SELECTIVE ANTISENSE COMPOUNDS AND USES THEREOF

• US 20150376625A1
• Filed: 02/04/2014
• Published: 12/31/2015
• Est. Priority Date: 02/04/2013
• Status: Active Application

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Oestergaard, Michael, Seth, Punit P., Swayze, Eric E.
• Granted Patent: US 10,260,069 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• 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 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• 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 2310/33 of the base
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/335 Modified T or U
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses
• CPC Class Codes: C12N 2320/53 reducing unwanted side-effects

Abstract

The present disclosure provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell. In certain embodiments, certain oligomeric compounds selectively reduce the expression of a target nucleic acid transcript relative to a non-target nucleic acid transcript.

Claims

1. A oligomeric compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides, wherein the modified oligonucleotide has a modification motif comprising:

a 5′

-region consisting of 1-9 linked 5′

-region nucleosides, each independently selected from among a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 5′

-region nucleoside is a modified nucleoside and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-10 linked 3′

-region nucleosides, wherein each 3′

-region nucleoside comprises a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 6-10 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; and

wherein the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target region of a nucleic acid associated with a huntingtin transcript.

2. The oligomeric compound of claim 1, wherein the nucleobase sequence of the target region of the target nucleic acid differs from the nucleobase sequence of at least one non-target nucleic acid by 1-3 differentiating nucleobases.

3. The oligomeric compound of claim 1, wherein the nucleobase sequence of the target region of the target nucleic acid differs from the nucleobase sequence of at least one non-target nucleic acid by a single differentiating nucleobase.

4. The oligomeric compound of claim 2 or 3, wherein the target nucleic acid and the non-target nucleic acid are transcripts from different genes.

5. The oligomeric compound of any of claims 2 to 4, wherein the non-target nucleic acid is bone morphogenetic protein receptor, type IA.

6. The oligomeric compound of claim 2 or 3, wherein the target nucleic acid and the non-target nucleic acid are alleles of the same gene.

7. The oligomeric compound of claim 6, wherein the single differentiating nucleobase is a single-nucleotide polymorphism.

8. The oligomeric compound of claim 7, wherein the single-nucleotide polymorphism is associated with a disease.

9. The oligomeric compound of claim 8, wherein the disease is Huntington'"'"'s disease.

10. The oligomeric compound of claim 7, wherein the single-nucleotide polymorphism is selected from among:

rs6446723, rs3856973, rs2285086, rs363092, rs916171, rs6844859, rs7691627, rs4690073, rs2024115, rs11731237, rs362296, rs10015979, rs7659144, rs363096, rs362273, rs16843804, rs362271, rs362275, rs3121419, rs362272, rs3775061, rs34315806, rs363099, rs2298967, rs363088, rs363064, rs363102, rs2798235, rs363080, rs363072, rs363125, rs362303, rs362310, rs10488840, rs362325, rs35892913, rs363102, rs363096, rs11731237, rs10015979, rs363080, rs2798235, rs1936032, rs2276881, rs363070, rs35892913, rs12502045, rs6446723, rs7685686, rs3733217, rs6844859, and rs362331.

11. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is selected from among:

rs7685686, rs362303 rs4690072, rs362273, rs2024115, rs6446723, rs363064, and rs363088.

12. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is selected from among:

rs7685686, rs363088, rs362303, rs362273, rs2024115, rs6446723, and rs363064.

13. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs7685686.

14. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs363088.

15. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs362303.

16. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs362273.

17. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs2024115.

18. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs6446723.

19. The oligomeric compound of claim 8, wherein the single-nucleotide polymorphism is rs363064.

20. The oligomeric compound of any of claims 1-19, wherein the 3′

-most 5′

-region nucleoside comprises a bicyclic sugar moiety.

21. The oligomeric compound of claim 20, wherein the 3′

-most 5′

-region nucleoside comprises a cEt sugar moiety.

22. The oligomeric compound of claim 20, wherein the 3′

-most 5′

-region nucleoside comprises an LNA sugar moiety.

23. The oligomeric compound of any of claims 1-22, wherein the central region consists of 6-10 linked nucleosides.

24. The oligomeric compound of any of claims 1-23, wherein the central region consists of 6-9 linked nucleosides.

25. The oligomeric compound of claim 24, wherein the central region consists of 6 linked nucleosides.

26. The oligomeric compound of claim 24, wherein the central region consists of 7 linked nucleosides.

27. The oligomeric compound of claim 24, wherein the central region consists of 8 linked nucleosides.

28. The oligomeric compound of claim 24, wherein the central region consists of 9 linked nucleosides.

29. The oligomeric compound of any of claims 1-28, wherein each central region nucleoside is an unmodified deoxynucleoside.

