Combinations of TGFβ and COX-2 inhibitors and methods for their therapeutic application

Inventors

Lu, Patrick Y. • Simonenko, Vera • Evans, David • Xu, John J.

Assignees

Sirnaomics Inc

Abstract

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.

Core Innovation

The invention relates to scarless-like wound healing by a therapy combining TGFβ1 inhibition and COX-2 inhibition, including the reduction of fibrosis and scar formation. It is based on a biological rationale that TGFβ1-driven inflammation and fibrosis and COX-2-driven inflammatory and fibroblast proliferation contribute to scarring outcomes, and that combined targeting provides a synergistic effect.

The invention provides multi-target siRNA strategies that silence TGFβ1 and Cox-2, and optionally Hoxb13, using selected siRNA duplexes. The disclosed compositions include 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), optionally with further inhibitor components described as targeting the same axes.

The siRNA molecules are delivered with a pharmaceutically acceptable histidine-lysine polymer carrier (HMK histidine-lysine polymer, including HKP/H3K4b/PT73) that forms nanoparticles with the siRNA molecules. The disclosed formulations are intended for topical administration for wound healing, and the document further describes use for tissue fibrosis associated with chronic inflammation and scarring in organs such as liver, lung, kidney, and heart.

Claims Coverage

The independent claims cover pharmaceutical compositions and associated therapeutic uses defined by specific hmTF-25-2 and hmCX-25-1 siRNA molecules, optional restriction to only those siRNAs, and nanoparticle formation with a histidine-lysine polymer carrier, together with treatment indications for wounds and tissue fibrosis in specified organs. Across the independent claims, there are 2 core formulation inventive features and 2 core use inventive features.

Overall, the independent claims are centered on compositions that include the specific hmTF-25-2 and hmCX-25-1 siRNA molecules and, in key embodiments, a pharmaceutically acceptable histidine-lysine polymer that forms nanoparticles with the siRNAs. The claims further connect the compositions to treating inflamed/neovascularized wounds with minimized scar formation and to treating tissue fibrosis associated with scarring after chronic inflammation in the liver, lung, kidney, and heart.

Stated Advantages

Documented Applications