A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency
A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency
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DOI：
10.1038/s41467-020-17577-8
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发表时间：
2020-08-06
影响因子：
16.6
通讯作者：
Thebaud, Bernard
中科院分区：
文献类型：
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作者：
Kang, Martin H.;van Lieshout, Laura P.;Thebaud, Bernard
表面活性蛋白B（SP-B）缺乏症是一种常染色体隐性遗传疾病，损害表面活性物质的稳态，表现为致命的呼吸窘迫。一个令人信服的论点存在基因疗法治疗这种疾病，从头蛋白合成的SP-B肺泡2型上皮细胞是必要的适当的表面活性剂的生产。在这里，我们报告了一个合理设计的腺相关病毒（AAV）6衣壳，证明效率在肺上皮细胞转导的基础上成像和流式细胞术分析。向SP-B缺陷小鼠体内施用递送鼠或人proSFTPB cDNA的该载体恢复表面活性剂稳态，防止肺损伤，并改善肺生理学。未经治疗的SP-B缺陷小鼠在两天内发生致命的呼吸窘迫。基因治疗可使中位生存期延长至200天以上。该载体还转导人肺组织，证明了其针对这种致命疾病的临床转化潜力。表面活性蛋白B（SP-B）缺乏症是一种遗传性肺部疾病，在出生后数月内导致致命的呼吸窘迫。在这里，作者描述了一种基因治疗策略，使用合理设计的AAV 6衣壳，恢复表面活性物质的稳态，防止肺损伤，并提高SP-B缺乏症小鼠模型的生存率。
Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease. Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.