Carneiro Ana, Lee Hyuncheol, Lin Li, van Haasteren Joost, Schaffer David V
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California, USA.
California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, California, USA.
Hum Gene Ther. 2020 Sep;31(17-18):996-1009. doi: 10.1089/hum.2020.169. Epub 2020 Sep 8.
Efforts to identify mutations that underlie inherited genetic diseases combined with strides in the development of gene therapy vectors over the last three decades have culminated in the approval of several adeno-associated virus (AAV)-based gene therapies. Genetic diseases that manifest in the lung such as cystic fibrosis (CF) and surfactant deficiencies, however, have so far proven to be elusive targets. Early clinical trials in CF using AAV serotype 2 (AAV2) achieved safety, but not efficacy endpoints; however, importantly, these studies provided critical information on barriers that need to be surmounted to translate AAV lung gene therapy toward clinical success. Bolstered with an improved understanding of AAV biology and more clinically relevant lung models, next-generation molecular biology and bioinformatics approaches have given rise to novel AAV capsid variants that offer improvements in transduction efficiency, immunological profile, and the ability to circumvent physical barriers in the lung such as mucus. This review discusses the principal limiting barriers to clinical success in lung gene therapy and focuses on novel engineered AAV capsid variants that have been developed to overcome those challenges.
在过去三十年里，人们致力于识别遗传性疾病背后的突变，同时基因治疗载体的开发也取得了长足进展，最终促成了几种基于腺相关病毒（AAV）的基因疗法获得批准。然而，诸如囊性纤维化（CF）和表面活性剂缺乏症等在肺部表现出症状的遗传性疾病，至今仍是难以攻克的目标。早期使用2型腺相关病毒（AAV2）对CF进行的临床试验实现了安全性，但未达到疗效终点；然而，重要的是，这些研究提供了关键信息，说明要使AAV肺部基因治疗取得临床成功需要克服哪些障碍。随着对AAV生物学的理解不断加深以及建立了更多与临床相关的肺部模型，新一代分子生物学和生物信息学方法催生了新型AAV衣壳变体，这些变体在转导效率、免疫特性以及规避肺部物理屏障（如黏液）的能力方面都有所改进。本文综述讨论了肺部基因治疗临床成功的主要限制障碍，并重点介绍了为克服这些挑战而开发的新型工程化AAV衣壳变体。
