Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters—Brief Report

Abstract

Objective: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare human disease characterized by very low HDL (high-density lipoprotein) and elevated free cholesterol, in which renal injury has been confirmed in, but whether familial LCAT deficiency patients were at higher risk of atherosclerosis-related cardiovascular disease was highly controversial. Using CRISPR/Cas9 gene-editing technology, we established LCAT knockout (LCAT −/− ) hamster model showing both diet-induced and spontaneous atherosclerosis, indicating that this animal model provides a platform for the therapeutic study of renal disease and atherosclerosis caused by LCAT deficiency. Approach and Results: To explore an efficient therapy for familial LCAT deficiency and then investigate whether correction of LCAT deficiency will exert a beneficial role in atherosclerosis-related cardiovascular disease, herein we established a liver-specific adeno-associated virus 8 expressing human LCAT (AAV-hLCAT) to determine the efficacy of gene therapy for dyslipidemia, renal injury, and atherosclerosis-related cardiovascular disease in LCAT −/− hamsters. Single administration of AAV-hLCAT via intrajugular vein could completely restore LCAT expression in LCAT −/− animals in a dose-dependent manner and rapidly normalize plasma HDL levels within 2 weeks. In addition, upon high-fat diet intervention for 4 weeks, AAV-hLCAT administered LCAT −/− hamsters exhibited improved atherogenic lipoprotein profiles, lower urine protein/creatinine ratio, a significant increase in red blood cells and hemoglobin, thus eventually protecting against atherosclerotic development. Conclusions: Single administration of AAV-hLCAT effectively corrects LCAT deficiency for a long-term in LCAT −/− hamsters and completely rescue multiple abnormalities, including renal injury, anemia, and atherosclerosis, suggesting that AAV8-mediated hLCAT expression in liver will be a promising therapeutic approach for familial LCAT deficiency.

Novel therapeutic opportunities for familial lecithin:cholesterol acyltransferase deficiency: promises and challenges

“…In both species, AAV-LCAT induced LCAT expression and amelioration of the lipoprotein profile. Notably, in Lcat -deficient hamsters, which spontaneously develop renal and haematologic abnormalities, administration of AAV-LCAT reduced proteinuria and increased haemoglobin and red cell count [34 ▪▪ ]. These preclinical studies support the use of AAV-LCAT as a potential therapeutic platform for gene therapy of FLD and this approach is currently being evaluated by our laboratory.…”

“…Thus, similarly to gene therapy for haemophilia B [31], therapeutic levels may be reached with low doses of viral vector, limiting the adverse events [32]. AAV vectors expressing LCAT have been tested in Lcat -deficient mice [33] and more recently in hamsters [34 ▪▪ ]. In both species, AAV-LCAT induced LCAT expression and amelioration of the lipoprotein profile.…”

“…In preclinical and clinical studies, restoration of LCAT activity was associated with some improvement of renal and haematologic outcomes [16,34 ▪▪ ,58]. However, the levels of LCAT activity necessary for stabilization or regression of renal disease and the timeline for therapeutic intervention remain to be established.…”

Influence of lecithin cholesterol acyltransferase alteration during different pathophysiologic conditions: A 45 years bibliometrics analysis

“…Among them, AAV serotype 8 (AAV-8) is the best choice for studying lipoprotein metabolism in mice, with a particularly strong trend towards the liver (Verdera et al, 2020). Guo et al (2021) have proved that multiple abnormalities such as renal injury, anemia, and atherosclerosis in LCAT-deficient mice were completely rescued after a single injection of AAV-hLCAT.…”