CN-121987792-A - Application of HAND2 gene or HAND2 protein inhibitor in preparation of anti-hepatic fibrosis drugs

Abstract

The application discloses an application of an inhibitor of a HAND2 gene or a HAND2 protein in preparing an anti-hepatic fibrosis medicine, and relates to the technical field of biological medicines, and the application of the inhibitor of the HAND2 gene or the HAND2 protein in preparing the anti-hepatic fibrosis medicine, wherein the inhibitor is an inhibitor for inhibiting the expression of the HAND2 gene or an inhibitor for inhibiting the activity of the HAND2 protein; the inhibitor is at least one of a small molecular compound, siRNA, shRNA, antisense oligonucleotide, a nucleic acid aptamer, a CRISPR gene editing system or a neutralizing antibody aiming at a HAND2 protein and an antigen binding fragment thereof, is siRNA or shRNA of a target HAND2 gene, confirms the key effect of the HAND2 as a new target for treating hepatic fibrosis, fills the blank of the field, provides a clear, specific and practical technical scheme, realizes the spanning from target discovery to therapeutic drug application, and provides a solid basis for developing a novel drug.

Inventors

• BI XIAOJUAN
• YANG NING
• LIN RENYONG
• LV GUODONG
• LI LIANG
• ZHANG XUE
• CHU JIN

Assignees

• 新疆医科大学第一附属医院

Dates

Publication Date

20260508

Application Date

20260202

Claims (10)

1. 1. An application of an inhibitor of a HAND2 gene or HAND2 protein in preparing an anti-hepatic fibrosis medicine.
2. 2. The method of claim 1, wherein the inhibitor is an inhibitor that inhibits expression of the HAND2 gene or an inhibitor that inhibits activity of the HAND2 protein.
3. 3. The method of claim 1, wherein the inhibitor is at least one selected from the group consisting of small molecule compounds, siRNA, shRNA, antisense oligonucleotides, nucleic acid aptamers, CRISPR gene editing systems, neutralizing antibodies to HAND2 proteins, and antigen binding fragments thereof.
4. 4. The method of claim 3, wherein the inhibitor is a siRNA or shRNA targeting the HAND2 gene.
5. 5. The method of claim 4, wherein the sense strand sequence of the siRNA is shown as SEQ ID NO.1 and the antisense strand sequence is shown as SEQ ID NO. 2.
6. 6. The method according to claim 4, wherein the shRNA sequence is shown in SEQ ID NO. 3.
7. 7. The method of claim 1, wherein the liver fibrosis is caused by chemical injury, cholestasis or parasitic infection.
8. 8. An anti-hepatic fibrosis medicine is characterized by comprising an effective dose of an inhibitor of the HAND2 gene or HAND2 protein and a pharmaceutically acceptable carrier or adjuvant.
9. 9. The drug according to claim 8, wherein the drug is prepared into any one of injection, freeze-dried powder injection or nanoparticle delivery system.
10. 10. The agent according to claim 8, wherein the agent is used for reducing the expression level of the fibrosis markers alpha-smooth muscle actin and type I collagen in hepatic stellate cells or in hepatic fibrosis tissue.

Description

Application of HAND2 gene or HAND2 protein inhibitor in preparation of anti-hepatic fibrosis drugs Technical Field The invention relates to the technical field of biological medicines, in particular to application of an inhibitor of a HAND2 gene or HAND2 protein in preparation of anti-hepatic fibrosis medicines. Background Liver fibrosis (Liver Fibrosis) is a consequence of progressive repair reactions of the liver following chronic liver injury, characterized by excessive deposition and abnormal distribution of extracellular matrix (Extracellular Matrix, ECM) within the liver. The central pathological link of liver fibrosis is the activation of hepatic stellate cells (HEPATIC STELLATE CELL, HSC). In normal liver, HSCs are in resting state, with the primary function of storing vitamin a. When the liver is subjected to various injuries (e.g., viruses, toxins, metabolic stresses), resting HSCs are activated and transformed into myofibroblast-like cells (Myofibroblast). This transformation is accompanied by dramatic changes in cellular phenotype, enhanced proliferation, migration, loss of vitamin A lipid droplets, and massive synthesis and secretion of type I collagen-based ECM components. At the same time, activated HSCs also secrete pro-inflammatory and pro-fibrotic cytokines such as transforming growth factor-beta (TGF-beta), platelet Derived Growth Factor (PDGF), etc., forming a positive feedback loop, exacerbating the fibrotic process. Thus, activation of targeted HSCs is considered one of the most promising strategies for anti-liver fibrosis treatment. Transcription factor HAND2 (Heart and neural CREST DERIVATIVES expressed protein 2, a human Heart and neural crest derivative expressing transcription factor 2) belongs to the basic helix-loop-helix (bHLH) protein family, and has important roles in various physiological and pathological processes, but the prior art has contradiction to its functional cognition in tissue fibrosis and is highly dependent on organ environment, especially lacks systematic study of its mechanism of action and expression rules in liver fibrosis, which results in that the feasibility and direction of action of using it as a therapeutic target for liver fibrosis cannot be judged by those skilled in the art. Currently, specific small molecule drugs or biologics that directly target HSC activation or ECM deposition are extremely limited, and efficacy and safety are to be further validated. Meanwhile, the clinical application of the drug treatment strategy aiming at the known wide-range action targets (such as TGF-beta) is often limited due to serious side effects accompanied by the indispensable channel in the physiological process. The lack of highly effective targeted drugs for the treatment of hepatic fibrosis, despite targeting hepatic stellate cell activation is a accepted drug treatment strategy, is still clinically lacking a safe and effective drug capable of specifically interfering with this process. Some of the existing broad-spectrum anti-fibrosis means are difficult to meet clinical requirements due to undefined action mechanisms or large side effects. The application prospect of the HAND2 as a therapeutic target is unknown, although the HAND2 is reported in various fibrosis diseases, the specific role and expression rule of the HAND2 in liver fibrosis are completely unknown, and different studies have contradictions in conclusion of organs such as heart, so that the person skilled in the art cannot judge whether the HAND2 plays a promoting or inhibiting role in liver fibrosis or can take the HAND2 as a reliable drug intervention target. The lack of a direct association of HAND2 with anti-liver fibrosis drugs suggests that the prior art does not teach or suggest that a drug for treating liver fibrosis can be prepared by inhibiting the expression or activity of HAND 2. In particular, there is no prior art disclosing or suggesting a complete technical logic chain for up-regulation of band 2 expression in liver fibrosis-band 2 directly driving hepatic stellate cell activation-thus, inhibition of band 2 could be an effective therapeutic drug strategy against liver fibrosis. Aiming at the technical problems, the invention discloses that the expression of HAND2 is specifically up-regulated in various liver fibrosis models for the first time and directly drives hepatic stellate cell activation. Based on the above, a new strategy for treating liver fibrosis by inhibiting HAND2 is provided and verified for the first time, and clear experimental basis and technical teaching are provided for developing anti-liver fibrosis drugs targeting HAND 2. Disclosure of Invention In view of the above, the present invention aims at overcoming the defects of the prior art, and its main purpose is to provide an application of an inhibitor of the band 2 gene or the band 2 protein in preparing anti-hepatic fibrosis drugs, which provides a brand-new anti-hepatic fibrosis therapeutic drug strategy b