COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT

• US 20160002627A1
• Filed: 01/09/2014
• Published: 01/07/2016
• Est. Priority Date: 01/09/2013
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Bennett, C. Frank, Hung, Gene, Rigo, Frank
• Granted Patent: US 9,926,559 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61B 5/316 Modalities, i.e. specific diagnostic methods
• CPC Class Codes: A61B 5/389 Electromyography [EMG]
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism

Abstract

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

Claims

1. A method of treating a human patient having spinal muscular atrophy comprising administering to the human patient at least one dose of an antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 pre-mRNA, wherein the antisense compound is administered into the cerebrospinal fluid at a dose of 0.1 to 20 milligrams;

and thereby ameliorating at least one symptom of spinal muscular atrophy in the human patient.

2. The method of claim 1, wherein the dose is from 0.1 to 15 milligrams.

3. The method of claim 1, wherein the dose is from 0.1 to 10 milligrams.

4. The method of claim 1, wherein the dose is from 0.1 to 5 milligrams.

5. The method of claim 1, wherein the dose is from 0.1 to 1 milligrams.

6. The method of claim 1, wherein the dose is from 0.1 to 0.5 milligrams.

7. The method of claim 1, wherein the dose is from 0.5 to 20 milligrams.

8. The method of claim 1, wherein the dose is from 0.5 to 15 milligrams.

9. The method of claim 1, wherein the dose is from 0.5 to 10 milligrams.

10. The method of claim 1, wherein the dose is from 0.5 to 5 milligrams.

11. The method of claim 1, wherein the dose is from 0.5 to 1 milligrams.

12. The method of claim 1, wherein the dose is from 1 to 20 milligrams.

13. The method of claim 1, wherein the dose is from 1 to 15 milligrams.

14. The method of claim 1, wherein the dose is from 1 to 10 milligrams.

15. The method of claim 1, wherein the dose is from 1 to 5 milligrams.

16. The method of claim 1, wherein the dose is from 3 to 20 milligrams.

17. The method of claim 1, wherein the dose is from 3 to 15 milligrams.

18. The method of claim 1, wherein the dose is from 3 to 10 milligrams.

19. The method of claim 1, wherein the dose is from 3 to 5 milligrams.

20. The method of claim 1, wherein the dose is from 5 to 20 milligrams.

21. The method of claim 1, wherein the dose is from 5 to 15 milligrams.

22. The method of claim 1, wherein the dose is from 5 to 10 milligrams.

23. The method of claim 1, wherein the dose is from 10 to 15 milligrams.

24. The method of claim 1, wherein the dose is from 10 to 20 milligrams.

25. The method of claim 1, wherein the dose is from 15 to 20 milligrams.

26. The method of claim 1, wherein the dose is about 0.1 milligrams.

27. The method of claim 1, wherein the dose is about 0.3 milligrams.

28. The method of claim 1, wherein the dose is about 0.5 milligrams.

29. The method of claim 1, wherein the dose is about 1 milligram.

30. The method of claim 1, wherein the dose is about 2 milligrams.

31. The method of claim 1, wherein the dose is about 3 milligrams.

32. The method of claim 1, wherein the dose is about 4 milligrams.

33. The method of claim 1, wherein the dose is about 5 milligrams.

34. The method of claim 1, wherein the dose is about 6 milligrams.

35. The method of claim 1, wherein the dose is about 7 milligrams.

36. The method of claim 1, wherein the dose is about 8 milligrams.

37. The method of claim 1, wherein the dose is about 9 milligrams.

38. The method of claim 1, wherein the dose is about 10 milligrams.

39. The method of claim 1, wherein the dose is about 11 milligrams.

40. The method of claim 1, wherein the dose is about 12 milligrams.

41. The method of claim 1, wherein the dose is about 13 milligrams.

42. The method of claim 1, wherein the dose is about 14 milligrams.

43. The method of claim 1, wherein the dose is about 15 milligrams.

44. The method of claim 1, wherein the dose is less than 20 milligrams.

