SELECTIVE REDUCTION OF ALLELIC VARIANTS

• US 20130046008A1
• Filed: 02/08/2011
• Published: 02/21/2013
• Est. Priority Date: 02/08/2010
• Status: Active Grant

• Current Assignee: University of British Columbia
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bennett, C. Frank, Hayden, Michael, Freier, Susan M., Carroll, Jeffrey, Swayze, Eric E., Greenlee, Sarah, Warby, Simon
• Granted Patent: US 9,006,198 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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: 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 2320/34 Allele or polymorphism specific uses
• CPC Class Codes: C12Q 1/6811 Selection methods for production or design of target specific oligonucleotides or binding molecules
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 1/6897 involving reporter genes operably linked to promoters
• CPC Class Codes: C12Q 2521/327 RNAse, e.g. RNAseH
• CPC Class Codes: C12Q 2525/121 incorporating both deoxyribonucleotides and ribonucleotides
• CPC Class Codes: C12Q 2525/185 incorporating bases where the precise position of the bases in the nucleic acid string is important
• CPC Class Codes: C12Q 2525/207 siRNA, miRNA
• CPC Class Codes: C12Q 2535/131 Allele specific probes
• CPC Class Codes: C12Q 2539/107 Representational Difference Analysis [RDA]
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

Disclosed herein are antisense compounds and methods for selectively reducing expression of an allelic variant of a huntingtin gene containing a single nucleotide polymorphism (SNP). Such methods, compounds, and composition are useful to treat, prevent, or ameliorate Huntington'"'"'s Disease (HD).

Claims

1-97. -97. (canceled)

98. A method of selectively reducing the expression of a mutant huntingtin allele in a cell, tissue, or animal comprising administering to the cell, tissue, or animal a compound comprising a modified oligonucleotide complementary to the mutant huntingtin allele at a position comprising a single nucleotide polymorphism, wherein the expression of the mutant huntingtin allele is selectively reduced.

99. The method of claim 98, wherein the modified oligonucleotide consists of 15 to 20 linked nucleosides and position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the modified oligonucleotide, as counted from the 5′

terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism.

100. The method of claim 99, wherein at least one nucleoside comprises a modified sugar.

101. The method of claim 100, wherein the modified sugar is a high-affinity sugar modification.

102. The method of claim 101, wherein the high-affinity sugar is a bicyclic sugar.

103. The method of claim 102, wherein each bicyclic sugar comprises a 4′

-CH(CH₃)—

O-2′

bridge.

104. The method of claim 101, wherein the at least one modified sugar comprises a 2′

-O-methoxyethyl.

105. The method of claim 99, wherein the modified oligonucleotide comprises a wing-gap-wing motif.

106. The method of claim 105, wherein the wing-gap-wing motif is any of the group consisting of 2-9-6, 3-9-3, 3-9-4, 3-9-5, 4-7-4, 4-9-4, 4-9-5, 4-10-5, 4-11-4, 4-11-5, 5-7-5, 5-8-6, 5-9-3, 5-9-5, 5-10-4, 5-10-5, 6-7-6, 6-8-5, and 6-9-2.

107. The method of claim 106, wherein each nucleoside positioned in the wing segment of the modified oligonucleotide comprises a 2′

-O-methoxyethyl modification.

108. The method of claim 106, wherein at least one of the wing regions comprises a 4′

to 2′

bicyclic nucleoside and at least one of the remaining wing nucleosides is a non-bicyclic 2′

-modified nucleoside.

109. The method of claim 108, wherein the non-bicyclic 2′

-modified nucleoside is a 2′

-O-methoxyethyl nucleoside.

110. The method of claim 108, wherein the 4′

to 2′

bicyclic nucleoside is a 4′

-CH(CH₃)—

O-2′

bicyclic nucleoside.

111. The method of claim 105, wherein at least one nucleoside comprises a modified nucleobase.

112. The method of claim 111, wherein the at least one modified nucleobase is a 5′

-methylcytosine.

113. The method of claim 99, wherein the modified oligonucleotide is 95% complementary to the mutant huntingtin allele.

114. The method of claim 99, wherein the modified oligonucleotide is 100% complementary to the mutant huntingtin allele.

115. The method of claim 106, wherein at least one internucleoside linkage is a modified internucleoside linkage.

116. The method of claim 115, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

117. A method of treating, ameliorating, or slowing the onset or progression of Huntington'"'"'s Disease, comprising administering to an animal a compound comprising a modified oligonucleotide complementary to a mutant huntingtin allele at a position on the allele comprising a single nucleotide polymorphism site, wherein the compound administered to the animal treats, ameliorates or slows the onset or progression Huntington'"'"'s Disease by selectively reducing the mutant huntingtin allele.