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Advances in Alpha-1 Antitrypsin Gene Therapy.
American Journal of Respiratory Cell and Molecular Biology ( IF 6.4 ) Pub Date : 2020-10-30 , DOI: 10.1165/rcmb.2020-0159ps
Reka Lorincz 1 , David T Curiel 1
Affiliation  

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.



中文翻译:

Alpha-1 抗胰蛋白酶基因治疗的进展。

AAT(α-1 抗胰蛋白酶)缺乏症 (AATD) 的特点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,被认为是基因治疗的理想候选者。尽管病毒载体介导的肝脏转导已证明可用于血友病,但 AATD 尚未取得类似的成功。AAT 基因治疗的挑战是在肺部局部实现 AAT 的保护水平,并减轻与全身给药病毒载体相关的潜在肝毒性。正在进行的临床试验的当前策略涉及不同的腺相关病毒给药途径,例如肌肉内和胸膜内注射,以从非肝器官部位提供一致的治疗水平。然而,该领域对探索非肝源 AAT 的替代方法引起了极大的兴趣。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,具有规避肝脏毒性的潜在益处。此外,将 CRISPR/Cas9(CRISPR 相关蛋白 9)核酸酶系统纳入基因递送技术,为 AATD 患者提供了可完全实现 AAT 持续、终生表达的一次性治疗的辅助技术。

更新日期:2020-10-30
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