Selective reduction of allelic variants

• US 8,957,040 B2
• Filed: 02/08/2011
• Issued: 02/17/2015
• Est. Priority Date: 02/08/2010
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bennett, C. Frank, Freier, Susan M., Greenlee, Sarah, Swayze, Eric E.
• Primary Examiner(s): Vivlemore, Tracy
• Assistant Examiner(s): POLIAKOVA-GEORGA, EKATERINA
• Application Number:
  US13/577,616
• Publication Number:
  US 20130046007A1
• Time in Patent Office: 1,470 Days
• US Class Current: 514/44.A
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: A61P 9/12 : Antihypertensives
• 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 2310/3231 : having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 : 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 : Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 : having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2320/34 : Allele or polymorphism specific uses
• CPC Class Codes: C12N 2320/35 : based on a specific dosage / administration regimen

Abstract

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

Claims

1. A compound comprising a modified antisense oligonucleotide consisting of 12 to 30 linked nucleosides targeted to a single nucleotide polymorphism site, wherein the modified oligonucleotide comprises a wing-gap-wing motif with a 5′

wing region positioned at the 5′

end of a deoxynucleoside gap, and a 3′

wing region positioned at the 3′

end of the deoxynucleoside gap, wherein position 8, 9, or 10 of the modified oligonucleotide, as counted from the 5′

terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism, and wherein the single nucleotide polymorphism is on a mutant allele that is associated with Huntington'"'"'s Disease.

2. The compound of claim 1, wherein the single nucleotide polymorphism site contains a differentiating polymorphism.

3. The compound of claim 1, wherein the modified antisense oligonucleotide consists of 15 to 20 linked nucleosides.

4. The compound of claim 1, wherein the gap region is 7-11 nucleosides in length, the 5′

wing region is 1-6 nucleobases in length and the 3′

wing region is 1-6 nucleobases in length.

5. The compound of claim 4, wherein the wing-gap-wing motif is any one of the group consisting of 5-10-5, 2-9-6, 3-9-3, 3-9-4, 3-9-5, 4-7-4, 4-9-3, 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.

6. The compound of claim 5, wherein the wing-gap-wing motif is any one of the group consisting of 2-9-6, 4-9-5, and 4-11-4.

7. The compound of claim 4, wherein at least one nucleoside of at least one of the wing regions comprises a modified sugar or sugar surrogate.

8. The compound of claim 4, wherein each of the nucleosides of each wing region comprises a modified sugar or sugar surrogate.

9. The compound of claim 8, wherein the modified sugar comprises a 2′

-O-methoxyethyl modified sugar.

10. The compound of claim 4, 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.

11. The compound of claim 10, wherein the non-bicyclic 2′

-modified nucleoside is a 2′

-O-methoxyethyl nucleoside.

12. The compound of claim 10, wherein the 4′

to 2′

bicyclic nucleoside is 4′

-CH(CH₃)—

O-2′

bicyclic nucleoside.

13. The compound of claim 4, wherein at least one internucleoside linkage is a modified internucleoside linkage.

14. The compound of claim 4, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

15. The compound of claim 4, wherein at least one nucleoside comprises a modified nucleobase.

16. The compound of claim 15, wherein the modified nucleobase is a 5′

-methylcytosine.