MODULATION OF HUNTINGTIN EXPRESSION

• US 20160312217A1
• Filed: 01/25/2016
• Published: 10/27/2016
• Est. Priority Date: 09/11/2009
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Hung, Gene, Bennett, C. Frank, Freier, Susan M., Kordasiewicz, Holly, Stanek, Lisa, Cleveland, Don W., Cheng, Seng H., Shihabuddin, Lamya
• Granted Patent: US 9,683,236 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 2310/113 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 2310/3341 : 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 : Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/345 : having at least two different backbone modifications
• CPC Class Codes: C12N 2310/346 : having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 : MOE, methoxyethoxy

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of huntingtin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate Huntington'"'"'s disease, or a symptom thereof.

Claims

1-76. -76. (canceled)

77. A single-stranded modified oligonucleotide consisting of 20 linked nucleosides and having:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment;

wherein each nucleoside of each wing segment comprises a 2′

O-methoxyethyl sugar; and

wherein the nucleobase sequence of the oligonucleotide consists of the sequence recited in SEQ ID NO;

28,

or a pharmaceutically acceptable salt thereof.

78. The single-stranded modified oligonucleotide of claim 77, wherein at least one nucleoside comprises a modified nucleobase.

79. The single-stranded modified oligonucleotide of claim 78, wherein the modified nucleobase is a 5-methylcytosine.

80. The single-stranded modified oligonucleotide of claim 77, wherein each cytosine is a 5-methylcytosine.

81. The single-stranded modified oligonucleotide of claim 77, wherein at least one internucleoside linkage is a modified internucleoside linkage.

82. The compound of claim 77, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

83. The single-stranded modified oligonucleotide of claim 80, wherein at least one internucleoside linkage is a modified internucleoside linkage.

84. The compound of claim 80, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

85. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 77 and at least one pharmaceutically acceptable carrier or diluent.

86. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 80 and at least one pharmaceutically acceptable carrier or diluent.

87. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 82 and at least one pharmaceutically acceptable carrier or diluent.

88. A composition comprising the single-stranded modified oligonucleotide or pharmaceutically acceptable salt thereof of claim 84 and at least one pharmaceutically acceptable carrier or diluent.

89. The single-stranded modified oligonucleotide of claim 77, which is capable of inhibiting huntingtin expression.

90. The single-stranded modified oligonucleotide of claim 80, which is capable of inhibiting huntingtin expression.

91. The single-stranded modified oligonucleotide of claim 82, which is capable of inhibiting huntingtin expression.

92. The single-stranded modified oligonucleotide of claim 84, which is capable of inhibiting huntingtin expression.