COMPOUNDS AND METHODS FOR MODULATION OF SMN2

• US 20190323006A1
• Filed: 07/17/2017
• Published: 10/24/2019
• Est. Priority Date: 07/15/2016
• Status: Abandoned Application

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Rigo, Frank, Prakash, Thazha P., Seth, Punit P.
• Application Number:
  US16/310,766
• Publication Number:
  US 20190323006A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/11 Antisense
• 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 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of spinal muscular atrophy.

Claims

1. An oligomeric compound comprising a modified oligonucleotide consisting of 14-25 linked nucleosides, wherein the modified oligonucleotide is complementary to an SMN2 pre-mRNA;

and wherein at least one nucleoside of the modified oligonucleotide has a structure of Formula II;

2. The oligomeric compound of claim 1, comprising at least one nucleoside of Formula II wherein one of R¹ and R² is not hydrogen.

3. The oligomeric compound of any of claims 1-2, wherein R¹ is hydrogen and R² is selected from among methyl, ethyl, propyl, or isopropyl for at least one nucleoside having a structure of Formula II.

4. The oligomeric compound of any of claims 1-3, comprising at least one nucleoside of Formula II wherein R¹ is hydrogen and R² is selected from among methyl or ethyl.

5. The oligomeric compound of any of claims 1-4, comprising at least one nucleoside of Formula II wherein at least one of R¹ and R² is methyl.

6. The oligomeric compound of any of claims 1-5, comprising at least one nucleoside of Formula II wherein one of R¹ and R² is hydrogen and the other of R¹ and R² is methyl.

7. The oligomeric compound of any of claims 1-6, wherein the selection for R¹ is different for at least two of the nucleosides having a structure of Formula II.

8. The oligomeric compound of any of claims 1-7, wherein the selection for R² is different for at least two of the nucleosides having a structure of Formula II.

9. The oligomeric compound of any of claims 1-6, wherein the selection for R¹ is the same for each of the nucleosides having a structure of Formula II, and the selection for R² is the same for each of the nucleosides having a structure of Formula II.

10. The oligomeric compound of any of claims 1-9, wherein Bx is selected from among adenine, guanine, cytosine, thymine, uracil, and 5-methyl cytosine.

11. The oligomeric compound of claim 1 or 2, wherein R¹ is methyl.

12. The oligomeric compound of any of claims 1-11, wherein each of at least 2 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

13. The oligomeric compound of any of claims 1-11, wherein each of 7 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

14. The oligomeric compound of any of claims 1-11, wherein each of 8 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

15. The oligomeric compound of any of claims 1-11, wherein each of 9 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

16. The oligomeric compound of any of claims 1-11, wherein each of 10 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

17. The oligomeric compound of any of claims 1-11, wherein each of 11 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

18. The oligomeric compound of any of claims 1-11, wherein each of 12 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

19. The oligomeric compound of any of claims 1-11, wherein each of 13 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

20. The oligomeric compound of any of claims 1-11, wherein each of 14 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

21. The oligomeric compound of any of claims 1-11, wherein each of 15 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

22. The oligomeric compound of any of claims 1-11, wherein each of 16 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

23. The oligomeric compound of any of claims 1-11, wherein each of 17 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

24. The oligomeric compound of any of claims 1-11, wherein each of 18 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

25. The oligomeric compound of any of claims 1-11, wherein each of 19 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

26. The oligomeric compound of any of claims 1-11, wherein each of 20 nucleosides of the modified oligonucleotide has a structure independently selected from Formula II.

27. The oligomeric compound of any of claims 1-26, wherein R¹ of at least one nucleoside having a structure of Formula II is methyl.

28. The oligomeric compound of any of claims 1-27, wherein R¹ is the same for all of the nucleosides having a structure of Formula II.

53. The oligomeric compound of any of claims 1-52, wherein the modified oligonucleotide consists of 16-23 linked nucleosides.

54. The oligomeric compound of any of claims 1-52, wherein the modified oligonucleotide consists of 18-20 linked nucleosides.

55. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide consists of 16 nucleosides.

56. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide consists of 17 nucleosides.

57. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide consists of 18 nucleosides.

58. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide consists of 19 nucleosides.

59. The oligomeric compound of any of claims 1-53, wherein the modified oligonucleotide consists of 20 nucleosides.

60. The oligomeric compound of any of claims 1-59, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

61. The oligomeric compound of any of claims 1-60, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

62. The oligomeric compound of claim 61, wherein each internucleoside linkage of the modified oligonucleotide is selected from among a phosphorothioate intemucleoside linkage and a phosphate internucleoside linkage.

63. The oligomeric compound of claim 62, wherein the phosphate intemucleoside linkage is a phosphodiester internucleoside linkage.

64. The oligomeric compound of claim 62, wherein the modified oligonucleotide has 5 phosphodiester internucleoside linkage.

65. The oligomeric compound of claim 62, wherein the modified oligonucleotide has 6 phosphodiester internucleoside linkages.

66. The oligomeric compound of claim 62, wherein the modified oligonucleotide has at least 6 phosphodiester internucleoside linkages.

67. The oligomeric compound of any of claims 1-66, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

68. The oligomeric compound of any of claims 1-67, wherein the modified oligonucleotide comprises at least one modified nucleobase.

69. The oligomeric compound of any of claims 1-68, wherein the modified oligonucleotide comprises at least one 5-methyl cytosine.

70. The oligomeric compound of any of claims 1-69, wherein each nucleobase of the modified oligonucleotide is selected from among thymine, 5-methyl cytosine, cytosine, adenine, uracil, and guanine.

71. The oligomeric compound of any of claims 1-70, wherein each cytosine of the modified oligonucleotide is a 5-methyl cytosine.

72. The oligomeric compound of any of claims 1-65, wherein each nucleobase of the modified oligonucleotide is selected from among thymine, 5-methyl cytosine, adenine, and guanine.

73. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 70% complementary to the SMN2 pre-mRNA.

74. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 75% complementary to the SMN2 pre-mRNA.

75. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 80% complementary to the SMN2 pre-mRNA.

76. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 85% complementary to the SMN2 pre-mRNA.

77. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 90% complementary to the SMN2 pre-mRNA.

78. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 95% complementary to the SMN2 pre-mRNA.

79. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is at least 100% complementary to the SMN2 pre-mRNA.

80. The oligomeric compound of any of claims 1-72, wherein the modified oligonucleotide is complementary to intron 7 of the SMN2 pre-mRNA.

81. The oligomeric compound of any of claims 1-80, wherein the modified oligonucleotide is complementary to ISS-N1 of the SMN2 pre-mRNA.

82. The oligomeric compound of any of claims 1-79, wherein the nucleobase sequence of the modified oligonucleotide comprises a sequence selected from among SEQ ID NOs:

1, 2, or 3.

83. The oligomeric compound of any of claims 1-79, wherein the nucleobase sequence of the modified oligonucleotide comprises a sequence selected from among any of SEQ ID NOs:

12-239 or 241-265.

84. The oligomeric compound of any of claims 1-79, wherein the nucleobase sequence of the modified oligonucleotide comprises a sequence selected from among any of SEQ ID NOs:

241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, or 265.

85. The oligomeric compound of any of claims 1-79, wherein the nucleobase sequence of the modified oligonucleotide consists of a sequence selected from among any of SEQ ID NOs:

1, 2, 3, or 12-239 or 241-265.

86. The oligomeric compound of any of claims 1-79, wherein the nucleobase sequence of the modified oligonucleotide consists of a sequence selected from among any of SEQ ID NOs:

241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, or 265.

87. The oligomeric compound of claim 1-79, wherein the modified oligonucleotide is complementary to exon 7 of the SMN2 pre-mRNA.

88. The oligomeric compound of claim 1-79, wherein the modified oligonucleotide is complementary to intron 6 of the SMN2 pre-mRNA.

89. The oligomeric compound of any of claims 1-79, wherein the modified oligonucleotide is complementary to an exonic splicing enhancer in exon 7 of the SMN2 pre-mRNA.

90. The oligomeric compound of any of claims 1-79, wherein the modified oligonucleotide is complementary to an aberrant exonic splicing silencer in exon 7 of the SMN2 pre-mRNA.