30. The oligomeric compound of any of claims 1-28, wherein at least one central region nucleoside is a modified nucleoside.

31. The oligomeric compound of claim 30, wherein one central region nucleoside is a modified nucleoside and each of the other central region nucleosides is an unmodified deoxynucleoside.

32. The oligomeric compound of any of claims 30-31, wherein the modified central region nucleoside comprises a modified nucleobase.

33. The oligomeric compound of claim 32, wherein the modified nucleobase is selected from among a 2-thio pyrimidine and a 5-propyne pyrimidine.

34. The oligomeric compound of claim 32, wherein the modified nucleobase is 2-thiothymine.

35. The oligomeric compound of any of claims 30-34, wherein the 2^nd nucleoside from the 5′

-end of the central region is a modified nucleoside.

36. The oligomeric compound of any of claims 30-34, wherein the 8^th nucleoside from the 3′

-end of the central region is a modified nucleoside.

37. The oligomeric compound of any of claims 30-34, wherein the 7^th nucleoside from the 3′

-end of the central region is a modified nucleoside.

38. The oligomeric compound of any of claims 30-34, wherein the modified nucleoside is a 2-thio pyrimidine.

39. The oligomeric compound of any of claims 30-34, wherein the modified nucleobase is 2-thiothymine.

40. The oligomeric compound of any of claims 1-39, wherein the central region has a nucleoside motif selected from among:

DDDDDDD, DDDDDDDD, DDDDDDDDD, DXDDDDD, DXDDDDDD, and DXDDDDDDD;

wherein

each D is an unmodified deoxynucleoside; and

each X is a modified nucleoside.

41. The oligomeric compound of claim 40, wherein each X comprises a modified nucleobase.

42. The oligomeric compound of claim 40, wherein each X comprises 2-thio-thymidine.

43. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 1 nucleoside.

44. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 2 linked 5′

-region nucleosides.

45. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 3 linked 5′

-region nucleosides.

46. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 4 linked 5′

-region nucleosides.

47. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 5 linked 5′

-region nucleosides.

48. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 6 linked 5′

-region nucleosides.

49. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 7 linked 5′

-region nucleosides.

50. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 8 linked 5′

-region nucleosides.

51. The oligomeric compound of any of claims 1-42, wherein the 5′

region consists of 9 linked 5′

-region nucleosides.

52. The oligomeric compound of any of claims 1-51 wherein at least one 5′

-region nucleoside is an RNA-like nucleoside.

53. The oligomeric compound of any of claims 1-51 wherein each 5′

-region nucleoside is an RNA-like nucleoside.

54. The oligomeric compound of any of claims 1-53 comprising at least one modified 5′

-region nucleoside comprising a modified sugar.

55. The oligomeric compound of claim 54 comprising at least one modified 5′

-region nucleoside comprising a bicyclic sugar moiety.

56. The oligomeric compound of claim 55 comprising at least one modified 5′

-region nucleoside comprising a cEt sugar moiety.

57. The oligomeric compound of claim 55 comprising at least one modified 5′

-region nucleoside comprising an LNA sugar moiety.

58. The oligomeric compound of any of claims 54-57 comprising at least one modified 5′

-region nucleoside comprising a 2′

-substituted sugar moiety.

59. The oligomeric compound of any of claims 54-58 comprising at least one modified 5′

-region nucleoside comprising a 2′

-MOE sugar moiety.

60. The oligomeric compound of any of claims 1-59, wherein the 5′

-region has a motif selected from among;

eeeedk, eeeee, eeeeedk, eeeeeeeek, eeeeeeek, eeeeek, eeeek, eeeekk, eeek, eeek, eeekk, eek, eekk, ek, ekek, ekek, ekk, ekkdk, ekkkk, and k, wherein each “

e”

is a 2′

MOE modified nucleoside, each “

k”

is a cEt modified nucleoside, and each “

d”

is an unmodified deoxynucleoside.

61. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 2 linked 3′

-region nucleosides.

62. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 3 linked 3′

-region nucleosides.

63. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 4 linked 3′

-region nucleosides.

64. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 5 linked 3′

-region nucleosides.

65. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 6 linked 3′

-region nucleosides.

66. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 7 linked 3′

-region nucleosides.

67. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 8 linked 3′

-region nucleosides.

68. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 9 linked 3′

-region nucleosides.

69. The oligomeric compound of any of claims 1-60, wherein the 3′

region consists of 10 linked 3′

-region nucleosides.

