Claims
- 1. A nucleic acid construct comprising: a T-cell factor (TCF) response element comprising:
at least one TCF binding element having the sequence CTTTGNN wherein N is A or T; an operably linked promoter, and an expressible gene that is useful for the treatment of a disease that is characterised by
deregulation in Wnt pathway signalling, wherein the expressible gene is operably linked to both the TCF binding element and the promoter, which enables inducible expression of the gene.
- 2. A nucleic acid construct comprising: a T-cell factor (TCF) response element comprising:
at least one TCF binding element having the sequence CTTTGNN wherein N is A or T; an operably linked promoter, and an expressible gene that is useful for the treatment of a disease that is characterised by the presence of TCF/β-catenin heterodimers in diseased cells wherein the expressible gene is operably linked to both the TCF binding element and the promoter, which enables inducible expression of the gene.
- 3. A nucleic acid construct comprising: a T-cell factor (TCF) response element comprising:
at least one TCF binding element having the sequence CTTTGNN wherein N is A or T; an operably linked promoter, and an expressible gene that is useful for the treatment of a cancer that is characterised by the presence of TCF/β-catenin heterodimers in diseased cells wherein the expressible gene is operably linked to both the TCF binding element and the promoter, which enables inducible expression of the gene.
- 4. The nucleic acid construct of any one of claims 1 to 3 wherein the expressible gene is selected from the group consisting of: a gene encoding a toxin, a prodrug-activating enzyme or an immunomodulatory agent; a tumor-supressor gene or an apoptotic gene.
- 5. The nucleic acid construct of claim 4, wherein the expressible gene encodes a toxin or prodrug-activating enzyme.
- 6. The nucleic acid construct of claim 5, wherein the therapeutic gene encodes a nitroreductase capable of activating CB1954.
- 7. The nucleic acid construct of any one of claims 1 to 3 wherein the promoter is selected from the group consisting of the SV40 promoter, the E1B promoter, and the c-Fos promoter.
- 8. The nucleic acid construct of claim 7, wherein the promoter is the E1B promoter.
- 9. A nucleic acid construct comprising: 1) a TCF response element comprising: at least 5 TCF binding elements having the sequence CTTTGNN, wherein N is A or T; and an operably linked promoter; and 2) an expressible gene that is useful in the treatment of a disease that is characterised by the presence of TCF/β-catenin heterodimers in diseased cells.
- 10. The nucleic acid construct of claim 9 wherein the TCF response element comprises between 5 and 10 TCF binding elements.
- 11. The nucleic acid construct of claim 10 wherein the TCF response element comprises 5 TCF binding elements.
- 12. A nucleic acid construct comprising: 1) a TCF response element comprising: at least two TCF binding elements having the sequence CTTTGNN, wherein N is A or T; and an operably linked promoter; and 2) an expressible gene that is useful in the treatment of a disease that is characterised by the presence of TCF/β-catenin heterodimers in diseased cells, wherein the expressible gene is operably linked to the TCF response element which enables inducible expression of the gene, and wherein the TCF binding elements are separated from each other by between 3 and 20 nucleotides.
- 13. The nucleic acid construct of claim 12 wherein the TCF binding elements are separated from each other by between 3 and 12 nucleotides.
- 14. The nucleic acid construct of claim 13 wherein the TCF binding elements are separated from each other by between 10 and 12 nucleotides.
- 15. A nucleic acid construct comprising: 1) a TCF response element comprising: at least one TCF binding element having the sequence CTTTGNN, wherein N is A or T; and an operably linked promoter; and 2) an expressible gene that is useful in the treatment of a disease that is characterised by the presence of TCF/1-catenin heterodimers in diseased cells, wherein the expressible gene is operably linked to the TCF response element which enables inducible expression of the gene, and wherein the TCF binding element closest to the promoter is between 140 and 10 nucleotides from the TATA box of the promoter.
- 16. The nucleic acid construct of claim 15 wherein the promoter contains a TATA box, and the TCF binding element closest to the promoter is between 100 and 10 nucleotides from the TATA box of the promoter.
- 17. The nucleic acid construct of claim 16 wherein the promoter contains a TATA box, and the TCF binding element closest to the promoter is between 50 and 10 nucleotides from the TATA box of the promoter.
- 18. The nucleic acid construct of claim 17 wherein the promoter contains a TATA box, and the TCF binding element closest to the promoter is between 30 and 15 nucleotides from the TATA box of the promoter.
- 19. The nucleic acid construct of claim 12 wherein the TCF binding elements are separated from each other by 3 or 4 nucleotides and wherein the promoter comprises a TATA box, and the TCF binding element closest to the promoter is 25 nucleotides from the TATA box of the promoter.
- 20. The nucleic acid construct of any one of claims 1 to 3, 9, 12, 15, 29, 30 or 31, wherein the TCF binding element has the nucleotide sequence CTTTGAT.
- 21. A vector comprising the nucleic acid construct of any one of claims 1 to 3, 9, 12, 15, 29, 30 or 31.
- 22. A host cell transfected with the vector of claim 21.
- 23. A method of treatment of a disease characterised by a deregulation in Wnt pathway signalling or the presence of TCF/β-catenin heterodimers in diseased cells, comprising administering to a patient in need of such treatment an effective dose of the nucleic acid construct of any one of claims 1 to 3, 9, 12 or 15.
- 24. A method of treatment of a disease characterised by a deregulation in Wnt pathway signalling or the presence of TCF/β-catenin heterodimers in diseased cells, comprising administering to a patient in need of such treatment an effective dose of the vector of claim 21.
- 25. A method of treatment of a disease characterised by a deregulation in Wnt pathway signalling or the presence of TCF/β-catenin heterodimers in diseased cells, comprising administering to a patient in need of such treatment an effective dose of the host cell of claim 22.
- 26. A composition comprising the nucleic acid construct of any of claims 1 to 3, 9, 12 or 15 and a pharmaceutically acceptable excipient.
- 27. A composition comprising the vector of claim 21.
- 28. A composition comprising the host cell of claim 22 and a pharmaceutically acceptable excipient.
- 29. The nucleic acid construct according to claim 9, wherein the expressible gene is selected from the groups consisting of: a gene encoding a toxin, a prodrug activating enzyme, or an immunomodulatory element; a tumor suppressor gene; and an apoptotic gene.
- 30. The nucleic acid construct according to claim 12, wherein the expressible gene is selected from the groups consisting of: a gene encoding a toxin, a prodrug activating enzyme, or an immunomodulatory element; a tumor suppressor gene; and an apoptotic gene.
- 31. The nucleic acid construct according to claim 15, wherein the expressible gene is selected from the groups consisting of: a gene encoding a toxin, a prodrug activating enzyme, or an immunomodulatory element; a tumor suppressor gene; and an apoptotic gene.
Priority Claims (2)
Number |
Date |
Country |
Kind |
0005099.7 |
Mar 2000 |
GB |
|
PCT/GB01/00856 |
Mar 2001 |
WO |
|
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application which claims priority under 35 U.S.C. § 119(a)-(d) of United Kingdom Application No. 0005099.7, filed Mar. 2, 2000 and also claims the benefit under 35 U.S.C. § 119(e) of U.S. Application Serial No. 60/187,465, filed Mar. 6, 2000, and claims benefit under 35 U.S.C. § 119(a)-(d) of PCT Application No. PCT/GB01/00856, filed Mar. 1, 2001, all applications incorporated herein by reference in their entireties.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60187465 |
Mar 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09798128 |
Mar 2001 |
US |
Child |
10607479 |
Jun 2003 |
US |