METHODS AND COMPOUNDS USEFUL IN CONDITIONS RELATED TO REPEAT EXPANSION

• US 20140316121A1
• Filed: 08/29/2012
• Published: 10/23/2014
• Est. Priority Date: 08/29/2011
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated, Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Prakash, Thazha P., Swayze, Eric E., Corey, David, Yu, Dongbo
• Granted Patent: US 9,976,138 B2
• Time in Patent Office: Days
• US Class Current: 536/23.1
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• 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 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/343 having patterns, e.g. ==--==--==--
• CPC Class Codes: C12N 2310/344 Position-specific modifications, e.g. on every purine, at the 3'-end
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 2310/533 having a mismatch or nick in at least one of the strands
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses

Abstract

Described are compounds and methods useful for the treatment and investigation of diseases and disorders associated with expanded repeat-containing RNA molecules.

Claims

1-146. -146. (canceled)

147. A compound comprising a single-stranded oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence complementary to a repeat region of an expanded repeat-containing target RNA, wherein the 5′

-terminal nucleoside of the single-stranded oligonucleotide comprises a stabilized phosphate moiety and an internucleoside linking group linking the 5′

-terminal nucleoside to the remainder of the oligonucleotide.

148. The compound of claim 147, wherein the 5′

-terminal nucleoside of the single-stranded oligonucleotide has Formula I;

149. The compound of claim 148, wherein M₃ is O.

150. The compound of claim 149, wherein each of J₄, J₅, J₆ and J₇ is H.

151. The compound of claim 150, wherein A has the formula:

152. The compound of claim 151, wherein G is selected from among:

a halogen, OCH₃, OCH₂F, OCHF₂, OCF₃, OCH₂CH₃, O(CH₂)₂F, OCH₂CHF₂, OCH₂CF₃, OCH₂—

CH═

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

SCH₃, O(CH₂)₂—

OCF₃, O(CH₂)₃—

N(R₁₀)(R₁₁), O(CH₂)₂-0N(R₁₀)(R₁₁), O(CH₂)₂—

O(CH₂)₂—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₂)—

(CH₂)₂—

N(R₁₀)(R₁₁), and O(CH₂)₂—

N(R₁₂)—

C(═

NR₁₃)[N(R₁₀)(R₁₁)];

wherein R₁₀, R₁₁, R₁₂ and R₁₃ are each, independently, H or C₁-C₆ alkyl.

153. The compound of claim 152, wherein G is selected from among:

a halogen, OCH₃, OCF₃, OCH₂CH₃, OCH₂CF₃, OCH₂—

CH—

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

O(CH₂)₂—

N(CH₃)₂, OCH₂C(═

O)—

N(H)CH₃, OCH₂C(═

O)—

N(H)—

(CH₂)₂—

N(CH₃)₂, and OCH₂—

N(H)—

C(═

NH)NH₂.

154. The compound of claim 153, wherein G is selected from among:

F, OCH₃, and O(CH₂)₂—

OCH₃.

155. The compound of claim 154, wherein the oligonucleotide comprises a hybridizing region and 0-4 3′

-terminal nucleosides.

156. The compound of claim 155, wherein the hybridizing region is 100% complementary to the repeat region of the expanded repeat-containing target RNA.

157. The compound of claim 155, wherein the hybridizing region has one mismatch relative to the repeat region of the expanded repeat-containing target RNA.

158. The compound of claim 155, wherein the hybridizing region has two mismatches relative to the repeat region of the expanded repeat-containing target RNA.

159. The compound of claim 155, wherein the hybridizing region has three mismatches relative to the repeat region of the expanded repeat-containing target RNA.

160. The compound of claim 155, wherein the hybridizing region has four mismatches relative to the repeat region of the expanded repeat-containing target RNA.

161. The compound of claim 159, having a mismatch at the eighth nucleobase from the 5′

-end of the hybridizing region.

162. The compound of claim 159, having a mismatch at the ninth nucleobase from the 5′

-end of the hybridizing region.

163. The compound of claim 159, having a mismatch at the tenth nucleobase from the 5′

-end of the hybridizing region.

164. The compound of claim 155, comprising at least one modified internucleoside linkage.

165. The compound of claim 155, wherein each internucleoside linkage is selected from phosphorothioate and phosphodiester.

166. The compound of claim 155, wherein each of the 6-10 3′

-most internucleoside linkages is phosphorothioate linkage.