Effect of Alipogene Tiparvovec (AAV1-LPLS447X) on Postprandial Chylomicron Metabolism in Lipoprotein Lipase-Deficient Patients
Effect of Alipogene Tiparvovec (AAV1-LPLS447X) on Postprandial Chylomicron Metabolism in Lipoprotein Lipase-Deficient Patients
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DOI：
10.1210/jc.2011-3002
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发表时间：
2012-05-01
影响因子：
5.8
通讯作者：
Gaudet, Daniel
中科院分区：
文献类型：
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作者：
Carpentier, Andre C.;Frisch, Frederique;Gaudet, Daniel
背景资料：脂蛋白脂酶缺乏（LPLD）的个体表现出明显的乳糜微粒血症和高胆固醇血症，与胰腺炎风险增加相关。本研究的目的是确定腺相关病毒载体（AAV 1）对肌肉中LPLS 447 X表达的影响图10示出了在LPLD个体中，使用脂肪基因（alipogene tiparvovec，AAV 1-LPLS 447 X）对餐后乳糜微粒代谢以及对非酯化脂肪酸（NEFA）和甘油代谢的影响。在一项开放标签临床试验（CT-AMT-011-02）中，LPLD受试者以1 x 10（12）个基因组拷贝/kg的剂量接受alipogene tiparvovec给药。在给药前2周和给药后14周，在摄入含H-3-棕榈酸酯的低脂餐后，测定乳糜微粒代谢和血浆棕榈酸酯和甘油出现率，（连续）静脉输注[U-C-13]棕榈酸酯和[1，1，2，3，3-H-2]甘油。主要发现：给予alipogene tiparvovec后，乳糜微粒组分的甘油三酯（TG）含量和乳糜微粒-TG/总血浆TG比值在整个餐后期间均降低。餐后峰值乳糜微粒H-3水平和乳糜微粒H-3曲线下面积显著降低（分别在试验餐后6和24 h降低79%和93%）。血浆NEFA和甘油出现率无显著变化。血浆葡萄糖，胰岛素和C-肽也没有改变。结论/意义：肌内给药的alipogene tiparvovec导致在LPLD患者的餐后乳糜微粒代谢的显着改善，不诱导大餐后NEFA溢出。（临床内分泌代谢杂志97：1635-1644，2012）
Background: Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect ofimadministration ofanadeno-associated viral vector (AAV1) for expression of LPLS447X in muscle (alipogene tiparvovec, AAV1-LPLS447X) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals.Methodology: In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 x 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing H-3-palmitate, combined with (continuous) iv infusion of [U-C-13] palmitate and [1,1,2,3,3-H-2] glycerol.Principal Findings: After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron-TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron H-3 level and chylomicron H-3 area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change.Conclusions/Significance: Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover. (J Clin Endocrinol Metab 97: 1635-1644, 2012)