Compositions and methods

• US 9,714,421 B2
• Filed: 05/01/2014
• Issued: 07/25/2017
• Est. Priority Date: 05/01/2013
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Prakash, Thazha P., Seth, Punit P., Swayze, Eric E.
• Primary Examiner(s): Poliakova-Georgantas, Kate
• Application Number:
  US14/888,318
• Publication Number:
  US 20160076032A1
• Time in Patent Office: 1,181 Days
• Field of Search: None
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• 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 2310/3341 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 2310/351 : Conjugate
• CPC Class Codes: C12N 2310/3511 : intercalating or cleaving agent
• CPC Class Codes: C12N 2310/3513 : Protein; Peptide
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3525 : MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/353 : linked to the nucleic acid via an atom other than carbon
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12Y 301/03048 : Protein-tyrosine-phosphatase (3.1.3.48)

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

Claims

1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide is 10-30 linked nucleosides in length and consists of the nucleobase sequence of SEQ ID NO:

81, wherein the conjugate group comprises;

2. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar.

3. The compound of claim 2, wherein the modified sugar is a bicyclic sugar.

4. The compound of claim 3, wherein the bicyclic sugar is selected from the group consisting of:

4′

-(CH₂)—

O-2′

(LNA);

4′

-(CH₂)₂—

O-2′

(ENA); and

4′

-CH(CH₃)—

O-2′

(cEt).

5. The compound of claim 2, wherein the modified sugar is 2′

-O-methoxyethyl.

6. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified nucleobase.

7. The compound of claim 6, wherein the modified nucleobase is a 5-methylcytosine.

8. The compound of claim 1, wherein the compound is single-stranded.

9. The compound of claim 1, wherein the compound is double-stranded.

10. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

11. The compound of claim 10, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

12. The compound of claim 10, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

13. A composition comprising the compound of claim 1 or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.

14. A prodrug comprising the compound of claim 1.

15. A method comprising administering to an animal the compound or composition of claim 1.

16. The method of claim 15, wherein the animal is a human.

17. The method of claim 15, comprising co-administering the compound or composition and a second agent.