Open AccessExosome-based Ldlr gene therapy for familial hypercholesterolemia in a mouse model
Author(s) -
Zhelong Li,
Ping Zhao,
Yajun Zhang,
Jia Wang,
Chen Wang,
Yunnan Liu,
Guodong Yang,
Lijun Yuan
Publication year - 2021
Publication title -
theranostics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.689
H-Index - 97
ISSN - 1838-7640
DOI - 10.7150/thno.49874
Subject(s) - familial hypercholesterolemia , ldl receptor , genetic enhancement , exosome , cancer research , gene , medicine , chemistry , computational biology , biology , cholesterol , genetics , microvesicles , lipoprotein , microrna
Familial hypercholesterolemia (FH), with high LDL (low-density lipoprotein) cholesterol levels, is due to inherited mutations in genes, such as low-density lipoprotein receptor (LDLR). Development of therapeutic strategies for FH, which causes atherosclerosis and cardiovascular disease, is urgently needed. Methods: Mice with low-density lipoprotein receptor (Ldlr) deletion ( Ldlr -/- mice) were used as an FH model. Ldlr mRNA was encapsulated into exosomes by forced expression of Ldlr in the donor AML12 (alpha mouse liver) cells, and the resultant exosomes were denoted as Exo Ldlr . In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. The delivery efficiency of Ldlr mRNA was analyzed by qPCR and Western blotting. Therapeutic effects of Exo Ldlr were examined in Ldlr -/- mice by blood lipids and Oil Red O staining. Results: The encapsulated mRNA was stable and could be translated into functional protein in the recipient cells. Following tail vein injection, exosomes were mainly delivered into the liver, producing abundant LDLR protein, resembling the endogenous expression profile in the wild-type mouse. Compared with control exosomes, Exo Ldlr treatment significantly decreased lipid deposition in the liver and lowered the serum LDL-cholesterol level. Significantly, the number and size of atherosclerotic plaques and inflammation were reduced in the Exo Ldlr -treated mice. Conclusions: We have shown that exosome-mediated Ldlr mRNA delivery effectively restored receptor expression, treating the disorders in the Ldlr -/- mouse. Our study provided a new therapeutic approach for the treatment of FH patients and managing atherosclerosis.