Pharmaceutical compositions and methods of use for activation of human fibroblast and myofibroblast apoptosis
Inventors
Xu, John • Lu, Patrick Y. • Zhou, Jia • Li, Qingfeng • Simonenko, Vera
Assignees
Sirnaomics Medicine Technology Suzhou Co Ltd • Sirnaomics Inc
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Publication Number
US-11697813-B2
Publication Date
2023-07-11
Expiration Date
Abstract
The current invention provides a method of activating fibroblast and myofibroblast apoptosis in a tissue of a mammal, comprising administering to the tissue a therapeutically effective amount of a composition comprising an siRNA molecule that binds to an mRNA that codes for TGFB1 protein in a mammalian cell, an siRNA molecule that binds to an mRNA that codes for COX-2 protein in a mammalian cell, and a pharmaceutically acceptable carrier comprising a pharmaceutically acceptable histidine-lysine polymer. The invention also provides additional methods for using this composition.
Core Innovation
The invention provides a method of reducing fibrosis in the tissue of a mammal by administering a therapeutically effective amount of a composition comprising siRNA molecules and a pharmaceutically acceptable carrier comprising a histidine-lysine co-polymer. The composition includes an siRNA molecule that binds to an mRNA that codes for TGF-β1 protein and an siRNA molecule that binds to an mRNA that codes for COX-2 protein in a mammalian cell. The composition further comprises the siRNA molecule hmTF-25-2 and the siRNA molecule hmCX-25-1, each provided as sense and antisense forms.
The core approach targets fibrotic signaling by modulating TGF-β1 and COX-2 pathways through dual-gene silencing using hmTF-25-2 and hmCX-25-1. The described therapeutic concept is to activate fibroblast/myofibroblast apoptosis and downregulate fibrotic markers, including α-SMA and collagen/ECM-related markers associated with fibrosis. The documentation links reduced fibrotic outcomes to changes in gene and marker expression related to TGF-β1 and COX-2 modulation.
The delivery concept uses histidine-lysine co-polymer (HKP) formulated as nanoparticles with a size of about 150 nm, providing administration into scar tissue as described. The document states that preferred HKP species include H3K4b and PT73, and that the HKP repeating-unit formula is defined using variables including R, X, K, H, and N. The described delivery supports detectable gene silencing after administration and is reported to persist for up to several days.
Claims Coverage
The patent includes one independent claim directed to a method for reducing fibrosis in mammalian tissue using a dual siRNA composition targeting TGF-β1 and COX-2 mRNA, formulated with a pharmaceutically acceptable histidine-lysine co-polymer carrier. The independent claim is primarily narrowed and specified by dependent claims that limit tissue type, administration route, mammal, and the histidine-lysine co-polymer species and repeating-unit formula.
Dual siRNA targeting TGF-β1 and COX-2 mRNA for fibrosis reduction
A method of reducing fibrosis in the tissue of a mammal by administering a therapeutically effective amount of a composition comprising an siRNA molecule that binds to an mRNA that codes for TGF-β1 protein and an siRNA molecule that binds to an mRNA that codes for COX-2 protein, wherein the composition comprises the siRNA molecule hmTF-25-2 and the siRNA molecule hmCX-25-1.
Histidine-lysine co-polymer as a pharmaceutically acceptable carrier
The method wherein the composition further comprises a pharmaceutically acceptable carrier comprising a pharmaceutically acceptable histidine-lysine co-polymer.
Named HKP species for formulation
The method wherein the pharmaceutically acceptable histidine-lysine co-polymer comprises the species H3K4b or the species PT73.
HKP repeating-unit formula defined by R, X, K, H, and N
The method wherein the histidine-lysine copolymer has a particular repeating-unit formula with defined values for R, X, K, H, and N.
Across the claim set, the inventive coverage centers on a dual siRNA composition using hmTF-25-2 and hmCX-25-1 to reduce fibrosis, with delivery/formulation defined by a pharmaceutically acceptable histidine-lysine co-polymer carrier. Additional coverage narrows the carrier to specific HKP species and to an HKP repeating-unit formula defined by residue variables.
Stated Advantages
Reduces scar fibrosis in mammalian tissue.
Decreases scar size in a reported human hypertrophic scar/skin graft mouse-model outcome.
Reduces pro-fibrotic expression and increases apoptotic cell populations as reported.
Documented Applications
Therapeutic treatment of fibrosis, including scar fibrosis, by administering a dual siRNA composition targeting TGF-β1 mRNA and COX-2 mRNA formulated with a histidine-lysine co-polymer carrier.
Administration into scar tissue using intrascar injection/intraderma injection as described.
Use in a reported human hypertrophic scar/skin graft mouse-model to assess scar outcomes.
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