Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector
Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector
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DOI：
10.1073/pnas.241506298
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发表时间：
2001-11-06
影响因子：
11.1
通讯作者：
Chan, L
中科院分区：
文献类型：
--
作者：
Kim, IH;Jozkowicz, A;Chan, L
理想情况下，体细胞基因治疗应该导致遗传缺陷的终身逆转。然而，迄今为止，通过体内基因治疗在小鼠模型中对单基因高脂血症的表型校正是短暂的，并且与大量毒性相关。我们已经开发了一个辅助依赖的腺病毒载体（HD-Ad）载脂蛋白（apo）E基因。一个LV。注射该载体完全和稳定地纠正了apoE缺陷小鼠的高胆固醇血症，这种效果持续了小鼠的自然寿命。在2.5年时，对照组主动脉100%被动脉粥样硬化病变覆盖，而治疗组小鼠的主动脉基本上无病变。与治疗相关的毒性可忽略不计。我们还开发了一种重复给予HID-Ad载体的方法，该方法可应用于生物体，例如，人类，寿命超过2-3年。这些研究表明，HID-Ad是一个有前途的系统，肝定向基因治疗代谢性疾病。
Ideally, somatic gene therapy should result in lifetime reversal of genetic deficiencies. However, to date, phenotypic correction of monogenic hyperlipidemia in mouse models by in vivo gene therapy has been short-lived and associated with substantial toxicity. We have developed a helper-dependent adenoviral vector (HD-Ad) containing the apolipoprotein (apo) E gene. A single Lv. injection of this vector completely and stably corrected the hypercholesterolemia in apoE-deficient mice, an effect that lasted the natural lifespan of the mice. At 2.5 years, control aorta was covered 100% by atherosclerotic lesion, whereas aorta of treated mice was essentially lesion-free. There was negligible toxicity associated with the treatment. We also developed a method for repeated HID-Ad vector administration that could be applied to organisms, e.g., humans, with life spans longer than 2-3 years. These studies indicate that HID-Ad is a promising system for liver-directed gene therapy of metabolic diseases.