Adeno-associated virus-mediated gene transfer for lung diseases.
Adeno-associated virus-mediated gene transfer for lung diseases.
复制标题
腺相关病毒介导的肺部疾病基因转移。
DOI：
10.1089/hum.2005.16.643
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Flotte,TerenceR
中科院分区：
文献类型：
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作者：
Flotte,TerenceR
重组腺相关病毒(RAAV)基因转移治疗肺部疾病的临床经验相当广泛，包括1995年11月开始的一系列囊性纤维化(CF)的临床I期和II期试验，以及最近开始的1-抗胰蛋白酶(AAT)缺乏的临床试验。CF试验纳入了使用任何rAAV载体治疗的最大数量的个体。这些研究与大量的体外和体内研究一起，帮助确定了该系统的一系列优势和局限性，并引发了一些载体设计的创新，试图克服已确定的障碍。关键障碍包括细胞外因素、细胞表面受体的缺乏、蛋白酶体介导的载体降解、核进入效率低下、向双链DNA的转化以及载体DNA以一种将持续存在于靶细胞群体中的形式建立稳定的整合。克服这些障碍的新方法包括引入新的rAAV血清型、衣壳突变体、蛋白酶体抑制剂、自互补AAV载体、酪氨酸磷酸酶抑制剂和AAV-Rep介导的位点特异性整合。甚至rAAV的一个固有局限性，即它的小包装容量，也已经通过开发新的双重载体来接近。这些创新中的每一个都是在rAAV介导的肺部疾病基因治疗的背景下被考虑的。
THE CLINICAL EXPERIENCE with recombinant adeno-associ-ated virus (rAAV) gene transfer for lung diseases has been rather extensive, including a series of clinical phase I and phase II trials in cystic fibrosis (CF) dating back to November 1995 and more recently initiated trials in 1-antitrypsin (AAT) deficiency. The CF trials have included the largest number of individuals treated with any rAAV vector. These studies along with numerous in vitro and in vivo studies have helped to define a series of advantages and limitations of this system, and have triggered a number of innovations in vector design in an attempt to overcome the barriers that have been defined. The key barriers include extracellular factors, paucity of cell surface receptors, proteasome-mediated degradation of vector, inefficiencies of nuclear entry, conversion to double-stranded DNA, and the establishment of stable integration of vector DNA in a form that will persist within the target cell population. Novel approaches to overcome these barriers have included the introduction of new rAAV serotypes, capsid mutants, proteasome inhibitors, self-complementary AAV vectors, tyrosine phosphatase inhibitors, and AAV-Rep-mediated site-specific integration. Even the one intrinsic limitation of rAAV, its small packaging capacity, has been approached by the development of novel dual vectors. Each of these innovations is considered in the context of rAAV-mediated gene therapy for pulmonary diseases.