91. The oligomeric compound of any of claims 1-90, wherein the oligomeric compound comprises a conjugate group.

92. The oligomeric compound of claim 91, wherein the conjugate group comprises a lipid or lipophilic group.

93. The oligomeric compound of claim 92, wherein the lipid or lipophilic group is selected from among:

cholesterol, a C₁₀-C₂₆ saturated fatty acid, a C₁₀-C₂₆ unsaturated fatty acid, C₁₀-C₂₆ alkyl, a triglyceride, tocopherol, or cholic acid.

94. The oligomeric compound of claim 93, wherein the lipid or lipophilic group is a saturated hydrocarbon chain or an unsaturated hydrocarbon chain.

95. The oligomeric compound of any of claims 92-94, wherein the lipid or lipophilic group is a C₁₆ lipid.

96. The oligomeric compound of any of claims 92-94, wherein the lipid or lipophilic group is a C₁₈ lipid.

97. The oligomeric compound of any of claims 92-94, wherein the lipid or lipophilic group is C₁₆ alkyl.

98. The oligomeric compound of any of claims 92-94, wherein the lipid or lipophilic group is C₁₈ alkyl.

99. The oligomeric compound of claim 93, wherein the lipid or lipophilic group is cholesterol.

100. The oligomeric compound of claim 93, wherein the lipid or lipophilic group is tocopherol.

101. The oligomeric compound of claim 93, wherein the lipid or lipophilic group is saturated C₁₆.

102. The oligomeric compound of any of claims 91-101, wherein the conjugate group is attached to the modified oligonucleotide at the 5′

-end of the modified oligonucleotide.

103. The oligomeric compound of any of claims 91-101, wherein the conjugate group is attached to the modified oligonucleotide at the 3′

-end of the modified oligonucleotide.

104. The oligomeric compound of any of claims 91-103, wherein the conjugate group comprises a cleavable linker.

106. The oligomeric compound of any of claims 1-105 consisting of the modified oligonucleotide.

107. The oligomeric compound of any of claims 91-105 consisting of the modified oligonucleotide and the conjugate group.

108. The oligomeric compound of any of claims 1-108, wherein the oligomeric compound modulates splicing of the SMN2 pre-mRNA.

109. The oligomeric compound of any of claims 1-108, wherein the oligomeric compound is single stranded.

110. The oligomeric compound of any of claims 1-108, wherein the oligomeric compound is paired with a complementary oligomeric compound to form a double stranded compound.

111. The oligomeric compound of claim 110, wherein the complementary oligomeric compound comprises a conjugate group.

112. A pharmaceutical composition comprising the oligomeric compound of any of claims 1-111 and at least one pharmaceutically acceptable carrier or diluent.

113. A method of modulating splicing of an SMN2 pre-mRNA comprising contacting a cell, tissue, or organ with the oligomeric compound or composition of any of claims 1-112.

114. A method of promoting inclusion of exon 7 in SMN2 mRNA in a cell, tissue or organ, comprising contacting said cell, tissue or organ with the oligomeric compound of any of claims 1 to 111 or the composition of claim 112.

115. The method of claim 113 or 114, wherein the cell, tissue, or organ is in an animal.

116. The method of claims 113 or 114, wherein the cell, tissue, or organ is in a human.

117. A method comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a subject.

118. The method of claim 117, wherein the subject has SMA.

119. The method of claim 117, wherein the subject has Type I SMA.

120. The method of claim 117, wherein the subject has Type II SMA.

121. The method of claim 117, wherein the subject has Type III SMA.

122. The method of claim 117, wherein the subject has Type IV SMA.

123. A method of treating Spinal Muscular Atrophy in a patient, comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a patient in need thereof.

124. A method of treating Spinal Muscular Atrophy Type I in a patient, comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a patient in need thereof.

125. A method of treating Spinal Muscular Atrophy Type II in a patient, comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a patient in need thereof.

126. A method of treating Spinal Muscular Atrophy Type III in a patient, comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a patient in need thereof.

