COMPOUNDS AND METHODS FOR MODULATING EXPRESSION OF GCGR

• US 20120208864A1
• Filed: 04/27/2012
• Published: 08/16/2012
• Est. Priority Date: 05/05/2006
• Status: Abandoned Application

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bhanot, Sanjay, Geary, Richard S., McKay, Robert, Monia, Brett P., Seth, Punit P., Siwkowski, Andrew M., Swayze, Eric E., Wancewicz, Edward
• Application Number:
  US13/457,960
• Publication Number:
  US 20120208864A1
• Time in Patent Office: 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 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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 5/46 for decreasing, blocking or antagonising the activity of glucocorticosteroids
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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: 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 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/31 of the backbone
• 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 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/341 : Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3521 : Methyl
• CPC Class Codes: C12Y 203/0102 : Diacylglycerol O-acyltransferase (2.3.1.20)

Abstract

The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.

Claims

1. A method of treating a metabolic disorder in an animal, comprising administering to an animal a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′

-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR.

2. The method of claim 1, wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA_1c in the animal.

3. The method of claim 1, wherein the gap region is 5, 6, 7, 8, 9, or 10 nucleotides in length.

4. The method of claim 1, wherein said high-affinity modified monomers are sugar-modified nucleotides.

5. The method of claim 4, wherein at least one of the sugar-modified nucleotides comprises a bridge between the 4′

and the 2′

position of the sugar.

6. The method of claim 4, wherein each of said sugar-modified nucleotides comprises a 2′

-substituent group that is other than H or OH.

7. The method of claim 6, wherein at least one of said sugar-modified nucleotides is a 4′

to 2′

bridged bicyclic nucleotide.

8. The method of claim 6, wherein each of the 2′

-substituent groups is, independently, alkoxy, substituted alkoxy, or halogen.

9. The method of claim 8, wherein each of the 2′

-substituent groups is OCH₂CH₂OCH₃.

10. The method of claim 5, wherein the conformation of each of said sugar-modified nucleotides is, independently, β

-D or α

-L.

11. The method of claim 1, wherein each of the high-affinity modified monomers is independently selected from bicyclic nucleotides or other 2′

-modified nucleotides.

12. The method of claim 11, wherein the 2′

-modified nucleotides are selected from halogen, allyl, amino, azido, thio, O-allyl, O—

C₁-C₁₀ alkyl, —

OCF₃, O—

(CH₂)₂—

O—

CH₃, 2′

-O(CH₂)₂SCH₃, O—

(CH₂)₂—

O—

N(R_m)(R_n) or O—

CH₂—

C(═

O)—

N(R_m)(R_n), where each R_m and R_n is, independently, H or substituted or unsubstituted C₁-C₁₀ alkyl.

13. The method of claim 12, wherein the 2′

-modified nucleotide is a 2′

-OCH₂CH₂OCH₃ nucleotide.

14. The method of claim 1, wherein at least one monomeric linkage is a modified monomeric linkage.

15. The method of claim 14, wherein the modified monomeric linkage is a phosphorothioate linkage.

16. A method of modulating expression of GCGR by contacting a GCGR nucleic acid with a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′

-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR.

17. The method of claim 16, wherein the GCGR nucleic acid is in an animal.

18. The method of claim 17, wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA_1c in the animal.

19. A method of inhibiting expression of GCGR RNA in an animal, comprising administering to said animal a short antisense compound 10 to 14 monomers in length, said compound comprising a 2′

-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers and wherein the compound is targeted to a nucleic acid encoding GCGR.

20. The method of claim 19, wherein administering the antisense compound increases insulin sensitivity, decreases blood glucose and/or decreases HbA_1c in the animal.