Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters—Brief Report
Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters—Brief Report
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DOI：
10.1161/atvbaha.120.315719
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Mengmeng Guo;Sisi Ma;Yi-tong Xu;Wei Huang;Mingming Gao;Xiao-bing Wu;Xiao-yan Dong;Yuhui Wang;George Liu;X. Xian
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作者：
Mengmeng Guo;Sisi Ma;Yi-tong Xu;Wei Huang;Mingming Gao;Xiao-bing Wu;Xiao-yan Dong;Yuhui Wang;George Liu;X. Xian
补充数字内容可在文本中找到。目的：家族性卵磷脂：胆固醇酰基转移酶（LCAT）缺乏症是一种罕见的人类疾病，以高密度脂蛋白（HDL）极低和游离胆固醇升高为特征，已证实存在肾损伤，但家族性LCAT缺乏症患者发生动脉粥样硬化相关心血管疾病的风险是否较高尚无定论。利用CRISPR/Cas9基因编辑技术，我们建立了LCAT敲除（LCAT−/−）仓鼠模型，同时显示饮食诱导和自发性动脉粥样硬化，表明该动物模型为LCAT缺乏引起的肾脏疾病和动脉粥样硬化的治疗性研究提供了平台。方法与结果：为了探索家族性LCAT缺乏的有效治疗方法，并研究纠正LCAT缺乏是否会在动脉粥样硬化相关心血管疾病中发挥有益作用，我们在此建立了表达人类LCAT的肝脏特异性腺相关病毒8 (AAV-hLCAT)，以确定基因治疗LCAT - / -仓鼠血脂异常、肾损伤和动脉粥样硬化相关心血管疾病的疗效。单次经颈静脉给药AAV-hLCAT可完全恢复LCAT−/−动物的LCAT表达，且呈剂量依赖性，并在2周内迅速使血浆HDL水平恢复正常。此外，在高脂肪饮食干预4周后，给予AAV-hLCAT的LCAT - / -仓鼠表现出改善的动脉粥样硬化脂蛋白谱，较低的尿蛋白/肌酐比值，红细胞和血红蛋白的显著增加，从而最终防止动脉粥样硬化的发展。结论：单次给药AAV-hLCAT可有效纠正LCAT - / -仓鼠长期LCAT缺乏症，并完全挽救多种异常，包括肾损伤、贫血和动脉粥样硬化，提示aav8介导的肝脏hLCAT表达将是治疗家族性LCAT缺乏症的一种有希望的方法。
Supplemental Digital Content is available in the text. 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.