Compounds for the modulation of beta-catenin expression
AssigneesSantaris Pharma A/S, Enzon Pharmaceuticals, Inc.
InventorJesper WORM
Life of this patent
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Abstract
The invention relates to oligomer compounds (oligomers), which target beta-catenin mRNA in a cell, leading to reduced expression of beta-catenin. Reduction of beta-catenin expression is beneficial for a range of medical disorders, such as hyperproliferative disorders, such as cancer. The invention provides therapeutic compositions comprising oligomers and methods for modulating the expression of beta-catenin using said oligomers, including methods of treatment.
Claims27
An antisense oligonucleotide (such as the oligomer) capable of binding to a target sequence of the beta-catenin gene of SEQ ID NO:
- 173 or allele thereof and down-regulating expression of beta-catenin, said oligonucleotide comprising a sequence of 10-50 nucleobases corresponding to the target sequence.
The antisense oligonucleotide of embodiment 1, wherein the target sequence is selected from regions of the beta-catenin gene represented by SEQ ID NOS:
- 1-132 or an allelic variant thereof.
The oligonucleotide of embodiment 1 or embodiment 2 comprising a sequence of 10-16 nucleobases shown in SEQ 10 NOS:
- 1, 16, 17, 18, 33, 34, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 73, 88, 103, and 118 or an allelic variant thereof.
The oligonucleotide according to any one of embodiments 1-3 comprising sequences shown as SEQ ID NOS:
- 1-132.
The oligonucleotide of any one of the preceding embodiments represented by SEQ ID NOS:
- 133-172.
The oligonucleotide according to anyone of the preceding embodiments, wherein said nucleobase sequence comprises internucleobase linkages independently selected from phosphodiester, phosphorothioate and boranophosphate.
The oligonucleotide of anyone of the preceding embodiments, wherein at least two of said nucleobases are nucleotide analogues.
The oligonucleotide according to embodiment 5, wherein said sequence of nucleobases comprises, in a 5′ to 3′ direction (i) region A:
- a stretch of 2-4 nucleotide analogues, followed by (ii) region B:
- a stretch of 6-11 nucleotides or nucleotide analogues different from those of region A, followed by (iii) region C:
- a stretch of 2-4 nucleotide analogues, and optionally followed by (iv) region D:
- one or two nucleotides.
The oligonucleotide according to embodiment 8, wherein the region A comprises at least one phosphodiester linkage between two nucleotide analogue units and/or or a nucleotide analogue unit and a nucleobase unit of Region B.
The oligonucleotide according to embodiment 8 or embodiment 9, wherein region C comprises at least one phosphodiester linkage between two nucleotide analogue units and/or a nucleotide analogue unit and a nucleobase unit of Region B.
The oligonucleotide according to anyone of embodiments 1 to 6, wherein all the internucleobase linkages are phosphorothioate.
The oligonucleotide according to any one of embodiments 7 to 11, wherein said nucleotide analogue units are independently selected from 2′-O-alkyl-RNA, 2′-amino-DNA, 2′ fluoro-DNA, locked nucleic acid (LNA), arabin nucleic acid (ANA), 2′-fluoro-ANA, RNA, INA and 2′-MOE.
The oligonucleotide according to embodiment 12, wherein the nucleotide analogues are independently selected from 2′-MOE-RNA, 2′-fluoro-DNA, and LNA.
The oligonucleotide according to embodiment 13, wherein at least one of said nucleotide analogues is a locked nucleic acid (LNA).
The oligonucleotide according to embodiment 14, wherein all the nucleotide analogues are LNA.
The oligonucleotide according to anyone of embodiments 12 to 15, wherein LNA is selected from beta-D-oxy-LNA, alpha-L-oxy-LNA, beta-D-amino-LNA and beta-D-thio-LNA.
A conjugate comprising an oligonucleotide of any one of the preceding embodiments and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said oligonucleotide.
A conjugate according to embodiment 17, wherein said non-nucleotide or nonpolynucleotide moiety consists of or comprises a sterol group such as cholesterol.
A pharmaceutical composition comprising an oligonucleotide according to any one of the embodiments 1 to 16 or a conjugate according to embodiment 17 or embodiment 18, and a pharmaceutically acceptable diluent, carrier or adjuvant.
An oligonucleotide or a conjugate according to any one of embodiments 1 to 18 for use as a medicament.
Use of an oligonucleotide or as conjugate according to any one of embodiments 1 to 18 for the manufacture of a medicament for the treatment of abnormal levels of beta-catenin or a disease or condition for which down-regulation of beta-catenin expression is indicated.
The use according to embodiment 21, wherein said disease or condition is cancer.
A method of treating a subject suffering from cancer, the method comprising the step of administering a pharmaceutical composition, oligonucleotide or conjugate according to anyone of embodiments 1 to 19 to the subject in need thereof.
The use or the method of anyone of embodiments 21-23, wherein the cancer is selected from colorectal cancer, hepatocellular cancer, endometrial cancer, malignant melanoma, cancer of the ovary, pancreas, pituitary, oesophagus, lung, breast, kidney, haematopoetic system, cervix, CNS, bone, bilial tract and adrenal gland.
A target sequence within the beta-catenin gene, wherein an antisense oligonucleotide corresponding to said target sequence is capable of down-regulating the expression of beta-catenin.
The target sequence of embodiment 25, wherein the target sequence is selected from the regions of the beta-catenin gene complementary to SEQ ID NOs 1-132 or allelic variants thereof.
A method of down-regulating the expression of beta-catenin in a cell, comprising contacting the cell with an oligonucleotide according to anyone of embodiments 1-16.
Dependencies are inferred from the claim text.