127. A method of treating Spinal Muscular Atrophy Type IV in a patient, comprising administering the oligomeric compound of any of claims 1 to 111 or the composition of claim 112 to a patient in need thereof.

128. The method of any of claims 122-127, wherein the oligomeric compound is administered to the central nervous system.

129. The method of claim 128, wherein the oligomeric compound is administered intrathecally.

130. The method of any of claims 123-127, wherein the oligomeric compound is administered systemically.

131. The method of claim 130, wherein the oligomeric compound is administered subcutaneously.

132. The method of claim 130, wherein the oligomeric compound is administered intramuscularly.

133. The method of any of claims 122-132, wherein the oligomeric compound is administered to the central nervous system and systemically.

134. The method of any of claims 122-132, wherein the oligomeric compound is co-administered with a second compound.

135. The method of claim 134, wherein the second compound is selected from among a small molecule and an oligomeric compound.

136. The method of claim 135, wherein the second compound is an oligomeric compound according to claims 1-111.

137. The method of any of claims 134-136, wherein the second compound is administered to the CSF.

138. The method of claim 137, wherein the second compound is administered intrathecally.

139. The method of any of claims 134-138, wherein the second compound is a second oligomeric compound comprising a second modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety.

140. The method of claim 139, wherein the modified sugar moiety of the modified nucleoside of the second modified oligonucleotide of the second oligomeric compounds is selected from 2′

-OMe and 2′

-MOE.

141. The method of any of claims 139-140, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar moiety.

142. The method of claim 141, wherein the modified sugar moiety of the second oligonucleotide is a 2′

-MOE sugar moiety.

143. The method of claim 139, wherein the second compound is an oligomeric compound comprising a morpholino oligonucleotide.

144. The method of any of claims 134-143, wherein the second oligomeric compound has the nucleobase sequence of SEQ ID NO:

1.

145. The method of claim 144, wherein the second oligomeric compound has the nucleobase sequence and chemical modification motif of Isis 396443.

146. The method of any of claims 134-145, wherein the second oligomeric compound consists of the modified oligonucleotide.

147. The method of any of claims 134-146, wherein the second compound is administered prior to administration of the oligomeric compound of any of claims 1 to 111 or the composition of claim 112.

148. The method of any of claims 134-146, wherein the second compound is administered after administration of the oligomeric compound of any of claims 1 to 111 or the composition of claim 112.

149. The method of any of claims 134-146, wherein the second compound is administered less frequently than administration of the oligomeric compound of any of claims 1 to 111 or the composition of claim 112.

150. An oligomeric compound of any of claims 1 to 111 or the composition of claim 112 for use in therapy.

151. Use of an oligomeric compound of any of claims 1 to 111 or the composition of claim 112 for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type I.

152. Use of an oligomeric compound of any of claims 1 to 111 or the composition of claim 112 for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type II

153. Use of an oligomeric compound of any of claims 1 to 111 or the composition of claim 112 for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type III.

154. Use of an oligomeric compound of any of claims 1 to 111 or the composition of claim 112 for the preparation of a medicament for the treatment of Spinal Muscular Atrophy Type IV.

155. Use of an oligomeric compound of any of claims 1 to 112 for the preparation of a medicament for the treatment of Spinal Muscular Atrophy.

156. A method comprising (i) systemically administering a compound comprising the oligomeric compound of any of claims 1-112 and (ii) administering to the CNS a compound comprising the oligomeric compound of any of claims 1-112.

157. A method comprising (i) systemically administering a compound comprising the oligomeric compound or composition of any of claims 1-112 and (ii) administering to the CNS a compound comprising a modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety selected from 2′

-OMe and 2′

-MOE.

158. A method comprising (i) systemically administering a compound comprising the oligomeric compound of any of claims 1-112 and (ii) administering to the CNS a compound comprising the oligomeric compound of any of claims 1-112.

159. A method comprising (i) systemically administering a compound comprising the oligomeric compound of any of claims 85-106 and (ii) administering to the CNS a compound comprising a modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety selected from 2′

-OMe and 2′

-MOE.

