Advances in Alpha-1 Antitrypsin Gene Therapy.
Advances in Alpha-1 Antitrypsin Gene Therapy.
复制标题
Alpha-1 抗胰蛋白酶基因治疗的进展。
DOI：
10.1165/rcmb.2020-0159ps
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发表时间：
2020
影响因子：
6.4
通讯作者：
Curiel,DavidT
中科院分区：
文献类型：
--
作者：
Lorincz,Reka;Curiel,DavidT
AAT（α-1抗胰蛋白酶）缺乏症（AATD）的特征是循环丝氨酸蛋白酶抑制剂AAT水平低，导致肺气肿性破坏。遗传性血清缺乏症，如血友病和AATD，已被认为是基因治疗的理想候选者。虽然病毒载体介导的肝脏转导已证明在血友病中的实用性，但AATD尚未取得类似的成功。AAT基因治疗的挑战是在肺局部达到AAT的保护水平，并减轻与全身施用病毒载体相关的潜在肝毒性。目前正在进行的临床试验的策略涉及不同途径的腺相关病毒给药，如肌内和胸膜内注射，以提供一致的治疗水平，从非肝器官部位。然而，探索AAT的非肝来源的替代方法一直是该领域的极大兴趣。在这方面，肺内皮靶向腺病毒载体可能是实现下呼吸道内AAT局部增强的关键技术任务，具有规避肝毒性的潜在益处。此外，将CRISPR/Cas9（CRISPR相关蛋白9）核酸酶系统并入基因递送技术中提供了可完全实现AAT在AATD患者中持续终身表达的一次性治疗的创新技术。本综述将重点介绍腺相关病毒和腺病毒载体介导的基因治疗策略的肺部表现的AATD，并表明，努力使用基因组编辑技术将推进目前的策略，一个完全兼容的直接人类翻译。
AAT (alpha-1 antitrypsin) deficiency (AATD), characterized by low levels of circulating serine protease inhibitor AAT, results in emphysematous destruction of the lung. Inherited serum deficiency disorders, such as hemophilia and AATD, have been considered ideal candidates for gene therapy. Although viral vector–meditated transduction of the liver has demonstrated utility in hemophilia, similar success has not been achieved for AATD. The challenge for AAT gene therapy is achieving protective levels of AAT locally in the lung and mitigating potential liver toxicities linked to systemically administered viral vectors. Current strategies with ongoing clinical trials involve different routes of adeno-associated virus administrations, such as intramuscular and intrapleural injections, to provide consistent therapeutic levels from nonhepatic organ sites. Nevertheless, exploration of alternative methods of nonhepatic sourcing of AAT has been of great interest in the field. In this regard, pulmonary endothelium–targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities. In addition, incorporation of the CRISPR/Cas9 (CRISPR-associated protein 9) nuclease system into gene-delivery technologies has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD. This review will focus on the adeno-associated virus– and adenoviral vector–mediated gene therapy strategies for the pulmonary manifestations of AATD and show that endeavoring to use genome-editing techniques will advance the current strategy to one fully compatible with direct human translation.