A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting
A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting
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DOI：
10.1128/jvi.00265-20
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发表时间：
2020-05-01
影响因子：
5.4
通讯作者：
Curiel, David T.
中科院分区：
文献类型：
--
作者：
Lu, Zhi Hong;Dmitriev, Igor P.;Curiel, David T.
人腺病毒在基因治疗应用中具有许多吸引人的特征。然而，在全世界一般人群中对这些病毒的预先存在的免疫力的高流行率极大地限制了它们的临床用途。此外，最常用的人腺病毒，人腺病毒亚群C血清型5（HAd 5），当全身施用时，触发全身炎症和毒性，其中肝脏是受影响最严重的器官。在这里，我们评估了一种新的低血清阳性率大猩猩腺病毒（GAd; GC 46）作为小鼠基因转移载体的实用性和安全性。生物分布研究表明，全身施用的GAd具有选择性和稳健的肺内皮细胞（EC）向性，在许多其他器官和组织中具有最小的载体表达。给予高剂量的GAd在肺中实现了广泛的转基因表达，但在该器官中未引起可检测到的炎症组织病理学。此外，与HAd 5不同，GAd在小鼠中没有表现出嗜肝性或诱导肝脏炎症毒性，证明了载体相对于全身效用的特殊安全性。我们进一步证明了GAd衣壳纤维具有HAd 5等价物的灵活性，允许遗传修饰;在衣壳中掺入了泛EC靶向配体髓样细胞结合肽（MBP）的GAd显示出降低的肺向性，并有效地将基因表达重定向到其他器官中的血管床。我们的小鼠研究表明，GAd是一种有前景的基因治疗载体，其利用肺EC作为治疗有效负载产生的来源和高度期望的毒性特征。GAd衣壳的进一步基因工程有望实现体内载体向性修饰和靶向。
Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) tropism with minimal vector expression throughout many other organs and tissues. Administration of a high dose of GAd accomplished extensive transgene expression in the lung yet elicited no detectable inflammatory histopathology in this organ. Furthermore, GAd, unlike HAd5, did not exhibit hepatotropism or induce liver inflammatory toxicity in mice, demonstrating the exceptional safety profile of the vector vis-a-vis systemic utility. We further demonstrated that the GAd capsid fiber shared the flexibility of the HAd5 equivalent for permitting genetic modification; GAd with the pan-EC-targeting ligand myeloid cell-binding peptide (MBP) incorporated in the capsid displayed a reduced lung tropism and efficiently retargeted gene expression to vascular beds in other organs.IMPORTANCE In the aggregate, our mouse studies suggest that GAd is a promising gene therapy vector that utilizes lung ECs as a source of therapeutic payload production and a highly desirable toxicity profile. Further genetic engineering of the GAd capsid holds the promise of in vivo vector tropism modification and targeting.