Guggino William B, Cebotaru Liudmila
a Departments of Medicine and Physiology , Johns Hopkins University , Baltimore , MD , USA.
Expert Opin Biol Ther. 2017 Oct;17(10):1265-1273. doi: 10.1080/14712598.2017.1347630. Epub 2017 Jul 6.
Since the cystic fibrosis (CF) gene was discovered in 1989, researchers have worked to develop a gene therapy. One of the most promising and enduring vectors is the AAV, which has been shown to be safe. In particular, several clinical trials have been conducted with AAV serotype 2. All of them detected viral genomes, but identification of mRNA transduction was not consistent; clinical outcomes in Phase II studies were also inconsistent. The lack of a positive outcome has been attributed to a less-than-efficient viral infection by AAV2, a weak transgene promoter and the host immune response to the vector. Areas covered: Herein, the authors focus on AAV gene therapy for CF, evaluating past experience with this approach and identifying ways forward, based on the progress that has already been made in identifying and overcoming the limitations of AAV gene therapy. Expert opinion: Such progress makes it clear that this is an opportune time to push forward toward the development of a gene therapy for CF. Drugs to treat the basic defect in CF represent a remarkable advance but cannot treat a significant cohort of patients with rare mutations. Thus, there is a critical need to develop a gene therapy for those individuals.
自1989年发现囊性纤维化（CF）基因以来，研究人员一直致力于开发基因疗法。最有前景且持久的载体之一是腺相关病毒（AAV），已证明其具有安全性。特别是，已经针对2型AAV进行了多项临床试验。所有试验都检测到了病毒基因组，但mRNA转导的鉴定并不一致；II期研究的临床结果也不一致。缺乏阳性结果归因于AAV2病毒感染效率低下、转基因启动子较弱以及宿主对载体的免疫反应。涵盖领域：在此，作者聚焦于用于CF的AAV基因疗法，评估该方法过去的经验，并基于在识别和克服AAV基因疗法局限性方面已取得的进展确定前进方向。专家观点：这样的进展清楚地表明，现在是朝着开发CF基因疗法推进的恰当时机。治疗CF基本缺陷的药物代表了显著的进步，但无法治疗大量具有罕见突变的患者群体。因此，迫切需要为这些个体开发基因疗法。
