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-à-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.

中文翻译：

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一种具有自然肺趋化作用的新型大猩猩腺病毒载体可避免肝脏毒性，并适合衣壳工程和载体重新定向。

人腺病毒在基因治疗应用中具有许多吸引人的特征。然而，在世界范围内的普通人群中，针对这些病毒的既往免疫高度流行，极大地限制了它们的临床应用。另外，当全身给药时，最常用的人腺病毒，人腺病毒C亚型5血清型（HAd5），引发全身性炎症和毒性，其中肝脏是受影响最严重的器官。在这里，我们评估了一种新型的低血清流行性大猩猩腺病毒（GAd; GC46）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具有选择性和强健的肺内皮细胞（EC）向性，并且在许多其他器官和组织中的载体表达最少。高剂量的GAd的给药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的炎症组织病理学。此外，与HAd5不同，GAd在小鼠中未表现出肝硬化性或诱导肝炎性毒性，证明了该载体相对于全身应用具有卓越的安全性。我们进一步证明了GAd衣壳纤维具有HAd5等效物的灵活性，可以进行基因修饰。在衣壳中掺入泛EC靶向配体的髓样细胞结合肽（MBP）的GAd表现出降低的肺向性，并有效地将基因表达重新靶向其他器官的血管床。我们的小鼠研究表明，GAd是一种很有前途的基因治疗载体，它利用肺EC作为治疗有效载荷的来源和非常理想的毒性特征。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。