Antisense nucleic acid targeting pcsk9

Patent metadata

Field	Value
Publication number	US-2022160880-A1
Application number	US-202217649895-A
Country	US
Kind code	A1
Filing date	Feb 3, 2022
Priority date	May 26, 2017
Publication date	May 26, 2022
Grant date	—

Abstract

Provided is an oligonucleotide conjugate comprising an oligonucleotide and two or more linearly connected asialoglycoprotein receptor-binding molecules attached to the oligonucleotide, wherein the oligonucleotide comprises a locked nucleoside analog having a bridging structure between the 4′ and 2′ positions, is complementary to a human PCSK9 gene, and has inhibitory activity on the expression of the human PCSK9 gene. The oligonucleotide conjugate of the present invention can be used in the field of pharmaceutical products, in particular, the field of the development and production of therapeutic agents for diseases associated with a high LDL cholesterol level.

First claim

1 . (canceled)

2 . An oligonucleotide conjugate comprising an oligonucleotide and a functional molecule attached to the oligonucleotide via a linker,
wherein the functional molecule is capable of altering the activity of the oligonucleotide, wherein the linker comprises a main-chain linker that binds to the oligonucleotide and a side-chain linker that is branched from the main-chain and binds to the functional molecule, wherein the linker has the following structure (I):

wherein the LINKER moiety in the structure (I) has a functional group containing a terminal carbonyl group that forms a covalent bond with the amino group.

3 . The oligonucleotide conjugate according to claim 2 , wherein the linker has the following structure (II):

4 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of sugars, antibodies, aptamers, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic-acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, and pigments.

5 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of sugars, antibodies, and aptamers.

6 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of cholesterols, thiocholesterols, cholic-acid moieties, folic acid, lipids, phospholipids, biotin, and adamantane.

7 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of polyethylene glycols, thioethers, and polyethers.

8 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of intercalators, reporter molecules, polyamines, polyamides, anthraquinone, phenanthridine, acridine, and phenazine.

9 . The oligonucleotide conjugate according to claim 2 , wherein the functional molecule is at least one selected from the group consisting of fluorescein, rhodamine, coumarin, and pigments.

10 . A method for producing an oligonucleotide conjugate comprising an oligonucleotide and a functional molecule attached to the oligonucleotide via a linker,
wherein the functional molecule is capable of altering the activity of the oligonucleotide, wherein the linker comprises a main-chain linker that binds to the oligonucleotide and a side-chain linker that is branched from the main-chain and binds to the functional molecule, wherein the linker has the following structure (I):

wherein the LINKER moiety in the structure (I) has a functional group containing a terminal carbonyl group that forms a covalent bond with the amino group.

11 . The method according to claim 10 , wherein the linker has the following structure (II):

12 . The method according to claim 10 , wherein the functional molecule is at least one selected from the group consisting of sugars, antibodies, aptamers, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic-acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, and pigments.

Assignees

• Nat Cerebral & Cardiovascular Ct

Inventors

• Harada-Shiba Mariko
• Wada Fumito
• Obika Satoshi
• Yamamoto Tsuyoshi
• TACHIBANA Keisuke
• Kobayashi Tadayuki
• Ito Kosuke
• Sawamura Motoki

Classifications

• C12N15/1137 Primary

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title