CN-122005593-A - Application of FAD in preparation of medicine for treating dilated cardiomyopathy

Abstract

The invention provides an application of FAD in preparing a medicine for treating dilated cardiomyopathy. The invention discovers that exogenous complementary FAD has a recovery effect on energy metabolism of Lmna ‑/‑ mice myocardial cells and a reverse effect on myocardial mitochondrial injury and DCM phenotype of Lmna ‑/‑ mice under the condition of lamin A/C deletion. The invention expands the application of FAD to the field of cardiovascular diseases, in particular to LMNA related DCM which lacks effective treatment means at present, fills the treatment blank in the field, and has important originality and development. Based on FAD, a new treatment strategy of related DCM is established, and the method has good market application prospect.

Inventors

• XIE YUCAI
• Du Zunhui
• YIN TONG

Assignees

• 上海交通大学医学院附属瑞金医院

Dates

Publication Date

20260512

Application Date

20260228

Claims (10)

1. 1. An application of FAD in preparing medicine for treating dilated cardiomyopathy.
2. 2. The use according to claim 1, wherein the dilated cardiomyopathy comprises a gene mutation related dilated cardiomyopathy.
3. 3. The use according to claim 2, wherein the genetic mutation comprises a LMNA genetic mutation.
4. 4. The use according to claim 1, wherein the medicament further comprises any one or more of a pharmaceutically acceptable carrier or a pharmaceutically acceptable adjuvant.
5. 5. The use according to claim 4, wherein the pharmaceutically acceptable carrier is selected from any one or more of a capsule shell, a liposome, a microsphere, a polymer matrix, an adsorption carrier or water for injection.
6. 6. The method according to claim 5, wherein the adsorbent carrier is selected from any one or more of porous silica gel, microporous starch, activated carbon, and macroporous resin.
7. 7. The use according to claim 4, wherein the pharmaceutically acceptable excipients are selected from any one or more of diluents, binders, surfactants, wetting agents, lubricants, fillers or disintegrants.
8. 8. A pharmaceutical composition for treating dilated cardiomyopathy, which is characterized in that the pharmaceutical composition comprises FAD and pharmaceutically acceptable excipients.
9. 9. The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable excipients are selected from any one or more of diluents, binders, surfactants, wetting agents, lubricants, fillers or disintegrants.
10. 10. The pharmaceutical composition according to claim 9, wherein the dosage form of the pharmaceutical composition is selected from any one or more of injection or oral preparation; Preferably, the injection is selected from any one or more of injection or freeze-dried powder injection; Preferably, the oral formulation is selected from any one or more of tablets, pills, powders, capsules, solutions, suspensions, emulsions or granules.

Description

Application of FAD in preparation of medicine for treating dilated cardiomyopathy Technical Field The invention relates to the technical field of dilated cardiomyopathy treatment, in particular to application of FAD in preparation of a drug for treating dilated cardiomyopathy. Background Dilated Cardiomyopathy (DCM) is a cardiomyopathy characterized by impaired left-or dual-ventricular dilation and contraction functions with prevalence of up to 1/250. 20-30% of DCM patients are familial inherited, of which about 40% are due to single gene mutations. LMNA gene mutations are second to the common DCM-related genetic variations, associated with 5% familial and 5-10% sporadic DCM. More than 500 LMNA gene mutations have been found, with phenotypes exceeding 15, such as DCM, premature senility, muscular dystrophy syndrome, lipodystrophy, etc. DCM patients with mutations in the LMNA gene typically have lower left ventricular ejection fractions, and earlier severe heart conduction defects and malignant arrhythmias, with sudden cardiac death occurring at up to 46%. At present, no specific medicine and means for treating DCM caused by LMNA gene mutation exist, and heart transplantation is needed for nearly 20% of patients mainly through improving heart failure and implanting a heart defibrillator to prevent sudden cardiac death, so that social burden is greatly increased. In recent years, the relationship between LMNA gene mutation and metabolic regulation has been increasingly emphasized. Recent transcriptomic analysis results indicate that LMNA gene knocks out abnormal expression of genes related to mitochondrial oxidative phosphorylation in the heart of mice, LMNA gene deletion can cause damage to mitochondrial function of mouse embryo fibroblasts by inhibiting PGC1 alpha and NAMPT-NAD + pathways, and in addition, LMNA gene mutation can cause ectopic lipid deposition and mitochondrial dysfunction in adipose tissue. SIRT1 is an NAD+ -dependent histone deacetylase that plays an important role in metabolic homeostasis regulation, etc. In 2024, our studies found that lamin A/C regulated SIRT1 and further demonstrated that overexpression of SIRT1 could improve lamin A/C-deleted DCM by promoting mitochondrial energy metabolism. Therefore, the regulation and control of the LMNA gene on metabolism and the research of the mechanism thereof are new directions for exploring the treatment targets of LMNA related cardiomyopathy in the future. Flavin adenine dinucleotide (FLAVIN ADENINE Dinucleotide, FAD), an indispensable redox coenzyme, widely exists in all life domains from microorganisms to higher animals and plants, and is one of the active forms of riboflavin. FAD is one of the core molecules of cellular energy metabolism and plays an indispensable or critical role in electron transfer, biooxidation, and maintenance of cellular redox homeostasis. FAD and its related flavin coenzyme-Flavin Mononucleotide (FMN) together form the functional basis of the vital "flavin protease" family in organisms, and its diversity and importance in biological function makes it the focal molecule in biochemical, cell biological and metabolic disease research. FAD is critical in maintaining cellular energy metabolism, on the one hand, FAD is critical for the functioning of the mitochondrial electron transport chain. FAD acts as an electron transfer by accepting hydrogen ions and electrons from the mitochondrial flavoprotein substrate and reducing to FADH 2. Respiratory chain complex II components succinate dehydrogenase, electron transfer flavoprotein, etc. all have FAD dependence. Thus, FAD deficiency will not be sufficient to ensure proper assembly and electron transfer of the respiratory chain, so that respiratory chain protein levels are down-regulated, ATP producing capacity is reduced, and proper function of the cells cannot be maintained. On the other hand, FAD-dependent enzymes are involved in the fatty acid beta oxidation process. As a key molecule for beta oxidation of fatty acids. Exogenous administration of FAD is effective in improving mitochondrial fatty acid beta oxidation and ATP production, and thus FAD and riboflavin are used to treat various mitochondrial acyl-CoA dehydrogenase deficiencies. In addition, FAD can also be involved in cholesterol, amino acid metabolism, and epigenetic regulation mediated by lysine-specific demethylase 1, together with maintenance of stable cellular energy metabolism. Studies have shown that riboflavin and its active forms are closely related to myocardial energy metabolism. Treatment of diabetic cardiomyopathy rats with riboflavin improves cardiac oxidative stress, increases myocardial heme-oxygenase-1 (HO-1) levels, reduces myocardial connective tissue growth factor levels, improves left ventricular systolic and diastolic function, and relieves myocardial hypertrophy. In the spontaneous hypertension rat model and the cardiac hypertrophy mouse model, FAD treatment promotes fatty acid beta oxida