Institute of Physiology I, Life & Brain Center, University Clinic of Bonn, Germany.
Zentralinstitut für Medizintechnik (IMETUM), TU München, Germany.
J Control Release. 2016 Nov 10;241:164-173. doi: 10.1016/j.jconrel.2016.09.024. Epub 2016 Sep 22.
Gene therapy is a promising approach for chronic disorders that require continuous treatment such as cardiovascular disease. Overexpression of vasoprotective genes has generated encouraging results in animal models, but not in clinical trials. One major problem in humans is the delivery of sufficient amounts of genetic vectors to the endothelium which is impeded by blood flow, whereas prolonged stop-flow conditions impose the risk of ischemia. In the current study we have therefore developed a strategy for the efficient circumferential lentiviral gene transfer in the native endothelium under constant flow conditions. For that purpose we perfused vessels that were exposed to specially designed magnetic fields with complexes of lentivirus and magnetic nanoparticles thereby enabling overexpression of therapeutic genes such as endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). This treatment enhanced NO and VEGF production in the transduced endothelium and resulted in a reduction of vascular tone and increased angiogenesis. Thus, the combination of MNPs with magnetic fields is an innovative strategy for site-specific and efficient vascular gene therapy.
基因治疗是一种有前途的方法，可用于需要持续治疗的慢性疾病，如心血管疾病。在动物模型中，血管保护基因的过表达已经产生了令人鼓舞的结果，但在临床试验中没有。人类的一个主要问题是将足够数量的基因载体递送到内皮细胞，而血流会阻碍这一过程，而长时间的停流条件会带来缺血的风险。在目前的研究中，我们因此开发了一种在持续流动条件下对天然内皮细胞进行高效圆周性慢病毒基因转移的策略。为此，我们用慢病毒和磁性纳米颗粒的复合物灌注暴露于特殊设计的磁场中的血管，从而能够过表达治疗基因，如内皮型一氧化氮合酶（eNOS）和血管内皮生长因子（VEGF）。这种治疗方法增强了转导内皮细胞中 NO 和 VEGF 的产生，导致血管张力降低和血管生成增加。因此，MNPs 与磁场的结合是一种用于特定部位和高效血管基因治疗的创新策略。
