TREATMENT OF A NON-ALCOHOLIC FATTY LIVER DISEASE

1 . A method for treating a non-alcoholic fatty liver disease in a human subject in need thereof, comprising administering to the human subject a compound or a pharmaceutically acceptable salt thereof, at a dose of about 25 to about 200 mg, wherein the dose is calculated based on a free acid form of the compound, wherein the compound comprises a double-stranded oligonucleotide linked to a ligand, wherein the double-stranded oligonucleotide reduces expression of HSD17β13 in the human subject, and wherein the ligand comprises a chemical structure of:

stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the administration is a single dose.

3 . The method of claim 1 , wherein the administration is repeated at an interval of about 28 days, about 12 weeks, or about 3 months, between doses, optionally for about 52 weeks or about 1 year.

4 . The method of claim 1 , wherein the dose is about 50 mg to about 100 mg.

5 . The method of claim 1 , wherein the dose is about 100 mg to about 200 mg.

6 . The method of claim 1 , wherein the dose is about 50 mg to about 200 mg.

7 . The method of claim 1 , wherein the compound is in a sodium salt form.

8 . The method of claim 1 , wherein the compound is administered by an injection.

9 . The method of claim 8 , wherein the injection is a subcutaneous injection.

10 . The method of claim 1 , wherein the compound is present in a single unit dosage form.

11 . The method of claim 1 , wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH).

12 . The method of claim 1 , wherein the human subject has a HSD17β13 rs72613567 mutation, PNPLA3 rs738409 (I148M) mutation, or a combination thereof.

13 . The method of claim 1 , wherein the double-stranded oligonucleotide comprises an antisense strand that comprises a modified nucleotide sequence that differs by 0 or 1 nucleotides from one of the following sequences (5′→3′):

(nucleotide sequence SEQ ID NO: 1)

usCfsas UfcUfaucagAfcUfuCfuUfaCfsg;

(nucleotide sequence SEQ ID NO: 5)

usCfsasUfcUfaUfcAfgAfcUfuCfuUfaCfsg;

(nucleotide sequence SEQ ID NO: 6)

usGfsasUfcCfaAfaAfaUfgUfcCfuAfgGfsc;

or

(nucleotide sequence SEQ ID NO: 7)

usGfsasUfcCfaaaaaUfgUfcCfuAfgGfsc;

and wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively; Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively; and s represents a phosphorothioate linkage.

14 . The method of claim 1 , wherein the double-stranded oligonucleotide comprises a sense strand that comprises a modified nucleotide sequence that differs by 0 or 1 nucleotides from one of the following sequences (5′→3′):

(nucleotide sequence SEQ ID NO: 3)

cguaagaaGfuCfuGfauagauga;

(nucleotide sequence SEQ ID NO: 8)

cguaagaaGfUfCfugauagauga;

(nucleotide sequence SEQ ID NO: 9)

gccuaggaCfAfUfuuuugiauca; 

or

(nucleotide sequence SEQ ID NO: 10)

gccuaggaCfaUfuUfuugiauca;

and wherein a, c, g, i, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, 2′-O-methyl inosine, and 2′-O-methyl uridine, respectively; Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively; and s represents a phosphorothioate linkage.

15 . The method of claim 1 , wherein the double-stranded oligonucleotide comprises an antisense strand that comprises a sequence (5′→3′): usCfsasUfcUfaucagAfcUfuCfuUfaCfsg (nucleotide sequence SEQ ID NO:1), and a sense strand that comprises a sequence (5′→3′):

(nucleotide sequence SEQ ID NO: 11)

(NAG37)s(invAb)scguaagaaGfuCfuGfauagaugas(invAb), 

and wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively; Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively; s represents a phosphorothioate linkage; and (invAb) represents an inverted abasic deoxyribose residue.

16 . The method of claim 1 , wherein the method reduces the expression of HSD17β13 mRNA in the human subject by at least about 50% compared with that prior to the administration, as measured by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR) with a liver biopsy sample from the human subject.

17 . The method of claim 1 , wherein the method reduces the expression of HSD17β13 protein in the human subject by at least about 30% compared with that prior to the administration, as measured by Western Blot with a liver biopsy sample from the human subject.

18 . The method of claim 1 , wherein the method reduces ALT (alanine aminotransferase) level in the human subject by at least about 40% compared with that prior to the administration, as measured in the human subject's serum.

19 . The method of claim 1 , wherein the method reduces AST (aspartate aminotransferase) level in the human subject by at least about 20% compared with that prior to the administration, as measured in the human subject's serum.

20 . The method of claim 1 , wherein the method reduces or slows an increase of the human subject's liver fat fraction compared with that prior to the administration, as measured by magnetic resonance imaging.

21 . The method of claim 1 , wherein the method reduces or slows an increase of the human subject's liver stiffness compared with that prior to the administration, as measured by transient elastography.

22 . The method of claim 1 , wherein the chemical structure of the ligand comprises:

23 . The method of claim 22 , wherein the compound is in a free acid form having a chemical structure as illustrated in FIG. 5 A to 5 D .

24 . The method of claim 1 , wherein the chemical structure of the ligand comprises:

25 . The method of claim 24 , wherein the compound is in a sodium salt form having a chemical structure as illustrated in FIG. 6 A to 6 D .

26 . The method of claim 1 , wherein the dose is about 50 mg.

27 . The method of claim 1 , wherein the dose is about 100 mg.

28 . The method of claim 1 , wherein the dose is about 200 mg.

29 . (canceled)

30 . (canceled)

31 . (canceled)

32 . (canceled)