Splice-switching oligonucleotides and methods of use
The present disclosure provides methods and compositions for the treatment of cancer. In some aspects, the present disclosure provides splice-switching oligonucleotides that downregulate AR expression and methods of using these splice-switching oligonucleotides to treat cancer, specifically castrate resistant prostate cancer.
1. An anti-sense compound comprising a modified splice-switching oligonucleotide (SSO) consisting of 22 to 30 linked nucleosides and having a nucleobase sequence at least 80% complementary to the corresponding nucleotide sequence within SEQ ID NO:5, wherein the SSO comprises a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11 and SEQ ID NO: 13, and a sequence with at least 80% identity to SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11 or SEQ ID NO: 13, wherein each nucleoside of the SSO comprises a sugar modification.
2. The anti-sense compound of claim 1 , wherein the sugar modification is a 2′-O-Me phosphorothioate backbone or wherein said oligonucleotide is a morpholino oligomer.
3. The anti-sense compound of claim 1 , wherein the SSO consists of a nucleobase sequence complementary to the nucleotide sequence selected from the group consisting of SEQ ID NO:12, SEQ ID NO:14 and a sequence with at least 80% identity to SEQ ID NO:12 or SEQ ID NO:14, and wherein said oligonucleotide is a Morpholino oligomer.
4. The anti-sense compound of claim 1 , wherein said oligonucleotide comprises a morpholino modification.
5. A composition comprising the anti-sense compound of claim 1 .
6. A method of treating a subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , wherein the prostate cancer is treated.
7. The method of claim 6 , wherein the subject has prostate cancer that is non-responsive to androgen therapy or is castrate-resistant prostate cancer.
8. The method of claim 6 , wherein the subject is a human.
9. The method of claim 6 , wherein the subject is an African American male suffering from prostate cancer.
10. The method of claim 6 , wherein the method further comprises administering to the subject a second cancer therapy.
11. The method of claim 10 , wherein the second cancer therapy is selected from the group consisting of chemotherapy, hormone therapy, androgen therapy, radiation, surgery, vaccine therapy and combinations thereof.
12. The method of claim 10 , wherein the second cancer therapy is androgen therapy.
13. The method of claim 11 , wherein the androgen therapy is enzalutamide.
14. A kit for treating prostate cancer comprising at least one splice-switching oligonucleotide (SSO) as set forth in claim 1 .
15. The anti-sense compound of claim 1 , wherein said the SSO is SEQ ID NO:11 and comprises a morpholino modification.
16. The anti-sense compound of claim 1 , wherein said the SSO is SEQ ID NO:13 and comprises a morpholino modification.
17. The anti-sense compound of claim 15 , wherein said SSO is a Morpholino oligomer.
18. The anti-sense compound of claim 16 , wherein said SSO is a Morpholino oligomer.
19. A composition comprising the anti-sense compound of claim 17 .
20. A composition comprising the anti-sense compound of claim 18 .
21. A kit for treating prostate cancer comprising a splice-switching oligonucleotide (SSO) as set forth in claim 17 .
22. A kit for treating prostate cancer comprising a splice-switching oligonucleotide (SSO) as set forth in claim 18 .