160. A method comprising (i) systemically administering a modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety selected from 2′

-OMe and 2′

-MOE and a conjugate, and (ii) administering to the CNS a compound comprising the oligomeric compound of any of claims 1-112.

162. The method of claim 160, wherein the conjugate group comprises a lipid or lipophilic group selected from cholesterol, a C10-C26 saturated fatty acid, a C10-C26 unsaturated fatty acid, C10-C26 alkyl, a triglyceride, tocopherol, and cholic acid.

163. The compound or method of any of claims 1-162, wherein the SMN2 pre-mRNA is a nucleobase sequence selected from any of SEQ ID NO:

10, 11, or 240.

29. An oligomeric compound comprising a modified oligonucleotide consisting of 14-25 linked nucleosides, wherein the modified oligonucleotide is complementary to an SMN2 pre-mRNA;

and wherein at least one nucleoside of the modified oligonucleotide comprises a 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

30. The oligomeric compound of claim 29, wherein the sugar moiety of each nucleoside comprising a 2′

-O—

(N-alkyl acetamide) modified sugar moiety is selected from 2′

-O—

(N-methyl acetamide) and 2′

-O—

(N-ethyl acetamide).

31. The oligomeric compound of claim 29 or 30, wherein each of 7 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

32. The oligomeric compound of claim 29 or 30, wherein each of 8 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

33. The oligomeric compound of claim 29 or 30, wherein each of 9 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

34. The oligomeric compound of claim 29 or 30, wherein each of 10 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

35. The oligomeric compound of claim 29 or 30, wherein each of 11 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

36. The oligomeric compound of claim 29 or 30, wherein each of 12 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

37. The oligomeric compound of claim 29 or 30, wherein each of 13 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

38. The oligomeric compound of claim 29 or 30, wherein each of 14 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

39. The oligomeric compound of claim 29 or 30, wherein each of 15 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

40. The oligomeric compound of claim 29 or 30, wherein each of 16 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

41. The oligomeric compound of claim 29 or 30, wherein each of 17 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

42. The oligomeric compound of claim 29 or 30, wherein each of 18 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

43. The oligomeric compound of claim 29 or 30, wherein each of 19 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

44. The oligomeric compound of claim 29 or 30, wherein each of 20 nucleosides of the modified oligonucleotide comprises an independently selected 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

45. The oligomeric compound of any of claims 29-44, wherein the sugar moiety of at least one of the nucleosides comprising a 2′

-O—

(N-alkyl acetamide) modified sugar moiety is a 2′

-O—

(N-methyl acetamide) modified sugar moiety.

46. The oligomeric compound of any of claims 29-45, wherein the N-alkyl group of each of the 2′

-O—

(N-alkyl acetamide) modified sugar moieties is the same N-alkyl group.

47. The oligomeric compound of any of claims 29-46, wherein each of the 2′

-O—

(N-alkyl acetamide) modified sugar moieties is a 2′

-O—

(N-methyl acetamide) sugar moiety.

48. The oligomeric compound of any of claims 29-47, wherein each sugar moiety of each nucleoside of the modified oligonucleotide is a 2′

-O—

(N-methyl acetamide) modified sugar moiety.

49. The oligomeric compound of any of claims 29-47, wherein at least one sugar moiety is not a 2′

-O—

(N-alkyl acetamide) modified sugar moiety.

50. The oligomeric compound of any of claims 29-47, wherein at least one sugar moiety is not a 2′

-O—

(N-methyl acetamide) modified sugar moiety.

51. The oligomeric compound of any of claims 29-47, wherein at least one sugar moiety is a modified sugar moiety 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-0-2′

) bicyclic nucleoside; and

a morpholino.

52. The oligomeric compound of any of claims 29-51, wherein at least one sugar moiety is an unmodified sugar moiety.

105. The oligomeric compound of claim 105 wherein the cleavable linker comprises one or more linker nucleosides.

161. A method comprising (i) systemically administering a modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety selected from 2′

-OMe and 2′

-MOE and a conjugate group, and (ii) administering to the CNS a compound comprising a modified oligonucleotide having at least one modified nucleoside comprising a modified sugar moiety selected from 2′

-OMe and 2′

-MOE.