Improved Animal Models for Testing Gene Therapy for Atherosclerosis
Improved Animal Models for Testing Gene Therapy for Atherosclerosis
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DOI：
10.1089/hgtb.2013.199
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发表时间：
2014-04-01
影响因子：
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通讯作者：
Dichek, David A.
中科院分区：
文献类型：
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作者：
Du, Liang;Zhang, Jingwan;Dichek, David A.
传递到血管壁的基因疗法可以增强当前的动脉粥样硬化疗法，包括全身药物疗法和支架置入术。然而，临床上有用的载体和有效的治疗转基因的鉴定仍处于临床前阶段。动物模型的可用性将加速有效载体和转基因的鉴定，这些动物模型允许对血管壁定向基因治疗进行实用和快速的测试。此类模型将包括在适合有效基因传递的血管中快速发展的类人病变。此外，由于人类动脉粥样硬化是在正常血管中发生的，因此预防动脉粥样硬化的基因疗法最合乎逻辑的是在相对正常的动脉中进行测试。同样，导致动脉粥样硬化消退的基因治疗需要将基因递送至现有病变。在这里，我们报告了三种新的兔子模型的开发，用于测试预防或逆转动脉粥样硬化的血管壁定向基因疗法。这些新模型中的颈动脉内膜病变在开始高脂肪饮食后 2-7 个月内形成，并且比我们之前描述的模型中的病变大 20-80 倍。个别模型允许产生巨噬细胞或平滑肌细胞相对丰富的病变，从而允许测试针对任一细胞类型的基因治疗策略。其中两个模型包括将基因传递到基本正常的动脉，将有助于确定预防病变发展的策略。第三种模型在未经载体的动物中快速产生病变，可用于测试促进病变消退的基因治疗。这些模型针对测试辅助依赖性腺病毒（HDAd）介导的基因治疗进行了优化；然而，它们可以很容易地适用于测试其他载体或不同类型的分子疗法，直接传递到血管壁。我们的数据还支持 HDAd 的承诺，即通过血管内皮提供长期治疗，而不会加速动脉粥样硬化疾病。
Gene therapy delivered to the blood vessel wall could augment current therapies for atherosclerosis, including systemic drug therapy and stenting. However, identification of clinically useful vectors and effective therapeutic transgenes remains at the preclinical stage. Identification of effective vectors and transgenes would be accelerated by availability of animal models that allow practical and expeditious testing of vessel-wall-directed gene therapy. Such models would include humanlike lesions that develop rapidly in vessels that are amenable to efficient gene delivery. Moreover, because human atherosclerosis develops in normal vessels, gene therapy that prevents atherosclerosis is most logically tested in relatively normal arteries. Similarly, gene therapy that causes atherosclerosis regression requires gene delivery to an existing lesion. Here we report development of three new rabbit models for testing vessel-wall-directed gene therapy that either prevents or reverses atherosclerosis. Carotid artery intimal lesions in these new models develop within 2-7 months after initiation of a high-fat diet and are 20-80 times larger than lesions in a model we described previously. Individual models allow generation of lesions that are relatively rich in either macrophages or smooth muscle cells, permitting testing of gene therapy strategies targeted at either cell type. Two of the models include gene delivery to essentially normal arteries and will be useful for identifying strategies that prevent lesion development. The third model generates lesions rapidly in vector-naive animals and can be used for testing gene therapy that promotes lesion regression. These models are optimized for testing helper-dependent adenovirus (HDAd)-mediated gene therapy; however, they could be easily adapted for testing of other vectors or of different types of molecular therapies, delivered directly to the blood vessel wall. Our data also supports the promise of HDAd to deliver long-term therapy from vascular endothelium without accelerating atherosclerotic disease.