70. The oligomeric compound of any of claims 1-69, wherein each 3′

-region nucleoside is a modified nucleoside.

71. The oligomeric compound of any of claims 1-69, wherein at least one 3′

-region nucleoside is an RNA-like nucleoside.

72. The oligomeric compound of any of claims 1-69, wherein each 3′

-region nucleoside is an RNA-like nucleoside.

73. The oligomeric compound of any of claims 1-72, comprising at least one modified 3′

-region nucleoside comprising a modified sugar.

74. The oligomeric compound of claim 73, comprising at least one modified 3′

-region nucleoside comprising a bicyclic sugar moiety.

75. The oligomeric compound of claim 74, comprising at least one modified 3′

-region nucleoside comprising a cEt sugar moiety.

76. The oligomeric compound of claim 74, comprising at least one modified 3′

-region nucleoside comprising an LNA sugar moiety.

77. The oligomeric compound of any of claims 1-73 wherein each modified 3′

-region nucleoside comprises a 2′

-substituted sugar moiety.

78. The oligomeric compound of any of claims 1-73 wherein at least one modified 3′

-region nucleoside comprises a 2′

-substituted sugar moiety.

79. The oligomeric compound of claim 77 or 78, wherein the modified 3′

-region nucleoside is a 2′

-MOE sugar moiety.

80. The oligomeric compound of any of claims 1-73, wherein the 3′

-region has a motif selected from among;

eee, eeee, eeeee, eeeeee, eeeeeee, eeeeeeee, eeeeeeeee, eeeeeeeeee, eeeekek, eeeekeke, eeek, eeeke, eeekek, eeekeke, eeekekee, eeekk, eeke, eekek, eekeke, eekekee, eekk, kee, keee, keeee, keeeke, keeekee, keek, keeke, keekee, keekeee, keekk, keke, kekee, kke, kkeee, kkeek, and kkke, wherein each “

e”

is a 2′

MOE modified nucleoside and each “

k”

is a cEt modified nucleoside.

81. The oligomeric compound of claims 1-80, wherein the 5′

-region has a motif selected from among;

eeeedk, eeeee, eeeeedk, eeeeeeeek, eeeeeeek, eeeeek, eeeek, eeeekk, eeek, eeek, eeekk, eek, eekk, ek, ekek, ekek, ekk, ekkdk, ekkkk, and k;

wherein the 3′

-region has a motif selected from among;

eee, eeee, eeeee, eeeeee, eeeeeee, eeeeeeee, eeeeeeeee, eeeeeeeeee, eeeekek, eeeekeke, eeek, eeeke, eeekek, eeekeke, eeekekee, eeekk, eeke, eekek, eekeke, eekekee, eekk, kee, keee, keeee, keeeke, keeekee, keek, keeke, keekee, keekeee, keekk, keke, kekee, kke, kkeee, kkeek, and kkke;

wherein the central region has a nucleoside motif selected from among;

DDDDDDD, DDDDDDDD, DDDDDDDDD, DXDDDDD, DXDDDDDD, and DXDDDDDDD; and

wherein each “

e”

is a 2′

MOE modified nucleoside, each “

k”

is a cEt modified nucleoside, each “

d”

is an unmodified deoxynucleoside, and each “

X”

is a modified nucleoside or a modified nucleobase.

82. The oligomeric compound of claim 81, wherein each X comprises a 2-thio-thymidine.

83. The oligomeric compound of any of claims 1-82 comprising at least one modified internucleoside linkage.

84. The oligomeric compound of claim 83, wherein each internucleoside linkage is a modified internucleoside linkage.

85. The oligomeric compound of claim 83 or 84 comprising at least one phosphorothioate internucleoside linkage.

86. The oligomeric compound of claim 84, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

87. The oligomeric compound of claim 83, wherein the 5′

-most internucleoside linkage of the 5′

-region is a phosphorothioate internucleoside linkage, wherein the 3′

-most internucleoside linkage of the 3′

-region is a phosphorothioate internucleoside linkage, and wherein each internucleoside linkage of the central region is a phosphorothioate internucleoside linkage.

88. The oligomeric compound of claim 83, wherein the 5′

-most internucleoside linkage of the 5′

-region is a phosphorothioate internucleoside linkage, wherein the 3′

-most internucleoside linkage of the 3′

-region is a phosphorothioate internucleoside linkage, wherein each internucleoside linkage of the central region is a phosphorothioate internucleoside linkage, and wherein each remaining internucleoside linkage is a phosphodiester internucleoside linkage.

89. The oligomeric compound of claim 87, wherein the oligomeric compound contains 2 phosphodiester internucleoside linkages.

