NKX3-1 saRNA and KLF4 saRNA and uses thereof
View Patent ↗The present disclosure provides compositions, pharmaceutical preparations, kits and methods for increasing expression of a NKX3-1 gene product in a cell by contacting the cell with a small activating RNA (saRNA) molecule comprising a ribonucleic strand that is complementary to a promoter region sequence of the NKX3-1 gene. The present disclosure also provides compositions, pharmaceutical preparations, kits and methods for increasing expression of a KLF4 gene product in a cell by contacting the cell with a small activating RNA (saRNA) molecule comprising a ribonucleic strand that is complementary to a promoter region sequence of the KLF4 gene.
1. An isolated composition comprising,
a small activating RNA (saRNA) molecule comprising at least a first ribonucleic acid strand comprising a sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, wherein the sequence is complementary to a promoter region sequence of a NKX3-1 gene and is sufficient to activate transcription of the NKX3-1 gene.
2. The composition of claim 1 , wherein the saRNA molecule comprises a second ribonucleic acid strand and wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 2 and when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 3, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 4.
3. The composition of claim 1 , wherein the saRNA molecule comprises a thio modified internucleotide linkage.
4. The composition of claim 1 , wherein the composition comprises a second saRNA molecule comprising at least one ribonucleic acid strand, wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3 or SEQ ID NO: 4.
5. The composition of claim 4 , wherein when the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3, another ribonucleic acid strand of the second saRNA strand comprises a sequence from SEQ ID NO: 4.
6. The composition of claim 1 , wherein the composition further comprises at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient and a pharmaceutically acceptable adjuvant.
7. A kit comprising,
a small activating RNA (saRNA) molecule comprising at least a first ribonucleic acid strand comprising a sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, wherein the sequence is complementarity to a promoter region sequence of a NKX3-1 gene and is sufficient to activate transcription of the NKX3-1 gene.
8. The kit of claim 7 , wherein the saRNA molecule comprises a second ribonucleic acid strand and wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 2 and when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 3, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 4.
9. The kit of claim 7 , wherein the kit comprises a second saRNA molecule comprising at least one ribonucleic acid strand, wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3 or SEQ ID NO: 4.
10. The kit of claim 9 , wherein when the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3, another ribonucleic acid strand of the second saRNA strand comprises a sequence from SEQ ID NO: 4.
11. The kit of claim 7 , wherein the saRNA molecule comprises a thio modified internucleotide linkage.
12. The kit of claim 7 , wherein the kit further comprises at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable excipient and a pharmaceutically acceptable adjuvant.
13. A method to increase expression of a gene comprising:
introducing a small activating RNA (saRNA) molecule into a mammalian cell in an amount sufficient to increase expression of a NKX3-1 gene, wherein the saRNA molecule comprises at least a first ribonucleic acid strand comprising,
a sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4,
wherein the sequence is complementary to a promoter region sequence of the NKX3-1 gene, and
wherein the introducing results in an increase in expression of the NKX3-1 gene.
14. The method of claim 13 , wherein the saRNA molecule comprises a second ribonucleic acid and wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 2 and when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 3, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 4.
15. The method of claim 13 , wherein the introducing comprises introducing a second saRNA molecule, the second saRNA molecule comprising at least one ribonucleic acid strand, wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3 or SEQ ID NO: 4.
16. The method of claim 15 , wherein when the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3, another ribonucleic acid strand of the second saRNA strand comprises a sequence from SEQ ID NO: 4.
17. The method of claim 13 , wherein the saRNA molecule is introduced into the mammalian cell by introducing of a nucleic acid vector encoding the saRNA molecule.
18. The method of claim 13 , wherein the saRNA molecule comprises a thio modified internucleotide linkage.
19. A method of reducing proliferation of a cell in a subject having a cellular proliferative disease comprising,
administering to the subject an effective amount of a small activating RNA (saRNA) molecule, wherein the saRNA molecule comprises at least a first ribonucleic acid strand comprising
a sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4,
wherein the sequence is complementarity to a promoter region sequence of a NKX3-1 gene, and
wherein the administering provides for an increase in expression of NKX3-1 polypeptide and a decrease in cellular proliferation.
20. The method of claim 19 , wherein the saRNA molecule comprises a second ribonucleic acid strand and wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 2 and when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 3, the second ribonucleic acid strand comprises a sequence from SEQ ID NO: 4.
21. The method of claim 19 , wherein the administering comprises administering a second saRNA molecule, the second saRNA molecule comprising at least one ribonucleic acid strand, wherein when the first ribonucleic acid strand comprises a sequence from SEQ ID NO: 1, the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3 or SEQ ID NO: 4.
22. The method of claim 21 , wherein when the one ribonucleic acid strand of the second saRNA comprises a sequence from SEQ ID NO: 3, another ribonucleic acid strand of the second saRNA strand comprises a sequence from SEQ ID NO: 4.
23. The method of claim 19 , wherein the saRNA molecule is introduced into the mammalian cell by introducing of a nucleic acid vector encoding the saRNA molecule.
24. The method of claim 19 , wherein the saRNA molecule comprises a thio modified internucleotide linkage.
25. The method of claim 19 , wherein the cellular proliferative disease is prostate cancer.