Amphiregulin gene-specific double-stranded oligonucleotide and composition for preventing and treating fibrosis-related diseases and respiratory diseases, comprising same

12037,589

18/330853

June 07, 2023

The present invention relates to a double-stranded oligonucleotide which can highly specifically and efficiently inhibit an amphiregulin expression and, preferably, a double-stranded oligonucleotide comprising a sequence in the form of RNA/RNA, DNA/DNA or DNA/RNA hybrid, a double-stranded oligonucleotide structure comprising the double-stranded oligonucleotide, nanoparticles comprising the double-stranded oligonucleotide structure, and a fibrosis or respiratory disease preventive or therapeutic use thereof.

Bioneer Corporation (Daejeon, KR)

Bioneer Corporation (Daejeon, KR)

1. A compound having a structure of Formula (3) or (4): [chemical expression included] wherein A represents hexaethyleneglycol-(—PO 3 -hexaethyleneglycol)3, B represents C 24 (C 6 —S—S—C 18), X and Y each independently represent a simple covalent bond or a linker-mediated covalent bond, and S is a DNA sense strand and AS is an RNA antisense strand having a sequence complementary thereto, and wherein S and AS form a DNA-RNA hybrid.

2. The compound of claim 1 , wherein S is an amphiregulin-specific DNA sense strand.

3. The compound of claim 2 , wherein S is a DNA sense strand having a sequence selected from SEQ ID NO: 1-14 and AS is an RNA antisense strand having a sequence complementary to the DNA sense strand.

4. The compound of claim 2 , wherein S is a DNA sense strand having a sequence of SEQ ID NO: 10, 11, or 12.

5. The compound of claim 4 , wherein S is a DNA sense strand having a sequence of SEQ ID NO: 12.

6. The compound of claim 1 , wherein the DNA sense strand or the RNA antisense strand comprises a chemical modification.

7. The compound of claim 6 , wherein the chemical modification is selected from the group consisting of: a modification in which a hydroxyl (OH) group at the 2′ carbon position of a sugar structure in nucleotides is substituted with any one moiety selected from the group consisting of methyl (—CH 3), methoxy (—OCH 3), amine (—NH 2), fluorine (—F), —O-2-methoxyethyl, —O-propyl, —O-2-methylthioethyl, —O-3-aminopropyl, O-3-dimethylaminopropyl, —O—N-methylacetamido and —O-dimethylamidooxyethyl; a modification in which oxygen in a sugar structure in nucleotides is substituted with sulfur; a modification of a bond between nucleotides to any one bond selected from the group consisting of a phosphorothioate bond, a boranophosphophate bond and a methyl phosphonate bond; and a modification to PNA (peptide nucleic acid), LNA (locked nucleic acid) or UNA (unlocked nucleic acid).

8. The compound of claim 1 , wherein the covalent bond represented by X and Y is either a non-degradable bond or a degradable bond.

9. The compound of claim 8 , comprising a non-degradable bond, wherein the non-degradable bond is an amide bond or a phosphate bond.

10. The compound of claim 9 , comprising a degradable bond, wherein the degradable bond is selected from the group consisting of a disulfide bond, an acid-degradable bond, an ester bond, an anhydride bond, a biodegradable bond, and an enzyme-degradable bond.

11. The compound of claim 1 , further comprising hexosamine, sugar or carbohydrate conjugated to A.

12. The compound of claim 1 , further comprising N-acetyl galactosamine (NAG) conjugated to A.

13. The compound of claim 1 , further comprising glucose or mannose conjugated to A.

14. A nanoparticle comprising the compound of claim 1 .

15. The nanoparticle of claim 14 , wherein the nanoparticle comprises a mixture of double-stranded oligonucleotides, wherein each double-stranded oligonucleotide has a DNA sense strand with a unique sequence.

16. A pharmaceutical composition comprising, as an active ingredient, the compound of claim 1 .

17. A pharmaceutical composition comprising, as an active ingredient, the nanoparticle of claim 14 .

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