Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery.
Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery.
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DOI：
10.1038/mt.2012.162
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发表时间：
2012-12
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用于血管内递送的腺病毒载体的发展将需要提高其在体内的安全性和有效性。Ad5六邻体的高变区是中和抗体的靶标，但也与FX相互作用，促进肝细胞转导。Ad48是一种D型腺病毒，不与FX结合，血清阳性率低。因此，有研究表明，Ad5HVR48(1-7)，一个包含来自Ad48的7个HVRs的六联体嵌合载体，应该通过逃避预先存在的Ad5免疫和阻断FX相互作用而显示出有利的基因治疗特性。我们研究了Ad5、Ad5HVR48（1-7）和Ad48在静脉给药后的体内生物分布。Ad5HVR48（1-7）在库普弗细胞中的肝细胞转导和积累减少，但即使在相对低剂量的载体下也会引发强烈的促炎反应。我们检测到Ad5HVR48（1-7）处理动物的肝脏中血清转氨酶升高（48小时）和门静脉周围CD11b+/Gr-1+细胞数量增加（血管内递送，而不是肌肉内递送）。相反，Ad48不会升高转氨酶，也不会导致CD11b+/Gr-1+细胞的积累。总的来说，这些发现表明，大量的六邻体修饰可以导致无法从亲本病毒预测的意想不到的特性。因此，精细突变可能有利于成功开发需要血管内给药的靶向载体系统。
The development of adenoviral vectors for intravascular delivery will require improvements to their in vivo safety and efficacy. The hypervariable regions of the Ad5 hexon are a target for neutralizing antibodies, but also interact with FX, facilitating hepatocyte transduction. Ad48, a species D adenovirus, does not bind FX and has low seroprevalence. Therefore, it has been suggested that Ad5HVR48(1-7), a hexon-chimeric vector featuring the seven HVRs from Ad48, should display advantageous properties for gene therapy, by evading pre-existing Ad5 immunity and blocking FX interactions. We investigated the in vivo biodistribution of Ad5, Ad5HVR48(1-7) and Ad48 following iv delivery. Ad5HVR48(1-7) displayed reduced hepatocyte transduction and accumulation in Kupffer cells, but triggered a robust pro-inflammatory response, even at relatively low doses of vector. We detected elevated serum transaminases (48h) and increased numbers of peri-portal CD11b+/Gr-1+ cells in the livers of Ad5HVR48(1-7)-treated animals following intravascular, but not intramuscular, delivery. In contrast, Ad48 did not elevate transaminases or result in the accumulation of CD11b+/Gr-1+ cells. Collectively, these findings suggest that substantial hexon modifications can lead to unexpected properties which cannot be predicted from parental viruses. Therefore, refined mutations may be preferential for the successful development of targeted vector systems which require intravascular administration.
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