Methods for modulating metastasis-associated-in-lung-adenocarcinoma-transcript-1 (MALAT-1) expression

Patent metadata

Field	Value
Publication number	US-9546368-B2
Application number	US-201214368269-A
Country	US
Kind code	B2
Filing date	Dec 21, 2012
Priority date	Dec 22, 2011
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The present embodiments provide compounds and methods for reducing expression of Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) RNA and/or protein in an animal. Such methods are useful for treating cancer, such as colon cancer, intestinal cancer, lung cancer (e.g. non-small cell lung cancer), liver cancer, and/or prostate cancer. In various aspects, the cancer is a primary cancer.

First claim

What is claimed is:

1. A method of treating a primary cancer in an animal comprising administering to the animal a therapeutically effective amount of a single-stranded modified oligonucleotide 12 to 30 linked nucleosides in length having a nucleobase sequence at least 85% complementary to a Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) nucleic acid, thereby treating the primary cancer in the animal.

2. The method of claim 1 , wherein administering the modified oligonucleotide reduces expression of MALAT-1.

3. The method of claim 2 , wherein expression of MALAT-1 RNA is reduced.

4. The method of claim 1 , wherein the animal is a human.

5. The method of claim 1 , wherein the MALAT-1 nucleic acid is a human MALAT-1 nucleic acid.

6. The method of claim 5 , wherein the human MALAT-1 nucleic acid has a nucleotide sequence of SEQ ID NO: 1.

7. The method of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence 100% complementary to a human MALAT-1 nucleic acid.

8. The method of claim 1 , wherein administering the therapeutically effective amount of the modified oligonucleotide inhibits cancer growth.

9. The method of claim 1 , wherein administering the therapeutically effective amount of the modified oligonucleotide increases survival of the animal.

10. The method of claim 1 , wherein the therapeutically effective amount of the modified oligonucleotide is administered to an animal identified as having primary cancer.

11. The method of claim 1 , wherein the cancer is colon cancer, lung cancer, liver cancer, prostate cancer, or intestinal cancer.

12. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

13. The method of claim 12 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

14. The method of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.

15. The method of claim 14 , wherein the modified sugar is a bicyclic sugar.

16. The method of claim 15 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′, 4′-(CH 2 )—O-2′, or 4′-(CH 2 ) 2 —O-2′ bridge.

17. The method of claim 14 , wherein the modified sugar comprises a 2′-O-methoxyethyl group.

18. The method of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.

19. The method of claim 18 , wherein the modified nucleobase is a 5-methylcytosine.

20. The method of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides, wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Bennett C Frank
• Freier Susan M
• Marcusson Eric G
• Hsu Ssucheng J
• Macleod Robert A

Classifications

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C12N15/1136 Primary

  against growth factors, growth regulators, cytokines, lymphokines or hormones · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title