Site specific gene delivery in the cardiovascular system
Site specific gene delivery in the cardiovascular system
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DOI：
10.1016/j.jconrel.2005.09.031
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发表时间：
2005-12-05
影响因子：
10.8
通讯作者：
Levy, RJ
中科院分区：
文献类型：
--
作者：
Fishbein, I;Stachelek, SJ;Levy, RJ
基因疗法在治疗遗传性和获得性疾病方面具有广阔的前景。然而，有效的人类基因治疗的进展受到许多问题的阻碍，包括载体毒性、对患病组织的靶向性差以及宿主免疫和炎症活动等，仅举几个挑战。与癌症或囊性纤维化等其他疾病相比，心血管疾病的基因治疗的临床试验要少得多。然而，挑战是相似的。本文报告了与我们的假设相关的研究综述，即位点特异性心血管基因治疗代表了一种可以优化疗效并减少基因载体相关的全身不良反应影响的方法。我们报告的实验研究证明了三个领域的原理证明：心脏瓣膜疾病的基因治疗、基因传递干细胞和治疗心律失常的基因治疗。心脏瓣膜疾病是心脏直视手术的第二常见适应症，目前只能通过手术切除或修复患病的心脏瓣膜来治疗。我们的研究表明，基因载体可以固定在人工心脏瓣膜小叶的表面，从而能够对瓣膜环周围和小叶上的宿主细胞进行治疗性基因修饰。其他动物研究表明，用于缓解动脉阻塞的血管支架也可以用作基因传递系统，以提供治疗载体构建体，既可以局部预防支架置入后再阻塞（称为支架内再狭窄），又可以治疗潜在的血管疾病。心律失常是心脏病猝死的原因，并长期影响数百万人。我们的小组在动物研究中成功地研究了使用离子通道突变来治疗房性心律失常的局部基因疗法。 (c) 2005 Elsevier B.V. 保留所有权利。
Gene therapy holds great promise for treating both genetic and acquired disorders. However, progress toward effective human gene therapy has been thwarted by a number of problems including vector toxicity, poor targeting of diseased tissues, and host immune and inflammatory activity to name but a few of the challenges. Gene therapy for cardiovascular disease has been the subject of many fewer clinical trials than other disorders such as cancer or cystic fibrosis. Nevertheless, the challenges are comparable. The present paper reports a review of investigations related to our hypothesis that site specific cardiovascular gene therapy represents an approach that can lead to both optimizing efficacy and reducing the impact of gene vector-related systemic adverse effects. We report experimental studies demonstrating proof of principle in three areas: gene therapy for heart valve disease, gene delivery stems, and gene therapy to treat cardiac arrhythmias. Heart valve disease is the second most common indication for open heart surgery and is now only treatable by surgical removal or repair of the diseased heart valve. Our investigations demonstrate that gene vectors can be immobilized on the surface of prosthetic heart valve leaflets thereby enabling a therapeutic genetic modification of host cells around the valve annulus and on the leaflet. Other animal studies have shown that vascular stents used to relieve arterial obstruction can also be used as gene delivery systems to provide therapeutic vector constructs that can both locally prevent post stenting reobstruction, known as in-stent restenosis, and treat the underlying vascular disease. Cardiac arrhythmias are the cause of sudden death due to heart disease and affect millions of others on a chronic basis. Our group has successfully investigated in animal studies localized gene therapy using an ion channel mutation to treat atrial arrhythmias. (c) 2005 Elsevier B.V. All rights reserved.