90. The oligomeric compound of claim 87, wherein the oligomeric compound contains 3 phosphodiester internucleoside linkages.

91. The oligomeric compound of claim 87, wherein the oligomeric compound contains 4 phosphodiester internucleoside linkages.

92. The oligomeric compound of claim 87, wherein the oligomeric compound contains 5 phosphodiester internucleoside linkages.

93. The oligomeric compound of claim 87, wherein the oligomeric compound contains 6 phosphodiester internucleoside linkages.

94. The oligomeric compound of claim 87, wherein the 5′

-region of the oligomeric compound contains 1 phosphodiester internucleoside linkage.

95. The oligomeric compound of claim 87, wherein the 5′

-region of the oligomeric compound contains 2 phosphodiester internucleoside linkages.

96. The oligomeric compound of claim 87, wherein the 5′

-region of the oligomeric compound contains 3 phosphodiester internucleoside linkages.

97. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 1 phosphodiester internucleoside linkage.

98. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 2 phosphodiester internucleoside linkages.

99. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 3 phosphodiester internucleoside linkages.

100. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 4 phosphodiester internucleoside linkages.

101. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 5 phosphodiester internucleoside linkages.

102. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3′

-region of the oligomeric compound contains 6 phosphodiester internucleoside linkages.

103. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 2nd, internucleoside bond from 3′

-end of the oligomeric compound is a phosphodiester internucleoside linkage.

104. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3rd, internucleoside bond from 3′

-end of the oligomeric compound is a phosphodiester internucleoside linkage.

105. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 2^nd, 3^rd and 4^th internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

106. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3^rd and 4^th internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

107. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3^rd, 4^th, and 5^th, internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

108. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 4^th and 5^th internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

109. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 3^rd, 4^th, 5^th, and 6^th, internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

110. The oligomeric compound of any of claims 87 or 94 to 96, wherein the 2^nd, 3^rd, 4^th, 5^th, and 6^th, internucleoside bonds from 3′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

111. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 2^nd internucleoside bond from 5′

-end of the oligomeric compound is a phosphodiester internucleoside linkage.

112. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 3^rd internucleoside bond from 5′

-end of the oligomeric compound is a phosphodiester internucleoside linkage.

113. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 2^nd and 3^rd internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

114. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 2^nd, 3^rd and 4^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

115. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 3^rd and 4^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

116. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 2^nd, 3^rd, 4^th, and 5^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

117. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 3^rd, 4^th, and 5^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

118. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 3^rd, 4^th, 5^th, and 6^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

119. The oligomeric compound of any of claims 87 or 97 to 110, wherein the 3^rd, 4^th, 5^th, 6^th, and 7^th internucleoside bonds from 5′

-end of the oligomeric compound are phosphodiester internucleoside linkages.

120. The oligomeric compound of any of claims 1-119 comprising at least one conjugate group.

121. The oligomeric compound of claim 1-120, wherein the conjugate group consists of a conjugate.

122. The oligomeric compound of claim 120, wherein the conjugate group consists of a conjugate and a conjugate linker.

123. The oligomeric compound of any of claims 1-122, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to the nucleobase sequence of the target region of the target nucleic acid.

124. The oligomeric compound of any of claims 1-122, wherein the nucleobase sequence of the modified oligonucleotide contains one mismatch relative to the nucleobase sequence of the target region of the target nucleic acid.

125. The oligomeric compound of any of claims 1-122, wherein the nucleobase sequence of the modified oligonucleotide contains two mismatches relative to the nucleobase sequence of the target region of the target nucleic acid.

126. The oligomeric compound of any of claims 1-122, wherein the nucleobase sequence of the modified oligonucleotide comprises a hybridizing region and at least one non-targeting region, wherein the nucleobase sequence of the hybridizing region is complementary to the nucleobase sequence of the target region of the target nucleic acid.

127. The oligomeric compound of claim 126, wherein the nucleobase sequence of the hybridizing region is 90% complementary to the nucleobase sequence of the target region of the target nucleic acid.

128. The oligomeric compound of claim 126, wherein the nucleobase sequence of the hybridizing region is 95% complementary to the nucleobase sequence of the target region of the target nucleic acid.

129. The oligomeric compound of claim 126, wherein the nucleobase sequence of the hybridizing region is 100% complementary to the nucleobase sequence of the target region of the target nucleic acid.

130. The oligomeric compound of claim 126, wherein the nucleobase sequence of the hybridizing region contains one mismatch relative to the nucleobase sequence of the target region of the target nucleic acid.

