Granted Patent B2

US 12,331,294 · App. 17/405,482 · Granted Jun 17, 2025

Inventor: Balkrishen Bhat (Cambridge, MA)

Assignee: SANOFI

C12N15/113C12N2310/11C12N2310/113C12N2310/3231C12N2310/343C12N2310/35

Abstract

Claims (48)

1. A compound comprising a modified oligonucleotide consisting of 16 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to the nucleobase sequence of SEQ ID NO: 1, wherein;

(i) the modified oligonucleotide comprises at least 16 contiguous nucleosides of the following nucleoside pattern II in the 5′ to 3′ orientation:

N M -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z

and wherein;

(a) N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a 2′-O-methoxyethyl nucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

(b) N M is a 2′-O-methoxyethyl nucleoside;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside; or

(c) N M is a 2′-O-methoxyethyl nucleoside;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is an LNA nucleoside,

or

(ii) the modified oligonucleotide comprises one of the following nucleoside patterns in the 5′ to 3′ orientation:

(a) N M -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z ;

(b) N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z ;

(c) N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z ; or

(d) N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z ,

and wherein;

N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is an S-cEt nucleoside.

2. A method of treating, preventing or delaying the onset of a disease associated with miR-21 comprising administering to a subject having a disease associated with miR-21 a compound of claim 1 .

3. The method of claim 2 , wherein the disease is fibrosis.

4. The method of claim 3 , wherein the fibrosis is selected from kidney fibrosis, lung fibrosis, liver fibrosis, cardiac fibrosis, skin fibrosis, age-related fibrosis, spleen fibrosis, scleroderma, and post-transplant fibrosis.

5. The method of claim 2 , wherein the disease is cancer.

6. The method of claim 5 wherein the cancer is liver cancer, breast cancer, bladder cancer, prostate cancer, colon cancer, lung cancer, brain cancer, hematological cancer, pancreatic cancer, head and neck cancer, cancer of the tongue, stomach cancer, skin cancer, or thyroid cancer.

7. The compound of claim 1 , wherein the modified oligonucleotide of part (i) consists of 16, 17, or 18 linked nucleosides of said nucleoside pattern.

8. The compound of claim 1 , wherein the modified oligonucleotide of part (i) consists of 19 linked nucleosides of said nucleoside pattern.

9. The compound of claim 1 , wherein the oligonucleotide has the nucleobase sequence of SEQ ID NO: 3, in which each T in SEQ ID NO:3 is independently a T or a U in the oligonucleotide.

10. The compound of claim 1 , wherein the modified oligonucleotide has a structure selected from:

(SEQ ID NO: 3)

A E C S A E T E C S A E G E T E C S T E G E A E U S A E A E G E C S T E A E ,

(SEQ ID NO: 3)

A E C S ATC S AGTC S TGAU S AAGC S TA S ,

and

(SEQ ID NO: 3)

A E Me C S AT Me C S AGT Me C S TGAT S AAG Me C S TA S ,

wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides, nucleosides followed by a subscript “E” are 2′-MOE nucleosides, nucleosides followed by a subscript “S” are S-cEt nucleosides, and superscript “Me” indicates a 5-methyl group on the base of the nucleoside.

11. The compound of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.

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

13. The compound of claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

14. The compound of claim 1 , wherein at least one cytosine is a 5-methylcytosine.

Assignments (4)

Continuity (8)

References Cited (156)