45. The method of claim 1, wherein the dose is less than 15 milligrams.

46. The method of claim 1, wherein the dose is less than 10 milligrams.

47. The method of claim 1, wherein the dose is less than 5 milligrams.

48. The method of claim 1, wherein the dose is about 4.8 milligrams.

49. The method of claim 1, wherein the dose is about 5.16 milligrams.

50. The method of claim 1, wherein the dose is about 5.4 milligrams.

51. The method of claim 1, wherein the dose is about 7.2 milligrams.

52. The method of claim 1, wherein the dose is about 7.74 milligrams.

53. The method of claim 1, wherein the dose is about 8.10 milligrams.

54. The method of claim 1, wherein the dose is about 9.60 milligrams.

55. The method of claim 1, wherein the dose is about 10.32 milligrams.

56. The method of claim 1, wherein the dose is about 10.80 milligrams.

57. The method of claim 1, wherein the dose is about 11.3 milligrams.

58. The method of claim 1, wherein the dose is about 12.88 milligrams.

59. The method of claim 1, wherein the dose is about 13.5 milligrams.

60. The method of claim 1, wherein the dose is about 14.13 milligrams.

61. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 10 mL of a pharmaceutically acceptable diluent.

62. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 9 mL of a pharmaceutically acceptable diluent.

63. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 8 mL of a pharmaceutically acceptable diluent.

64. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 7 mL of a pharmaceutically acceptable diluent.

65. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 6 mL of a pharmaceutically acceptable diluent.

66. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 5 mL of a pharmaceutically acceptable diluent.

67. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 4 mL of a pharmaceutically acceptable diluent.

68. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 3 mL of a pharmaceutically acceptable diluent.

69. The method of any of claims 1-60, wherein the dose is delivered in a volume of 1 to 2 mL of a pharmaceutically acceptable diluent.

70. The method of any of claims 1-60, wherein the dose is delivered in a volume of 5 mL of a pharmaceutically acceptable diluent.

71. The method of any of claims 1-60, wherein the dose is delivered in a volume of 4 mL of a pharmaceutically acceptable diluent.

72. The method of any of claims 1-60, wherein the dose is delivered in a volume of 6 mL of a pharmaceutically acceptable diluent.

73. The method of any of claims 1-60, wherein the dose is delivered in a volume of 4.3 mL of a pharmaceutically acceptable diluent.

74. The method of any of claims 1-60, wherein the dose is delivered in a volume of 4.5 mL of a pharmaceutically acceptable diluent.

75. The method of any of claims 1-60, wherein the dose is delivered in a volume of 4.7 mL of a pharmaceutically acceptable diluent.

76. The method of any of claims 1-60, wherein the dose is delivered in a volume, wherein the volume of the pharmaceutically acceptable diluent is determined by CSF volume scaling.

77. The method of any of claims 1-60, wherein the pharmaceutically acceptable diluent is artificial CSF.

78. The method of any of claims 1-60, wherein the pharmaceutically acceptable diluent is CSF.

79. The method of any of claims 60-78, wherein the concentration of the antisense compound is 0.2 mg/mL.

80. The method of any of claims 60-78, wherein the concentration of the antisense compound is 0.6 mg/mL.

81. The method of any of claims 60-78, wherein the concentration of the antisense compound is 1.2 mg/mL.

82. The method of any of claims 60-78, wherein the concentration of the antisense compound is 1.8 mg/mL.

83. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.0 mg/mL.

84. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.2 mg/mL.

85. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.4 mg/mL.

86. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.6 mg/mL.

87. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.7 mg/mL.

88. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.8 mg/mL.

