Combinations of TGFβ and COX-2 inhibitors and methods for their therapeutic application
The present invention provides compositions and methods for using combinations of TGFβ1 and Cox-2 inhibitors and TGFβ1 and Hoxb13 inhibitors for the treatment of various medical conditions, including skin scaring due to trauma wounds and surgery, corneal and retina scaring due to injury and surgery, internal organ scaring due to injury and surgery, heart tissue scaring due to heart attack and surgery, and lung, liver, and kidney fibrosis due to inflammation and injury. One example is to use siRNA inhibitors to silence TGFβ1 and Cox-2 at the same time, resulting in significant less scar formation.
1. A composition consisting of the siRNA molecule hmTF-25-2 (SEQ ID NO: 36 and SEQ ID NO: 37), the siRNA molecule hmCX-25-1 (SEQ ID NO: 50 and SEQ ID NO: 51), and a pharmaceutically acceptable histidine-lysine polymer, wherein the siRNA molecules and the histidine-lysine polymer form nanoparticles.
2. The composition of claim 1 , wherein the nanoparticles have an average size of 150-200 nm.
3. A composition comprising siRNA molecules and a pharmaceutically acceptable carrier, wherein the only siRNA molecules present are the siRNA molecule hmTF-25-2 (SEQ ID NO: 36 and SEQ ID NO: 37) and the siRNA molecule hmCX-25-1 (SEQ ID NO: 50 and SEQ ID NO: 51).
4. The composition of claim 3 , wherein the pharmaceutically acceptable carrier comprises a histidine-lysine polymer.
5. The composition of claim 4 , wherein the siRNA molecules and the histidine-lysine polymer form nanoparticles.
6. The composition of claim 5 further comprising an additional direct inhibitor to TGFβ1 and/or an additional direct inhibitor to Cox-2, wherein the additional direct inhibitor is selected from the group consisting of small molecule antagonists, monoclonal antibodies, peptide inhibitors, aptamers, and antisense molecules.
7. The composition of claim 5 , further comprising a 1, 1.5, 2, 3, or 10 percent concentration of methylcellulose gel.
8. The composition of claim 7 , wherein the pharmaceutically acceptable histidine-lysine polymer comprises the histidine-lysine polymer species H3K4b or the histidine-lysine polymer species PT73.
9. the composition of claim 7 wherein the histidine-lysine polymer has the formula (R)K(R)-K(R)-(R)K(X), where R=KHHHKHHHKHHHKHHHK, or R=KHHHKHHHNHHHNHHHN, X=C(O)NH2, K=lysine, H=histidine, and N=asperagine.
10. A composition consisting of the siRNA molecule hmTF-25-2 (SEQ ID NO: 36 and SEQ ID NO: 37), the siRNA molecule hmCX-25-1 (SEQ ID NO: 50 and SEQ ID NO: 51), and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , wherein the pharmaceutically acceptable carrier comprises a histidine-lysine polymer.
12. The composition of claim 11 , wherein the siRNA molecules and the histidine-lysine polymer form nanoparticles.
13. A method for treating a wound in a mammal, wherein the wound is characterized at least in part by inflammation and neovascularization, comprising administering to the mammal or the wound a therapeutically effective amount of the composition claim 1 .
14. The method of claim 13 wherein the treatment results in minimized scar formation.
15. The method of claim 13 , wherein the wound is caused by trauma.
16. The method of claim 13 , wherein the wound is an ulcer.
17. The method of claim 13 , wherein the mammal is a laboratory animal.
18. The method of claim 13 , wherein the mammal is a human.
19. The method of claim 13 , wherein said administering comprises topical administration to the wound.
20. The method of claim 19 , wherein said mammal is a human.
21. A method for treating tissue fibrosis in a mammal caused by scaring after chronic inflammation of the tissue, wherein the tissue is part of the liver, lung, kidney or heart of the mammal, comprising the step of administering a therapeutically effective amount of the composition of claim 1 to the mammal or the tissue.
22. The method of claim 21 , wherein the mammal is a laboratory animal.
23. The method of claim 21 , wherein the mammal is a human.
24. A method for treating a wound in a mammal comprising administering to the mammal or the wound a therapeutically effective amount of the composition of claim 3 .
25. A method for treating tissue fibrosis in a mammal caused by scaring after chronic inflammation of the tissue, wherein the tissue is part of the liver, lung, kidney or heart of the mammal, comprising the step of administering a therapeutically effective amount of the composition of claim 3 to the mammal or the tissue.
26. A method for treating a wound in a human, wherein the wound is characterized at least in part by inflammation and neovascularization, comprising administering to the wound a therapeutically effective amount of the composition claim 7 .
27. A method for treating a wound in a human, wherein the wound is characterized at least in part by inflammation and neovascularization, comprising administering to the wound a therapeutically effective amount of the composition claim 8 .
28. A method for treating a wound in a mammal, comprising administering to the mammal or the wound a therapeutically effective amount of the composition claim 10 .
29. A method for treating tissue fibrosis in a mammal caused by scaring after chronic inflammation of the tissue, wherein the tissue is part of the liver, lung, kidney or heart of the mammal, comprising the step of administering a therapeutically effective amount of the composition of claim 10 to the mammal or the tissue.
30. The method of claim 28 , wherein the mammal is a human.
31. The method of claim 29 , wherein the mammal is a human.
32. The method of claim 24 , wherein the mammal is a human.
33. The method of claim 25 , wherein the mammal is a human.
34. A method for treating a wound in a mammal comprising administering to the mammal or the wound a therapeutically effective amount of the composition of claim 6 .
35. A method for treating tissue fibrosis in a mammal caused by scaring after chronic inflammation of the tissue, wherein the tissue is part of the liver, lung, kidney or heart of the mammal, comprising the step of administering a therapeutically effective amount of the composition of claim 6 to the mammal or the tissue.
36. The method of claim 34 , wherein the mammal is a human.
37. The method of claim 35 , wherein the mammal is a human.