Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters—Brief Report
- 1 July 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 41 (7), 2141-2148
- https://doi.org/10.1161/atvbaha.120.315719
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.Keywords
This publication has 28 references indexed in Scilit:
- Endgame: Glybera Finally Recommended for Approval as the First Gene Therapy Drug in the European UnionMolecular Therapy, 2012
- Effect of Recombinant Human Lecithin Cholesterol Acyltransferase Infusion on Lipoprotein Metabolism in MiceThe Journal of pharmacology and experimental therapeutics, 2010
- Changes in lipoprotein profile and urinary albumin excretion in familial LCAT deficiency with lipid lowering therapyAtherosclerosis, 2009
- Adenoviral expression of human lecithin-cholesterol acyltransferase in nonhuman primates leads to an antiatherogenic lipoprotein phenotype by increasing high-density lipoprotein and lowering low-density lipoproteinMetabolism, 2009
- Therapeutic management of a new case of LCAT deficiency with a multifactorial long-term approach based on high doses of angiotensin II receptor blockers (ARBs)Clinical Nephrology, 2008
- Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune responseNature Medicine, 2006
- Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese MiceJournal of the American College of Cardiology, 2003
- Deletion of N-terminal amino acids from human lecithin:cholesterol acyltransferase differentially affects enzyme activity toward α- and β-substrate lipoproteinsBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2003
- Efficient coexpression and secretion of anti-atherogenic human apolipoprotein AI and lecithin-cholesterol acyltransferase by cultured muscle cells using adeno-associated virus plasmid vectorsGene Therapy, 1998
- Mice overexpressing human lecithin: cholesterol acvltransferase are not protected against diet‐induced atherosclerosisAPMIS, 1997