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 or EGFR expression and methods of using these splice-switching oligonucleotides to treat cancer.
1. A modified splice-switching oligonucleotide (SSO), said SSO comprising:
(i) a nucleotide sequence set forth in SEQ ID NO: 6,
(ii) a length of at least 18 nucleotides and no more than 100 nucleotides,
(iii) full complementarity to a sequence within exon 18 (SEQ ID NO: 8) of an EGFR pre-mRNA, and
(iv) a modification selected from the group consisting of a 2′-O-methyl phosphorothioate, a morpholino, a phosphorodiamidate-linked morpholino (PMO), a locked nucleic acid (LNA), a peptide nucleic acid, a 2′-O-(2-methoxy ethyl) nucleotide, a G-clamp or 9-(aminoethoxy)phenoxazine nucleotide, and cytosine analogues that form 4 hydrogen bonds with guanosine.
2. The modified splice-switching oligonucleotide of claim 1 , wherein the oligonucleotide consisting of 18-26 nucleotides.
3. A modified splice-switching oligonucleotide of claim 1 , wherein the modified splice-switching oligonucleotide comprises a 2′-O-Me phosphorothioate backbone.
4. A composition comprising the splice-switching oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
5. A composition comprising the splice-switching oligonucleotide of claim 3 and a pharmaceutically acceptable carrier.
6. A modified splice-switching oligonucleotide of claim 1 , which is a morpholino oligonucleotide.
7. A composition comprising the splice-switching oligonucleotide of claim 6 and a pharmaceutically acceptable carrier.
8. The modified splice-switching oligonucleotide of claim 1 , wherein the modified splice-switching oligonucleotide comprises a 2′-O-(2-methoxyethyl) backbone.
9. A composition comprising the splice-switching oligonucleotide of claim 8 and a pharmaceutically acceptable carrier.
10. The modified splice-switching oligonucleotide of claim 1 , wherein the SSO has a length of at least 18 nucleotides and no more than 50 nucleotides.
11. The modified splice-switching oligonucleotide of claim 1 , wherein the SSO has a length of at least 18 nucleotides and no more than 40 nucleotides.
12. The modified splice-switching oligonucleotide of claim 1 , wherein the SSO has a length of at least 18 nucleotides and no more than 30 nucleotides.
13. The modified splice-switching oligonucleotide of claim 1 , wherein the SSO has a length of 18 nucleotides and comprises a phosphorodiamidate-linked morpholino (PMO) modification.
14. The modified splice-switching oligonucleotide of claim 1 , wherein the SSO has a length of 30 nucleotides and comprises a phosphorodiamidate-linked morpholino (PMO) modification.
15. The modified splice-switching oligonucleotide of claim 10 , wherein the SSO comprises a phosphorodiamidate-linked morpholino (PMO) modification.
16. The modified splice-switching oligonucleotide of claim 11 , wherein the SSO comprises a phosphorodiamidate-linked morpholino (PMO) modification.
17. The modified splice-switching oligonucleotide of claim 12 , wherein the SSO comprises a phosphorodiamidate-linked morpholino (PMO) modification.
18. A method of treating cancer in a subject, comprising administering to the subject a modified splice-switching oligonucleotide according to claim 1 in an amount effective to treat the cancer, thereby treating the cancer.
19. The method according to claim 18 , wherein the cancer comprises prostate cancer.
20. The method of claim 18 , wherein the subject is an African American male suffering from prostate cancer.
21. The method of claim 18 , wherein the method further comprises administering to the subject a second cancer therapy.
22. The method of claim 18 , wherein the modified splice-switching oligonucleotide comprising a 2′-O-Me phosphorothioate backbone.
23. A method of treating cancer in a subject, comprising administering to the subject a composition according to claim 4 in an amount effective to treat the cancer, thereby treating the cancer.
24. The method of claim 23 , wherein the cancer comprises prostate cancer.
25. The method of claim 23 , wherein the subject is an African American male suffering from prostate cancer.
26. The method of claim 23 , wherein the modified splice-switching oligonucleotide comprising a 2′-O-Me phosphorothioate backbone.
27. A method of treating cancer in a subject, comprising administering to the subject a modified splice-switching oligonucleotide according to claim 10 in an amount effective to treat the cancer, thereby treating the cancer.
28. A method of treating cancer in a subject, comprising administering to the subject a modified splice-switching oligonucleotide according to claim 11 in an amount effective to treat the cancer, thereby treating the cancer.
29. A method of treating cancer in a subject, comprising administering to the subject a modified splice-switching oligonucleotide according to claim 12 in an amount effective to treat the cancer, thereby treating the cancer.