Safe and sustained overexpression of functional apolipoprotein A-I/high-density lipoprotein in apolipoprotein A-I-null mice by muscular adeno-associated viral serotype 8 vector gene transfer.
Safe and sustained overexpression of functional apolipoprotein A-I/high-density lipoprotein in apolipoprotein A-I-null mice by muscular adeno-associated viral serotype 8 vector gene transfer.
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通过肌肉腺相关病毒血清型 8 载体基因转移，在载脂蛋白 A-I 缺失小鼠中安全、持续地过度表达功能性载脂蛋白 A-I/高密度脂蛋白。
DOI：
10.1097/fjc.0b013e3181bad264
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发表时间：
2009
影响因子：
3
通讯作者：
Badimon,JuanJ
中科院分区：
文献类型：
--
作者：
Cimmino,Giovanni;Chen,Wei;Speidl,WalterS;Giannarelli,Chiara;Ibanez,Borja;Fuster,Valentin;Hajjar,Roger;Walsh,ChristopherE;Badimon,JuanJ
高水平的高密度脂蛋白（HDL）对动脉粥样硬化和心血管疾病有保护作用。这些益处的假定作用机制是增强的胆固醇逆向转运。载脂蛋白AI（ApoA-I）是HDL的主要蛋白质。临床和流行病学研究已经明确了提高ApoA-I/HDL的临床益处。尽管有这些观察结果，但没有非常有效的药理学方法来提高HDL。通过病毒载体的ApoA-I基因递送似乎是提高ApoA-I/HDL水平的有希望的策略。使用腺相关病毒（AAV）载体已经实现了动物和人类中的持续基因表达。本研究的目的是确定使用AAV载体在小鼠中肌内递送的人ApoA-I的效率、安全性和生物活性。编码人ApoA-I转基因的AAV血清型8载体经门静脉内和肌内给予ApoA-I缺陷动物。给药后每2周测量一次ApoA-I水平。在胆固醇负载的巨噬细胞中体外测试所产生的HDL的有效性。载体的施用导致ApoA-I和HDL血浆水平的显著和持续增加，长达16周，两种施用途径的程度相似。所产生的HDL从胆固醇负载的巨噬细胞中去除胆固醇的活性在两组中相似。我们的数据表明，肌内AAV 8介导的人ApoA-I基因转移导致ApoA-I和功能性HDL显著且持续增加。
High levels of high-density lipoprotein (HDL) have protective effects against atherosclerosis and cardiovascular diseases. The postulated mechanism of action for these benefits is an enhanced reverse cholesterol transport. Apolipoprotein AI (ApoA-I) is the major protein of HDL. The clinical benefits of raising ApoA-I/HDL have been clearly established by clinical and epidemiological studies. Despite these observations, there are not very effective pharmacological means for raising HDL. ApoA-I gene delivery by viral vectors seems a promising strategy to raise ApoA-I/HDL levels. Sustained gene expression in animals and humans has been attained using adeno-associated viral (AAV) vectors. The aim of the present study was to determine the efficiency, safety, and biological activity of human ApoA-I intramuscularly delivered using an AAV vector in mice. AAV serotype 8 vectors encoding for human ApoA-I transgene were administered intraportally and intramuscularly in ApoA-I-deficient animals. ApoA-I levels were measured every 2 weeks post administration. The effectiveness of the generated HDL was tested in vitro in cholesterol-loaded macrophages. The administration of the vectors resulted in a significant and sustained increase in ApoA-I and HDL plasma levels for up to 16 weeks at similar extent by both routes of administration. Activity of the generated HDL in removal of cholesterol from cholesterol-loaded macrophages was similar in both groups. Our data suggest that intramuscular AAV8-mediated gene transfer of human ApoA-I results in a significant and maintained increase in ApoA-I and functional HDL.