Enhanced oligonucleotides for modulating fubp1 expression

Patent metadata

Field	Value
Publication number	US-2022031730-A1
Application number	US-202117359196-A
Country	US
Kind code	A1
Filing date	Jun 25, 2021
Priority date	Jun 26, 2020
Publication date	Feb 3, 2022
Grant date	—

Abstract

The present invention relates to enhanced antisense oligonucleotides that are complementary to the Far Upstream Element-Binding Protein 1 (FUBP1) and are capable of reducing a FUBP1 target nucleic acid, such as FUBP1 mRNA. The invention relates to enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for use in treating and/or preventing a hepatitis B virus (HBV) infection, in particular a chronic HBV infection. The invention in particular relates to the use of the enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for destabilizing cccDNA, such as HBV cccDNA. The invention further relates to enhanced antisense oligonucleotides targeting FUBP1 or conjugates thereof for use in treating cancer. A pharmaceutical composition and its use in the treatment and/or prevention of an HBV infection, or its use in the treatment of cancer is also disclosed.

First claim

1 . An antisense oligonucleotide selected from the group of antisense oligonucleotides consisting of

(SEQ ID NO: 7)

CTtAtgctttttatGgTT,

(SEQ ID NO: 18)

AcCAAttttcatttCtAC,

(SEQ ID NO: 6)

CTTatGctttttatgGT,

(SEQ ID NO: 6)

CTTaTgctttttatgGT,

(SEQ ID NO: 7)

CTtATgctttttatgGTT,

(SEQ ID NO: 7)

CTtAtgctttttatgGTT,

(SEQ ID NO: 7)

CTtAtgctttttatGGTT,

(SEQ ID NO: 8)

GcttTttatggtTtCAC, and

(SEQ ID NO: 9)

TATgcTtntatggtTTC,

wherein capital letters are beta-D-oxy LNA nucleosides, lowercase letters are DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

2 . A conjugate comprising the antisense oligonucleotide of claim 1 , and at least one conjugate moiety covalently attached to said antisense oligonucleotide.

3 . The conjugate of claim 2 , wherein the at least one conjugate moiety is capable of binding to an asialoglycoprotein receptor.

4 . The conjugate of claim 2 , wherein the conjugate moiety is selected from one of the trivalent GalNAc moieties in FIG. 9 as follows:

5 . The conjugate of claim 4 , wherein the conjugate moiety is the trivalent GalNAc moiety in FIG. 9 D 1 , or 9 D 2 or a mixture thereof as follows:

6 . The conjugate of claim 1 , comprising a linker positioned between the antisense oligonucleotide and the conjugate moiety.

7 . The conjugate of claim 6 , wherein the linker comprises or consists of 2 to 5 consecutive phosphodiester linked nucleosides.

8 . A conjugate selected from the group of conjugates shown in FIG. 1 , FIG. 2 , FIG. 3 , FIG. 4 , FIG. 5 , FIG. 6 , FIG. 7 , FIG. 8 and FIG. 8.1 as follows:

9 . A pharmaceutically acceptable salt of the oligonucleotide of claim 1 .

10 . A pharmaceutical composition comprising the antisense oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

11 . An in vivo or in vitro method for modulating FUBP1 expression in a target cell which is expressing FUBP1, said method comprising administering the antisense oligonucleotide of claim 1 in an effective amount to said cell.

12 . A method for treating or preventing a disease comprising administering a therapeutically or prophylactically effective amount of the antisense oligonucleotide of claim 1 to a subject suffering from or susceptible to the disease, wherein the disease is hepatitis B virus (HBV) infection and/or cancer.

13 . The antisense oligonucleotide of claim 1 , for use in medicine.

14 . The antisense oligonucleotide of claim 1 , for use in the treatment or prevention of hepatitis B virus (HBV) infection and/or cancer.

15 . Use of the antisense oligonucleotide of claim 1 , for the preparation of a medicament for treatment or prevention of a hepatitis B virus (HBV) infection and/or cancer.

16 . The method of claim 12 , wherein the disease is hepatitis B virus (HBV) infection, such as chronic HBV infection.

17 . The method of claim 12 , wherein the disease is cancer, such as hepatocellular carcinoma.

Assignees

• Hoffmann La Roche

Inventors

• Sewing Sabine
• Ottosen Søren
• Ravn Jacob
• Pedersen Lykke
• Luangsay Souphalone
• Koller Erich
• Walther Johanna Marie
• Gylling Helene Maria
• Hruschka Natascha
• Mohr Susanne
• D'Arienzo Valentina

Classifications

• A61K31/7088 Primary

  Compounds having three or more nucleosides or nucleotides · CPC title

• C12N2310/11

  Antisense · CPC title

• A61K31/7125

  Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters · CPC title

• C12N15/113 Primary

  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 title

• C12N2320/33

  Alteration of splicing · CPC title