CN-122005571-A - Composition for reversing organ fibrosis and application thereof

Abstract

The invention provides a composition for reversing organ fibrosis and application thereof, which belong to the technical field of biological medicines, the cocktail composition comprises valproic acid, CHIR99021, repsox, tranylcypromine and forskolin, the HAT inhibition composition comprises A485 and WM-8014, the cocktail composition and the HAT inhibition composition are singly used or jointly used to reverse liver fibrosis or pulmonary fibrosis, and when being jointly used, synergistic enhancement effects are shown in lung fibrosis and hepatic fibrosis models, the effects of improving fibrosis indexes and reversing apparent genetic ages are more remarkable, and the composition provided by the invention safely reverses the fibrosis pathological phenotype into a healthy or resting state by accurately controlling the apparent genetic program of cells, and further radically reverses the biological age of the fibrosis.

Inventors

• WANG GANG
• SHENG QIANGLONG
• CHEN SHI
• FU CHENGHONG
• Liang Shengrun

Assignees

• 珠海横琴奥纳再生医学有限公司

Dates

Publication Date

20260512

Application Date

20260413

Claims (5)

1. 1. A cocktail composition for reversing organ fibrosis by partial reprogramming is characterized by comprising valproic acid, CHIR99021, repsox, tranylcypromine and forskolin, wherein the use concentration of valproic acid is 200-300 mu M, the use concentration of CHIR99021 is 5-15 mu M, the use concentration of Repsox is 5-15 mu M, the use concentration of tranylcypromine is 4-6 mu M and the use concentration of forskolin is 40-60 mu M.
2. 2. A HAT inhibition composition for reversing organ fibrosis by partial reprogramming is characterized by comprising A485 and WM-8014, wherein the A485 is used at a concentration of 5-15 mu M, and the WM-8014 is used at a concentration of 4-6 mu M.
3. 3. A composition for reversing organ fibrosis by partial reprogramming comprising the cocktail composition of claim 1 and the HAT inhibitory composition of claim 2.
4. 4. Use of the cocktail composition of claim 1, the HAT inhibitory composition of claim 2, or the composition of claim 3 in the manufacture of a medicament for treating organ fibrosis.
5. 5. The use of claim 4, wherein the organ fibrosis comprises liver fibrosis and lung fibrosis.

Description

Composition for reversing organ fibrosis and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a composition for reversing organ fibrosis and application thereof. Background Organ fibrosis is a type of pathological repair abnormality caused by chronic injury, inflammation or metabolic disorder, and is characterized by excessive proliferation of fibroblasts and abnormal deposition of extracellular matrix (ECM), ultimately leading to destruction of organ structure and failure. The diseases can involve a plurality of important organs such as liver, lung and the like, and are particularly characterized by liver fibrosis, idiopathic pulmonary fibrosis and the like, and are one of important causes of increased morbidity and mortality in the global scope. For example, liver fibrosis will progress progressively to cirrhosis or even liver failure without effective intervention. However, despite the great threat of organ fibrosis to human health, there is still a lack of curative therapeutic means capable of directly targeting the core mechanisms of fibrosis occurrence and development in clinic, and existing intervention measures are limited to relieving symptoms or delaying disease progression, so that the therapeutic effect is in need of improvement. In recent years, the rise of cell reprogramming technology provides a new idea for the treatment of organ fibrosis. The technology can realize the identity remodelling of the somatic cells by regulating and controlling the cell fate related signal paths or the epigenetic state. Early researches have relied on over-expressed transcription factors (such as GATA4, MEF2c and TBX5 combination to induce myocardial cell reprogramming, HNF1β, EMX2 and PAX8 combination to induce tubular epithelial cell reprogramming) to realize cell fate transformation, but the reprogramming strategy based on the transgenes has a plurality of limitations that on one hand, the delivery of the transcription factors often depends on virus vectors, has gene integration risks and possibly induces safety problems such as tumors, and on the other hand, the reprogramming efficiency is lower and individual applicability difference is large, and the transformation efficiency of partial difficult-to-induce cell lines is difficult to meet clinical application requirements, and meanwhile, the problems of complex operation, difficult large-scale application and the like exist, so that the clinical transformation process is severely limited. To overcome the shortcomings of transgene reprogramming, chemical small molecule mediated reprogramming techniques have been developed. Research proves that the small molecular compound can regulate and control cell fate conversion in a non-virus dependent and highly controllable manner by directly targeting epigenetic regulation factors (such as histone modification enzyme KAT3A/B, KAT A and the like) or key nodes of a signal path, so that the gene integration risk can be effectively avoided, and the method has the advantages of easiness in synthesis, low cost, large-scale production and the like, and meets the requirement of clinical conversion. For example, small molecule combinations have been studied to successfully induce mouse and human somatic cells into pluripotent stem cells (CiPS cells) and have shown good potential in clinical therapeutic studies of diseases such as diabetes. Compared with complete reprogramming (complete remodelling of cell fate into other functional cells), partial reprogramming is taken as a gentle cell fate regulation mode, and the method has the unique advantages of reducing the risks (such as abnormal differentiation and tumorigenicity) related to reprogramming, namely, only moderately reversing the cell differentiation state, resetting the epigenetic marks related to cell aging and fibrosis, and recovering the normal physiological functions of cells or inhibiting the pro-fibrosis activity of the cells, and not completely changing the cell types. However, the research of the small molecule composition mediated partial reprogramming for organ fibrosis treatment is still under the exploring stage, the existing small molecule reprogramming system focuses on complete reprogramming or transdifferentiation of specific cell types, the optimized small molecule composition aiming at partial reprogramming is not clear, and the problems of insufficient induction efficiency, undefined action mechanism, in vivo anti-fibrosis effect and the like are existed. Disclosure of Invention In view of the above, the present invention aims to provide a composition for reversing organ fibrosis and application thereof, which aims to solve the problems of insufficient existing treatment means and limited clinical transformation of reprogramming technology. The invention provides a cocktail composition for reversing organ fibrosis through partial reprogramming, which comprises valpr