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.

中文翻译：

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用于治疗性基因递送的新型肺热带腺相关病毒衣壳。

在过去的 30 年里，鉴定遗传性遗传疾病基础的突变的努力以及基因治疗载体的发展取得了长足的进步，最终批准了几种基于腺相关病毒 (AAV) 的基因疗法。然而，迄今为止，在肺中表现出的遗传疾病，如囊性纤维化 (CF) 和表面活性剂缺乏，已被证明是难以捉摸的目标。使用 AAV 血清型 2 (AAV2) 的 CF 早期临床试验达到了安全性，但未达到疗效终点；然而，重要的是，这些研究提供了关于将 AAV 肺基因治疗转化为临床成功需要克服的障碍的关键信息。随着对 AAV 生物学和更多临床相关肺模型的更好理解，下一代分子生物学和生物信息学方法产生了新的 AAV 衣壳变体，这些变体提供了转导效率、免疫学特征和绕过肺部物理障碍（如粘液）的能力。本综述讨论了肺基因治疗临床成功的主要限制性障碍，并重点关注为克服这些挑战而开发的新型工程 AAV 衣壳变体。