LNA antisense oligonucleotides for the modulation of Myc expression
The disclosure relates to oligonucleotide compounds (oligomers) that target Myc mRNA in a cell, leading to reduced expression of Myc. Reduction of Myc expression is beneficial for the treatment of certain disorders, such as hyperproliferative disorders (e.g., cancer). The disclosure provides therapeutic compositions comprising oligomers and methods for modulating the expression of Myc using said oligomers, including methods of treatment.
1. An oligomer of between 10-30 nucleobases in length which comprises a contiguous nucleobase sequence of a total of between 10-16 nucleobases, wherein the contiguous nucleobase sequence comprises nucleotide analogues, and wherein the contiguous nucleobase sequence comprises between 0-2 mismatches to a corresponding region of a sequence selected from the group consisting of:
(SEQ ID NO: 5)
5′-TTCACCATGTCTCCTC-3′;
(SEQ ID NO: 11)
5′-GGTACAAGCTGGAGGT-3′;
and
(SEQ ID NO: 15)
5′-GTAGTTGTGCTGATGT-3′,
and,
wherein the oligomer inhibits Myc expression in a cell or tissue.
2. The oligomer according to claim 1 wherein the nucleotide analogues comprise one or more sugar modified nucleotides.
3. The oligomer according to claim 2 wherein the one or more nucleotide analogues comprise LNA units.
4. The oligomer according to claim 2 wherein the nucleotide comprises a gapmer design.
5. The oligomer according to claim 4 selected from the group consisting of:
(SEQ ID NO: 28)
5′-T s T s Me C s a s c s c s a s t s g s t s c s t s c s Me C s T s Me C-3′;
(SEQ ID NO: 34)
5′-G s G s T s a s c s a s a s g s c s t s g s g s a s G s G s T-3′;
and
(SEQ ID NO: 38)
5′-G s T s A s g s t s t s g s t s g s c s t s g s a s T s G s T-3′,
wherein capital letters represent LNA monomers, lower case letters represent DNA monomers, subscript “s” represents a phosphorothioate linkage group between the monomers, and Me C denotes an LNA monomer containing a 5-methylcytosine base.
6. The oligomer according to claim 5 wherein the LNA units consist of beta-D-oxy-LNA monomers.
7. A conjugate comprising the oligomer according claim 1 covalently attached to at least one moiety that is not a nucleic acid or a monomer.
8. A pharmaceutical composition comprising the oligomer according to claim 1 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
9. A method of inhibiting the expression of Myc in a cell, comprising contacting the cell with an effective amount of an oligomer according to claim 1 .
10. The method of claim 9 , wherein the cell is within a tissue of a mammal.
11. The method of claim 9 , wherein the Myc is c-Myc.
12. The method of claim 9 , wherein the Myc is N-Myc.
13. The method of claim 9 , wherein the Myc is c-Myc and N-Myc.
14. A method of treating a cancer disease in a mammal, comprising administering to the mammal an effective amount of an oligomer according to claim 1 , wherein the mammal is currently suffering from or at risk of suffering from the cancer disease.
15. The method of claim 14 , wherein the mammal is a human.
16. The method of claim 14 , wherein the cancer is selected from the group consisting of B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, neuroblastoma, oesophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma retinoblastoma, rhabdomyocarcoma and small cell lung carcinoma.
17. The method of claim 16 , wherein the cancer is selected from the group consisting of Burkitt's lymphoma, breast cancer, and multiple myeloma.
18. A pharmaceutical composition comprising a conjugate according to claim 7 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
19. A method of inhibiting the expression of Myc in a cell, comprising contacting the cell with an effective amount of a conjugate according to claim 7 .
20. A method of treating a cancer disease in a mammal, comprising administering to the mammal an effective amount of a conjugate according to claim 7 , wherein the mammal is currently suffering from or at risk of suffering from the cancer disease.