Improving lipoprotein profiles by liver-directed gene transfer of low density lipoprotein receptor gene in hypercholesterolaemia mice

Abstract

The defect of low density lipoprotein receptor disturbs cholesterol metabolism and causes familial hypercholesterolaemia (FH). In this study, we directly delivered exogenous Ldlr gene into the liver of FH model mice (Ldlr(-/-)) by lentiviral gene transfer system. The results showed that the Ldlr gene controlled by hepatocyte-specific human thyroxine-binding globulin (TBG) promoter successfully and exclusively expressed in livers.We found that, although, the content of high density lipoprotein in serum was not significantly affected by the Ldlr gene expression, the serum low density lipoprotein level was reduced by 46%, associated with a 30% and 28% decrease in triglyceride and total cholesterol, respectively, compared to uninjected Ldlr(-/-) mice. Moreover, the TBG directed expression of Ldlr significantly decreased the lipid accumulation in liver and reduced plaque burden in aorta (32%). Our results indicated that the hepatocyte-specific expression of Ldlr gene strikingly lowered serum lipid levels and resulted in amelioration of hypercholesterolaemia.

Molecular Dynamics Simulation Reveals Exposed Residues in the Ligand-Binding Domain of the Low-Density Lipoprotein Receptor that Interacts with Vesicular Stomatitis Virus-G Envelope

“…The low transduction efficiency in our study is comparable to that obtained by Grossman et al, where only a few transduced hepatocytes and a small reduction in LDL-C levels were observed in three subjects [21], despite promising results from studies in rabbits with LDLR [20]. In contrast, Ou et al obtained a remarkable reduction in LDL levels [51], although transduction efficiency was not provided in the analysis of LDLR mRNA and protein expression levels. Interestingly, we also found that LDLR affects the packaging of eGFP alone.…”

The Progression of Treatment for Refractory Hypercholesterolemia: Focus on the Prospect of Gene Therapy

“…The use of lentivirus vectors has improved ex vivo transduction efficiency, achieving transduction in nearly 90% of cells ( Oertel et al, 2003 ). Ou et al delivered Ldlr gene using lentiviral vector into FH mice and observed significant decrease of LDL-C by 46%, and amelioration of lipid accumulation ( Ou et al, 2016 ). Hytonen et al develop different virus-mediated gene transfer system in LDLR deficient rabbit model and found that lentiviral vector-LDLR resulted long-term reduction in lipid profile instead of AAV2, AAV9-LDLR ( Hytönen et al, 2019 ).…”