USE OF WNT INHIBITOR WNT-C59 IN PREPARATION OF DRUG FOR TREATING SCN5A MUTATION-INDUCED DILATED CARDIOMYOPATHY
20220370428 · 2022-11-24
Assignee
Inventors
Cpc classification
A61P9/04
HUMAN NECESSITIES
International classification
Abstract
The use of a Wnt inhibitor Wnt-C59 in the preparation of a drug for treating SCN5A mutation-induced dilated cardiomyopathy (DCM) is provided. With SCN5A genotype detection as a breakthrough point, a Wnt pathway-specific inhibitor Wnt-C59 is used to inhibit the abnormal activation of the Wntβ-Catenin pathway caused by SCN5A gene mutation, thereby improving the prognosis of cardiac function in a patient with SCN5A gene mutation-induced DCM. In experiments, aging and adriamycin-induced DCM models are constructed, and the therapeutic effect of Wnt-C59 on DCM is detected through indexes such as changes in cardiac function and activation of related signal molecules, which provides a theoretical basis for use of Wnt-C59 in the clinical treatment of DCM. A new treatment method for SCN5A mutation-induced DCM is provided to bring dawn to such patients and has promising application prospects.
Claims
1. Use of a Wnt inhibitor Wnt-C59 in the preparation of a drug for treating SCN5A mutation-induced dilated cardiomyopathy (DCM).
2. Use of a Wnt inhibitor Wnt-C59 in the preparation of a drug for treating SCN5A-R225Q mutant-induced DCM.
3. Use of a Wnt inhibitor Wnt-C59 in preparation of a drug for improving cardiac functions and prognosis of a patient with SCN5A-R225Q mutant-induced DCM.
4. Use of a Wnt inhibitor Wnt-C59 in the preparation of a drug for improving ventricular cavity enlargement, decreased myocardial contractility, and prognosis of a patient with SCN5A-R225Q mutant-induced DCM.
5. The use according to any one of claims 1 to 4, wherein a dosage form of the drug is tablet, powder, suspension, capsule, pill, or syrup.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0020]
[0021]
[0022]
[0023]
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0024] The present disclosure will be further described below with reference to specific implementations. It should be understood that these examples are only intended to describe the present disclosure, rather than to limit the scope of the present disclosure. In addition, it should be understood that various changes and modifications may be made on the present disclosure by those skilled in the art after reading the content of the present disclosure, and these equivalent forms also fall within the scope defined by the appended claims of the present disclosure.
[0025] In this study, based on pre-clinical data of patients with DCM (that is, 90 sporadic DCM patients are subjected to SCN5A mutation screening), it is found that the R225Q mutation (c.674G>A) rate is the highest (a total of 3 cases), and the onset age of DCM is high (77, 55, and 80 years old).
EXAMPLE 1
Animal Experiment
[0026] 1. Method
[0027] 1.1 Preparation of Experimental Animals and Animal Models
[0028] SPF-grade male C57BL/6 mice (purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.) and SCN5A heterozygous mutant mice (aging 8 to 10 weeks and weighing 20 g to 25 g) were selected and intraperitoneally injected with d-galactose (500 mg/kg. d, sigma G5388) continuously for 8 weeks to construct aging models. Then the mice were intraperitoneally injected with adriamycin (4 intraperitoneal injections, total 10 mg/kg, Sangon A603456) to construct DCM models. After the models were constructed, cardiomyocytes were isolated from mice in each of the KI group and the WT group. The experimental scheme was approved by the Animal Management and Ethics Committee of Fudan University.
[0029] The animal experiment showed that there was no statistical difference in the cardiac function between SCN5A heterozygous mutant mice and wild-type mice in natural aging models, pure galactose aging models, and pure adriamycin DCM models.
[0030] Early animal studies showed that, after being treated with galactose and adriamycin, SCN5A heterozygous mutant mice exhibited a DCM phenotype, namely, enlarged cardiac chamber, thinned left ventricular, and decreased ejection fraction, but the WT mice exhibited no cardiac function change. Cardiomyocytes were further isolated from mice in the KI group and the WT group and then subjected to Western blot assay, and results showed that the Wnt pathway was significantly activated in the KI group.
[0031] 1.2 Grouping
[0032] After the ultrasonic test, there were 3 groups for study: WT group, KI group, and KI+Wnt-C59 group. Adriamycin was used for molding, and at the same time, the KI+Wnt-C59 group was intragastrically administered with Wnt-C59 (1 mg/kg.d, MCE HY-15659) every day, and the WT and KI groups were intragastrically administered with an equal volume of sterile normal saline as a control. Mice in each group received normal diet and water, and the administration was conducted continuously for 2 weeks. The body weight was measured and recorded for mice in each group every day.
[0033] 1.3 Evaluation on Mouse Cardiac Function by Echocardiography
[0034] The echocardiogram was measured 2 weeks after the administration, with a probe frequency of 30 MHz. Specifically, the mice were anesthetized with isoflurane, and an M-mode image was recorded when a heart rate of the mice was maintained at 450 to 500 beats/min. B-Mode images were acquired along a parasternal long-axis section and an apical four-chamber section. Along a short axis of the parasternal left ventricle, a short-axis section of the left ventricle was shown by 2D ultrasound, and M-mode ultrasound was used to record the movement of the left ventricle at the papillary muscle level. Functional indexes included LVEF. The mice in the groups were compared in terms of the changes of cardiac morphology and function. All measurement values were average values of 5 consecutive cardiac cycles, which were conducted by 3 experienced technicians.
[0035] 1.4 Detection of Wnt Pathway in Cardiomyocytes by Western Blot
[0036] Cardiomyocyte proteins were extracted separately from the KI group and WT group, and Western blot assay was conducted.
[0037] 1.5 Material Collection
[0038] After 2 weeks of drug intervention, the mice were sacrificed and hearts thereof were collected for heart size comparison among the 3 groups.
[0039] 2. Results
[0040] 2.1 The results showed that the cardiac function index of mice in the KI group was significantly lower than that in the WT group, and the cardiac function of mice in the KI+Wnt-C59 group was improved. (as shown in
[0041] 2.2 The results showed that the Wnt pathway was significantly activated in the KI group. (as shown in
[0042] 2.3 The results showed that the heart of mice in the KI+Wnt-C59 group was significantly smaller than that in the KI group. (as shown in
[0043] 3. Conclusion
[0044] The Wnt signaling is involved in processes such as cardiac ventricular remodeling, myocardial hypertrophy, and cardiac failure. The activation of Wnt signaling pathway is related to the occurrence and development of DCM. Based on research results herein, the Wnt signaling pathway inhibitor Wnt-C59 can significantly improve the cardiac function of aging and adriamycin-induced DCM mice, which provides a theoretical basis for use of Wnt-C59 in the clinical treatment of DCM and also provides a new target for the treatment of DCM.
[0045] Except for significantly inhibiting the proliferation of 46 types of tumor cells, Wnt-C59 as a new tumor proliferation inhibitor can improve the cardiac function of galactose-induced aging and adriamycin-induced DCM mice, which provides a theoretical basis for use of Wnt-C59 in the clinical treatment of DCM. Wnt-C59 is an important supplement to the traditional treatment of myocardial damage caused by DCM, such as cardiotonic, diuretic, and vascular expansion therapies, which can delay the progression of myocardial damage and improve the life quality of a patient.
[0046] The above descriptions are merely preferred implementations of the present disclosure. It should be noted that a person of ordinary skill in the art may further make several improvements and supplements without departing from the principle of the present disclosure, but such improvements and supplements should be deemed as falling within the protection scope of the present disclosure.