131. The oligomeric compound of any of claims 126-129, wherein the nucleobase sequence of at least one non-targeting region is complementary to a portion of the hybridizing region of the modified oligonucleotide.

132. The oligomeric compound of claim 126, wherein the nucleobase sequence of at least one non-targeting region is 100% complementary to a portion of the hybridizing region of the modified oligonucleotide.

133. The oligomeric compound of claim 126 wherein the nucleobase sequence of the modified oligonucleotide comprises two non-targeting regions flanking a central hybridizing region.

134. The oligomeric compound of claim 133, wherein the two non-targeting regions are complementary to one another.

135. The oligomeric compound of claim 134, wherein the two non-targeting regions are 100% complementary to one another.

136. The oligomeric compound of any of claims 2-135, wherein the nucleobase sequence of the modified oligonucleotide aligns with the nucleobase sequence of the target region of the target nucleic acid such that a distinguishing nucleobase of the target region of the target nucleic acid aligns with a target-selective nucleoside within the central region of the modified oligonucleotide.

137. The oligomeric compound of any of claims 3-135, wherein the nucleobase sequence of the modified oligonucleotide aligns with the nucleobase of the target region of the target nucleic acid such that the single distinguishing nucleobase of the target region of the target nucleic acid aligns with a target-selective nucleoside within the central region of the modified oligonucleotide.

138. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is the 5′

-most nucleoside of the central region.

139. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is the 2^nd nucleoside from the 5′

-end of the central region.

140. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 3^th nucleoside from the 5′

-end of the central region.

141. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 4^th nucleoside from the 5′

-end of the central region.

142. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 5^th nucleoside from the 5′

-end of the central region.

143. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 6^th nucleoside from the 5′

-end of the central region.

144. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 7^th nucleoside from the 5′

-end of the central region.

145. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 8^th nucleoside from the 5′

-end of the central region.

146. The oligomeric compound of claim 136 or 137, wherein the target-selective nucleoside is at the 9^th nucleoside from the 5′

-end of the central region.

147. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 2^nd nucleoside from the 3′

-end of the central region.

148. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 3^rd nucleoside from the 3′

-end of the central region.

149. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 4^th nucleoside from the 3′

-end of the central region.

150. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 5^th nucleoside from the 3′

-end of the central region.

151. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 6^th nucleoside from the 3′

-end of the central region.

152. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 7^th nucleoside from the 3′

-end of the central region.

153. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 8^th nucleoside from the 3′

-end of the central region.

154. The oligomeric compound of any of claim 136 or 137, wherein the target-selective nucleoside is at the 9^th nucleoside from the 3′

-end of the central region.

155. The oligomeric compound of any of claims 1-154, wherein the oligomeric compound has a nucleobase sequence comprising a nucleobase sequence selected from among SEQ ID NO. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39.

156. The oligomeric compound of any of claims 1-154, wherein the oligomeric compound has a nucleobase sequence selected from among SEQ ID NO. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39.

157. The oligomeric compound of any of claims 1-156, wherein target-selective nucleoside is an unmodified deoxynucleoside.

158. The oligomeric compound of any of claims 1-156, wherein target-selective nucleoside is a modified nucleoside.

159. The oligomeric compound of any of claims 1-156, wherein the target-selective nucleoside is a sugar modified nucleoside.

160. The oligomeric compound of claim 159, wherein the target-selective nucleoside comprises a sugar modification selected from among:

2′

-MOE and cEt.

161. The oligomeric compound of any of claims 1-160, wherein the target-selective nucleoside comprises a nucleobase modification.

162. The oligomeric compound of claim 161, wherein the modified nucleobase is selected from among:

a 2-thio pyrimidine and a 5-propyne pyrimidine.

163. The oligomeric compound of any of claims 1-162, wherein the oligomeric compound is an antisense compound.

164. The oligomeric compound of claim 163, wherein the oligomeric compound selectively reduces expression of the target relative to the non-target.

165. The oligomeric compound of claim 164, wherein the oligomeric compound reduces expression of target at least two-fold more than it reduces expression of the non-target.

166. The oligomeric compound of claim 165, having an EC₅₀ for reduction of expression of target that is at least two-fold lower than its EC₅₀ for reduction of expression of the non-target, when measured in cells.

167. The oligomeric compound of claim 165, having an ED₅₀ for reduction of expression of target that is at least two-fold lower than its ED₅₀ for reduction of expression of the non-target, when measured in an animal.

168. A pharmaceutical composition comprising an oligomeric compound of any of claims 1-167 and a pharmaceutically acceptable carrier or diluent.