Davies Jane C, Alton Eric W F W
Department of Gene Therapy, Imperial College London, London SW3 6LR, United Kingdom.
Adv Genet. 2005;54:291-314. doi: 10.1016/S0065-2660(05)54012-4.
Given both the accessibility and the genetic basis of several pulmonary diseases, the lungs and airways initially seemed ideal candidates for gene therapy. Several routes of access are available, many of which have been refined and optimized for nongene drug delivery. Two respiratory diseases, cystic fibrosis (CF) and alpha1-antitrypsin (alpha1-AT) deficiency, are relatively common; the single gene responsible has been identified and current treatment strategies are not curative. This type of inherited disease was the obvious initial target for gene therapy, but it has become clear that nongenetic and acquired diseases, including cancer, may also be amenable to this approach. The majority of preclinical and clinical studies in the airway have involved viral vectors, although for diseases such as CF, likely to require repeated application, non-viral delivery systems have clear advantages. However, with both approaches a range of barriers to gene expression have been identified that are limiting success in the airway and alveolar region. This chapter reviews these issues, strategies aimed at overcoming them, and progress into clinical trials with non-viral vectors in a variety of pulmonary diseases.
鉴于多种肺部疾病的易感性和遗传基础，肺和气道最初似乎是基因治疗的理想候选对象。有几种给药途径可供选择，其中许多已针对非基因药物递送进行了改进和优化。两种呼吸系统疾病，囊性纤维化（CF）和α1-抗胰蛋白酶（α1-AT）缺乏症，相对常见；致病的单一基因已被确定，而目前的治疗策略无法治愈这些疾病。这类遗传性疾病显然是基因治疗最初的目标，但现在已经清楚，包括癌症在内的非遗传性和后天性疾病也可能适合这种方法。气道的大多数临床前和临床研究都涉及病毒载体，不过对于像CF这种可能需要反复治疗的疾病，非病毒递送系统具有明显优势。然而，对于这两种方法，都已发现一系列限制气道和肺泡区域基因表达成功的障碍。本章将综述这些问题、旨在克服这些问题的策略，以及非病毒载体在多种肺部疾病中进入临床试验的进展。
