugate is attached to the 5′

-end of the antisense oligonucleotide.

255. The compound of any of claim 253 or 254, wherein the internucleoside linkages of the antisense oligonucleotide comprise at least one phosphodiester linkage and at least one phosphorothioate linkage.

256. The compound of any of claims 254-255, wherein the conjugate group does not comprise cholane.

257. A compound comprising an antisense oligonucleotide and a conjugate, wherein the conjugate comprises at least one GalNAc, and wherein the antisense oligonucleotide alters splicing of a pre-mRNA.