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KR-102961523-B1 - Composition for preventing or treating degenerative valve diseases comprising PAD inhibitors

KR102961523B1KR 102961523 B1KR102961523 B1KR 102961523B1KR-102961523-B1

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of degenerative valve diseases, including aortic valve stenosis. It was completed by confirming that when the PAD (protein-arginine deiminase) protein is inhibited in valve cells derived from aortic valve patients, calcification or osteodifferentiation, fibrosis, and inflammation are effectively inhibited. In other words, since the present invention simultaneously inhibits calcification or osteodifferentiation, fibrosis, and inflammation of valve tissue, which are the major pathological mechanisms of degenerative valve disease, it is possible to fundamentally treat degenerative valve disease. Therefore, it is expected to be utilized as a therapeutic agent for various diseases caused by degenerative deformation of the valve.

Inventors

  • 이사민
  • 지은혜

Assignees

  • 재단법인 아산사회복지재단
  • 울산대학교 산학협력단

Dates

Publication Date
20260511
Application Date
20220808

Claims (10)

  1. A pharmaceutical composition for the prevention or treatment of degenerative valvular disease comprising a PAD (protein-arginine deiminase) 2 inhibitor as an active ingredient, The above inhibitor is an expression inhibitor of the PAD 2 gene, and The above expression inhibitor is a small interfering RNA (siRNA), and The above siRNA comprises one or more nucleotide sequences selected from the group consisting of SEQ ID NOs 3 to 6, and The aforementioned degenerative valve disease is aortic stenosis, and A pharmaceutical composition for the prevention or treatment of degenerative valve disease, wherein the above composition satisfies one or more features selected from the group consisting of the following: (a) Inhibits calcification or osteodifferentiation of valve tissue; (b) inhibiting fibrosis of valve tissue; and (c) Suppresses inflammation of the valve tissue.
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  6. In paragraph 1, A pharmaceutical composition for the prevention or treatment of degenerative valve disease, characterized in that the above valve is an aortic valve.
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  9. In paragraph 1, A pharmaceutical composition for the prevention or treatment of degenerative valvular disease, wherein the above composition is intended to treat degenerative valvular disease in patients with elevated levels of one or more selected from the group consisting of MCP1, CTGF, COL1A1, COL3A1, α-SMA, RUNX2, and BMP6.
  10. A kit for the prevention or treatment of degenerative valve disease comprising a pharmaceutical composition of any one of claims 1, 6, and 9, A kit for the prevention or treatment of degenerative valve disease, characterized in that the above-mentioned degenerative valve disease is aortic stenosis.

Description

Composition for preventing or treating degenerative valve diseases comprising PAD inhibitors The present invention relates to a composition for the prevention or treatment of degenerative valve disease comprising a PAD inhibitor, etc. Recently, with the rapid aging of the population, valvular diseases caused by degenerative changes in the valves (e.g., calcification or osteodifferentiation, fibrosis, and/or inflammation) are on the rise. If structural abnormalities occur in valves that were functioning normally, the valve's opening and closing function deteriorates, which can hinder smooth blood circulation and lead to secondary functional abnormalities in various organs, including the heart. Aortic stenosis (AS), a representative example of degenerative valvular disease, is a condition in which the diameter of the aortic valve narrows primarily due to calcification, preventing sufficient blood flow from the left ventricle to the aorta. It is the most commonly found valvular heart disease in modern society, characterized by an increasing proportion of the aging population. Aortic stenosis is caused by inflammation resulting from endothelial cell damage caused by mechanical stress, as well as leaflet fibrosis, thickening, and calcification caused by lipid penetration; in particular, aortic valve calcification serves as the primary pathological mechanism. While mild cases of Aortic stenosis are often asymptomatic and therefore have a long subclinical period, once the condition progresses to a moderate or severe stage, it hinders the smooth flow of blood throughout the body, causing dizziness, chest pain, and fainting, and can be fatal. It is known that if an aortic valve is left untreated, the annual mortality rate reaches 25%, and the average survival period is only 2 to 3 years. A drug that fundamentally improves aortic valve stenosis has not yet been identified; therefore, treatment typically consists of artificial valve replacement surgery, which involves removing the damaged valve and inserting an artificial one. However, valve replacement requires open-heart surgery, which places a burden on the patient, particularly because the heart must be stopped and a cardiopulmonary bypass machine used to take over cardiopulmonary function during the procedure. Furthermore, replacing the valve with a mechanical one presents the problem of requiring lifelong anticoagulant medication to prevent blood clotting. Recently, non-surgical treatment such as transcatheter aortic valve implantation (TAVR) has been performed for patients with a high surgical risk; however, since this involves the insertion of an artificially manufactured tissue valve, a fundamental cure for aortic valve stenosis remains impossible. Therefore, it is necessary to discover new treatment methods that address the pathogenesis of aortic valve stenosis to fundamentally treat the disease. Figures 1a and 1b show the results of confirming the PAD2 protein levels by Western blot after treating interstitial cells isolated from a patient with aortic valve stenosis with the siRNA to confirm the inhibitory effect of PAD2-targeted siRNA on PAD expression (Figure 1a) and the quantification results thereof (Figure 1b). Figures 2a and 2b show the results of comparing the levels of calcification or osteogenic differentiation markers after treating interstitial cells isolated from patients with aortic valve stenosis with PAD inhibitors at various concentrations (DISEASE CONT: untreated control group). Figures 3a and 3b show the results of comparing the levels of inflammation markers after treating interstitial valve cells isolated from patients with aortic valve stenosis with PAD inhibitors at various concentrations. Figures 4a and 4b show the results of comparing the levels of fibrosis markers after treating interstitial cells isolated from patients with aortic valve stenosis with PAD inhibitors at various concentrations. The present invention relates to a pharmaceutical composition for the prevention or treatment of degenerative valve disease, and was completed by confirming that when the expression or activity of PAD (protein-arginine deiminase), a protein involved in protein citrullination, is inhibited, major pathological mechanisms of degenerative valve disease, such as calcification or osteodifferentiation, fibrosis, and inflammation, are significantly reduced. Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of degenerative valve disease comprising a PAD (protein-arginine deiminase) inhibitor as an active ingredient. In the present invention, “PAD (protein-arginine deiminase)” refers to a hydrolytic enzyme that catalyzes arginine deimination and citrullination, which are post-translational modifications of proteins. Although abnormalities in the PAD protein are known to be associated with some autoimmune diseases or arthritis, there is no known association between the PAD protein and valvular heart d