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Application of PCSK9-targeted microRNA in treating LDLC related metabolic disease

A metabolic disease, targeted technology, applied in the field of drugs for the treatment of LDLC-related metabolic diseases, can solve the problem of untargeted miRNAs

Active Publication Date: 2019-07-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, miRNA-224 reported in the literature does not function in hepatocytes
Moreover, there are no reports of miRNAs targeting PCSK9 in hepatocytes

Method used

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  • Application of PCSK9-targeted microRNA in treating LDLC related metabolic disease
  • Application of PCSK9-targeted microRNA in treating LDLC related metabolic disease

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0059] Preparation of microRNA mimics

[0060]hsa-miR-19b-1-5p (sequence is 5'-aguuuugcagguuugcauccagc-3' (SEQ ID NO: 1)) used in the examples of the present invention; hsa-miR-21-3p (sequence is 5'-caacaccagucgaugggcugu- 3'(SEQ ID NO:2)); hsa-miR-100-5p (sequence is 5'-aacccguagauccgaacuugug-3'(SEQ ID NO:3)); hsa-miR-136-5p (sequence is 5'- acuccauuuguuuugaugaugga-3'(SEQ ID NO:4)); hsa-miR-147b (sequence is 5'-gugugcggaaaugcuucugcua-3'(SEQ ID NO:5)); hsa-miR-187-5p (sequence is 5'- ggcuacaacacaggacccgggc-3' (SEQ ID NO:6)); hsa-miR-203a-3p (sequence is 5'-gugaaauguuuaggaccacuag-3' (SEQ ID NO:7)); hsa-miR-203b-5p (sequence is 5 '-uagugguccuaaacauuucaca-3' (SEQ ID NO:8)); hsa-miR-214-5p (sequence is 5'-ugccugucuacacuugcugugc-3' (SEQ ID NO:9)); hsa-miR-324-3p (sequence hsa-miR-326 (sequence is 5'-ccucugggcccuuccuccag-3' (SEQ ID NO:11)); hsa-miR-337-3p (sequence is 5'-cuccuauaugaugccuuucuuc-3' (SEQ ID NO: 12)); hsa-miR-365a-3p (sequence is 5'-uaaugccccuaaaaauccuuau-3' (SEQ ID N...

Embodiment 1

[0062] Example 1 Detection of PCSK9 inhibitory effect of microRNA mimics involved in the present invention on human hepatoma cell (HepG2) culture medium.

[0063] The cell model used was human hepatoma cell HepG2 (ATCC Cell Bank, USA). Wherein, the medium used for the HepG2 cell line is MEM medium containing 10% fetal bovine serum, cultured in a constant temperature incubator at 37° C. containing 5% carbon dioxide. In HepG2 cells, hsa-miR-19b-1-5p, hsa-miR-21-3p, hsa-miR-100-5p, hsa-miR-136-5p, hsa-miR-147b were transfected at a concentration of 30nM , hsa-miR-187-5p, hsa-miR-203a-3p, hsa-miR-203b-5p, hsa-miR-214-5p, hsa-miR-324-3p, hsa-miR-326, hsa-miR -337-3p, hsa-miR-365a-3p, hsa-miR-376b-3p, hsa-miR-449b-5p, hsa-miR-452-5p, hsa-miR-498, hsa-miR-552-3p , hsa-miR-559, hsa-miR-641, hsa-miR-708, hsa-miR-1205, hsa-miR-1286, hsa-miR-1294, hsa-miR-2115-3p, hsa-miR-3130 -5p, hsa-miR-3174, hsa-miR-3622b-5p, hsa-miR-3690, hsa-miR-4677-5p, hsa-miR-6720-5p or NC (negative control, ...

Embodiment 2

[0085] Example 2 Detection of the inhibitory effect of the microRNA mimics involved in the present invention on PCSK9 in human liver cancer cells (HepG2 cells).

[0086] The cell model used was human hepatoma cell HepG2 (ATCC Cell Bank, USA). Wherein, the medium used for the HepG2 cell line is MEM medium containing 10% fetal bovine serum, cultured in a constant temperature incubator at 37° C. containing 5% carbon dioxide. In HepG2 cells, hsa-miR-19b-1-5p, hsa-miR-21-3p, hsa-miR-100-5p, hsa-miR-136-5p, hsa-miR-147b were transfected at a concentration of 30nM , hsa-miR-187-5p, hsa-miR-203a-3p, hsa-miR-203b-5p, hsa-miR-214-5p, hsa-miR-324-3p, hsa-miR-326, hsa-miR -337-3p, hsa-miR-365a-3p, hsa-miR-376b-3p, hsa-miR-449b-5p, hsa-miR-452-5p, hsa-miR-498, hsa-miR-552-3p , hsa-miR-559, hsa-miR-641, hsa-miR-708, hsa-miR-1205, hsa-miR-1286, hsa-miR-1294, hsa-miR-2115-3p, hsa-miR-3130 -5p, hsa-miR-3174, hsa-miR-3622b-5p, hsa-miR-3690, hsa-miR-4677-5p, hsa-miR-6720-5p or NC (negative co...

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Abstract

The invention provides application of PCSK9-targeted microRNA or a drug composition containing the same in preparing drug for inhibiting PCSK9 protein level. In addition, the invention further relatesto a drug composition for treating low-density lipoprotein cholesterol related metabolic disease. The drug composition comprises (a) drug in effective treatment amount and clinically for treating thelow-density lipoprotein cholesterol related metabolic disease and (b) PCSK9-targeted microRNA or the drug composition containing the same in effective treatment amount. Experiments verify that 31 types of microRNA can inhibit PCSK9 protein level in liver cells or liver cell culture liquid, thereby being capable of lowering level of LDLC so as to treat the LDLC related metabolic disease.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to the use of 31 microRNAs with inhibitory effect on PCSK9 or a pharmaceutical composition containing them in the preparation of medicines for treating LDLC-related metabolic diseases. Background technique [0002] Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein convertase family and is expressed in liver, kidney, brain, intestinal tract and other tissues (Proc Natl AcadSci USA 2003; 100:928– 33). According to reports, PCSK9 plays a role in regulating cholesterol metabolism in its main distribution tissue, that is, the liver. It is secreted into plasma by liver cells, binds to the extracellular segment of low-density lipoprotein receptor (Low-density lipoprotein (LDL) receptor, LDLR), and is internalized into liver parenchymal cells together with it, promoting LDLR in lysosomes The degradation of LDLR inhibits LDLR from returning to the cell me...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/7105A61P3/06A61P1/16A61P9/10
CPCA61K45/06A61K31/7105A61P3/06A61P9/10A61P1/16A61K2300/00
Inventor 任进戚新明陈静张佩琢侯蕾范磊苗茹段春晓董云霞陶周腾
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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