89. The method of any of claims 60-78, wherein the concentration of the antisense compound is 2.9 mg/mL.

90. The method of any of claims 60-78, wherein the concentration of the antisense compound is 3.0 mg/mL.

91. The method of any of claims 60-78, wherein the concentration of the antisense compound is 3.1 mg/mL.

92. The method of any of claims 60-78, wherein the concentration of the antisense compound is 3.2 mg/mL.

93. The method of any of claims 60-78, wherein the concentration of the antisense compound is 3.3 mg/mL.

94. The method of any of claims 60-78, wherein the antisense compound consists of ISIS 396443.

95. The method of any of claims 1-94, wherein the dose is an equivalent dose.

96. The method of any of claims 1-94, wherein the dose is an adjusted dose.

97. The method of claim 96, wherein the adjusted dose is determined by CSF volume scaling.

98. The method of any of claims 1-97, wherein the administration is into the intrathecal space.

99. The method of any of claims 1-98, wherein the administration is into the intrathecal space between the L3 and L4 vertebrae.

100. The method of any of claims 1-98, wherein the administration is into the intrathecal space between the L2 and L3 vertebrae.

101. The method of any of claims 1-98, wherein the administration is into the intrathecal space between the L4 and L5 vertebrae.

102. The method of any of claims 1-98, wherein the administration is into the intrathecal space between the L5 and L6 vertebrae.

103. The method of any of claims 1-102, wherein the administration is by a bolus injection.

104. The method of any of claims 1-103, wherein the administration is by infusion with a delivery pump.

105. The method of any of claims 1-104, wherein the administration is by lumbar puncture.

106. The method of any of claims 1-105, wherein the administration is through a 21, 22, 23, 24, or 25 gauge needle.

107. The method of any of claims 1-105, wherein the administration is through a 21 gauge needle.

108. The method of any of claims 1-105, wherein the administration is through a 22 gauge needle.

109. The method of any of claims 1-105, wherein the administration is through a 23 gauge needle.

110. The method of any of claims 1-105, wherein the administration is through a 24 gauge needle.

111. The method of any of claims 1-105, wherein the administration is through a 25 gauge needle.

112. The method of any of claims 106-111, wherein the needle is a spinal anesthesia needle.

113. The method of any of claims 1-112 comprising administering a series of at least two doses.

114. The method of any of claims 1-112 comprising administering a series of at least three doses.

115. The method of any of claims 1-112 comprising administering a series of at least four doses.

116. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about two weeks between doses.

117. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about three weeks between doses.

118. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about four weeks between doses.

119. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about five weeks between doses.

120. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about six weeks between doses.

121. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about seven weeks between doses.

122. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about eight weeks between doses.

123. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about three months between doses.

124. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about four months between doses.

125. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about six months between doses.

126. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about 11 months between doses.

127. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about 12 months between doses.

128. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about 13 months between doses.

129. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about 14 months between doses.

130. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of about 15 months between doses.

131. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least one month between doses.

132. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least two months between doses.

133. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least three months between doses.

134. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least four months between doses.

135. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least five months between doses.

136. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least six months between doses.

137. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least 11 months between doses.

138. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least 12 months between doses.

139. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least 13 months between doses.

140. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least 14 months between doses.

141. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of at least 15 months between doses.

142. The method of any of claims 113-115, wherein the doses are administered with a dose frequency of more than six months between doses.

143. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 12-18 days after the first dose.

144. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 15 days after the first dose.

145. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 24-34 days after the first dose.

146. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 29 days after the first dose.

147. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 80-90 days after the first dose.

148. The method of any of claims 113-115, wherein a first dose is administered and wherein the second dose is administered 85 days after the first dose.

149. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 12-18 days after the first dose, and wherein a third dose is administered 80-90 days after the first dose.

150. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 24-34 days after the first dose, and wherein a third dose is administered 80-90 days after the first dose.

151. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 15 days after the first dose, and wherein a third dose is administered 80-90 days after the first dose.

152. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 29 days after the first dose, and wherein a third dose is administered 80-90 days after the first dose.

153. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 12-18 days after the first dose, and wherein a third dose is administered 85 days after the first dose.

154. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 24-34 days after the first dose, and wherein a third dose is administered 85 days after the first dose.

155. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 15 days after the first dose, and wherein a third dose is administered 85 days after the first dose.

156. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 15 days after the first dose, and wherein a third dose is administered 85 days after the first dose.

157. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 13-16 days after the first dose, and wherein a third dose is administered 208 to 215 days after the first dose.

158. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 15 days after the first dose, and wherein a third dose is administered 208 to 215 days after the first dose.

159. The method of any of claims 113-115, wherein a first dose is administered, wherein a second dose is administered 15 days after the first dose, and wherein a third dose is administered 211 days after the first dose.

160. The method of any of claims 1-159, comprising co-administration of the antisense compound and at least one other therapy.

161. The method of claim 160, wherein antisense compound and at least one other therapy are co-administered at the same time.

162. The method of claim 160, wherein the antisense compound is administered prior to administration of the at least one other therapy.

163. The method of claim 160, wherein the antisense compound is administered after administration of the at least one other therapy.

164. The method of any of claims 160-163 wherein the at least one other therapy comprises administration of one or more of valproic acid, riluzole, hydroxyurea, and a butyrate.

165. The method of any of claims 160-163 wherein at least one other therapy comprises administration of trichostatin-A.

166. The method of any of claims 160-163 wherein the at least one other therapy comprises administration of stem cells.

167. The method of any of claims 160-163 wherein at least one other therapy comprises administration of Insulin-like Growth Factor-1.

168. The method of any of claims 160-163 wherein at least one other therapy is gene therapy.

169. The method of any of claims 1-168, wherein the subject has type I SMA

170. The method of any of claims 1-168, wherein the subject has type II SMA.

171. The method of any of claims 1-168, claims wherein the subject has type III SMA.

172. The method of any of claims 1-171, wherein a first dose is administered in utero.

173. The method of any of claims 1-171, wherein a first dose is administered within 1 week of birth of the subject.

174. The method of any of claims 1-171, wherein a first dose is administered within 1 month of birth of the subject.

175. The method of any of claims 1-171, wherein a first dose is administered within 3 months of birth of the subject.

176. The method of any of claims 1-171, wherein a first dose is administered within 6 months of birth of the subject.

177. The method of any of claims 1-171, wherein a first dose is administered when the subject is from 1 to 2 years of age.

178. The method of any of claims 1-171, wherein a first dose is administered when the subject is from 1 to 15 years of age.

179. The method of any of claims 1-171, wherein a first dose is administered when the subject is older than 15 years of age.

180. The method of any of claims 1-179, comprising identifying a subject having SMA.

181. The method of claim 180, wherein the subject is identified by measuring electrical activity of one or more muscles of the subject.

182. The method of claim 180, wherein the subject is identified by a genetic test to determine whether the subject has a mutation in the subject'"'"'s SMN1 gene.

183. The method of claim 180, wherein the subject is identified by muscle biopsy.

184. The method of any of claims 1-183, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises improved motor function in the subject.

185. The method of any of claims 1-184, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises delayed or reduced loss of motor function in the subject.

186. The method of any of claims 1-184, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises improved respiratory function.

187. The method of any of claims 1-184, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises improved survival.

188. The method of any of claims 1-184, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises stable CMAP.

189. The method of any of claims 1-184, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded.

190. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 3 points.

191. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 4 points.

192. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 5 points.

193. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 6 points.

194. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 7 points.

195. The method of claim 189, wherein the patient demonstrates an increase in a patient'"'"'s Hammersmith Motor Function Scale-Expanded greater than 8 points.

196. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded occurs 85 days after first dose.

197. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded improves up to 85 days after first dose.

198. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded occurs 9, 10, 11, 12, or 13 months after first dose.

199. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded improves up to 9, 10, 11, 12, or 13 months after first dose.

200. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded occurs 14 months after first dose.

201. The method of any of claims 189 to 195, wherein the increase a patient'"'"'s Hammersmith Motor Function Scale-Expanded improves up to 14 months after first dose.

202. The method of any of claims 1-202, wherein ameliorating at least one symptom of spinal muscular atrophy comprises a stable Hammersmith Motor Function Scale-Expanded.

203. The method of any of claims 1-202, wherein the ameliorating at least one symptom of spinal muscular atrophy comprises an increase in a patient'"'"'s MUNE.

204. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 5.

205. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 8.

206. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 10.

207. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 12.

208. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 14.

209. The method of claim 203, wherein the patient demonstrates an increase in a patient'"'"'s MUNE of at least 20.

210. The method of any of claims 1-209, wherein at least one nucleoside of the antisense oligonucleotide comprises a modified sugar moiety.

211. The method of claim 210, wherein the at least one modified sugar moiety comprises a 2′

-methoxyethyl sugar moiety.

212. The method of any of claims 1-211, wherein essentially each nucleoside of the antisense oligonucleotide comprises a modified sugar moiety.

213. The method of claim 212, wherein the nucleosides comprising a modified sugar moiety all comprise the same sugar modification.

214. The method of claim 213, wherein each modified sugar moiety comprises a 2′

-methoxyethyl sugar moiety.

215. The method of any of claims 1-214, wherein each nucleoside of the antisense oligonucleotide comprises a modified sugar moiety.

216. The method of claim 215, wherein the nucleosides all comprise the same sugar modification.

217. The method of claim 216, wherein each modified sugar moiety comprises a 2′

-methoxyethyl sugar moiety.

218. The method of any of claims 1-217, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

219. The method of claim 218, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

220. The method of any of claims 1-219, wherein the antisense oligonucleotide consists of 10 to 25 linked nucleosides.

221. The method of any of claims 1-220, wherein the antisense oligonucleotide consists of 12 to 22 linked nucleosides.

222. The method of any of claims 1-220, wherein the antisense oligonucleotide consists of 15 to 20 linked nucleosides.

223. The method of any of claims 1-220, wherein the antisense oligonucleotide consists of 18 linked nucleosides.

224. The method of any of claims 1-223, wherein the antisense oligonucleotide is at least 90% complementary to the nucleic acid encoding human SMN2.

225. The method of claim 224, wherein the antisense oligonucleotide is fully complementary to the nucleic acid encoding human SMN2.

226. The method of any of claims 1-225, wherein the oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of the nucleobase sequence SEQ ID NO:

1.

227. The method of claim 226, wherein the oligonucleotide has a nucleobase sequence comprising at least 15 contiguous nucleobases of the nucleobase sequence SEQ ID NO:

1.

228. The method of claim 227, wherein the oligonucleotide has a nucleobase sequence comprising the nucleobase sequence SEQ ID NO:

1.

229. The method of claim 226, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO:

1.

230. The method of any of claims 1-229, wherein the antisense compound comprises a conjugate group or terminal group.

231. The method of any of claims 1-230, wherein the antisense compound consists of the antisense oligonucleotide.

232. The method of any of claims 1-231, wherein the antisense compound is administered into the cerebrospinal fluid and is also administered systemically.

233. The method of claim 232, wherein the systemic administration is by intravenous or intraperitoneal injection.

234. The method of claim 232 or 233, wherein the systemic administration and the administration into the central nervous system are performed at the same time.

235. The method of claim 232 or 233, wherein the systemic administration and the administration into the central nervous system are performed at different times.

236. An antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2, for use in a method according to any of claims 1-235.

237. The antisense compound according to claim 236, for use in treating a disease or condition associated with survival motor neuron 1 (SMN1).

238. Use of an antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 in the manufacture of a medicament for use in a method according to any preceding claim.

239. The use according to claim 238, wherein the medicament is for treating a disease or condition associated with survival motor neuron 1 (SMN1).

240. Use of an antisense compound comprising an antisense oligonucleotide complementary to intron 7 of a nucleic acid encoding human SMN2 in the manufacture of a medicament for use in a method according to any of claims 1 to 237.