Descamps Delphyne, Benihoud Karim
Institut Pasteur, Unité de Défense Innée et Inflammation, 75724 Paris cedex 15, France.
Curr Gene Ther. 2009 Apr;9(2):115-27. doi: 10.2174/156652309787909544.
Adenovirus (Ad) are valuable vectors for liver gene therapy because of their intrinsic ability to transduce hepatocytes following intravenous administration. However, the effective application of these vectors, including helper-dependent Ad unable to trigger viral gene expression, for liver gene therapy in humans has been limited due to several obstacles. First, their high immunogenicity triggers a complex immune response, both innate and adaptive, that leads to hepatocyte destruction, reducing the duration of transgene expression. This high immunogenicity also induces a long lasting cellular and humoral immunity that impairs subsequent re-administration. Second, Ad vectors transduce not only hepatocytes but also other cell types from the liver or other organs. This Ad vector dissemination contributes to their toxicity and immunogenicity, further reducing the effective period of transgene expression. A better understanding of the interactions between Ad vectors and their host underlying the acute liver toxicity and hepatocyte transduction is required to improve the efficacy and duration of gene delivery in vivo. The aim of this review is to discuss insights into the cellular and molecular mechanisms involved in Ad vector-mediated innate immune responses. Current advances in the knowledge of Ad liver tropism and the influence of blood components on Ad vector uptake by the liver will be discussed. Finally, different approaches developed to minimize Ad vector toxicity, optimize delivery and increase transgene expression will be summarized. The full potential of Ad vectors will only be reached when their immunogenicity is abolished and hepatocyte-specific transduction achieved.
腺病毒（Ad）是肝脏基因治疗中有价值的载体，因为其在静脉注射后具有转导肝细胞的内在能力。然而，由于一些障碍，这些载体，包括无法触发病毒基因表达的辅助依赖型腺病毒，在人类肝脏基因治疗中的有效应用受到了限制。首先，它们的高免疫原性会引发复杂的免疫反应，包括先天性免疫和适应性免疫，这会导致肝细胞破坏，缩短转基因表达的持续时间。这种高免疫原性还会诱导持久的细胞免疫和体液免疫，从而影响后续的再次给药。其次，腺病毒载体不仅能转导肝细胞，还能转导肝脏或其他器官的其他细胞类型。这种腺病毒载体的扩散会导致其毒性和免疫原性增加，进一步缩短转基因表达的有效期。为了提高体内基因递送的疗效和持续时间，需要更好地了解腺病毒载体与其宿主之间在急性肝毒性和肝细胞转导方面的相互作用。本综述的目的是讨论对腺病毒载体介导的先天性免疫反应所涉及的细胞和分子机制的见解。将讨论腺病毒肝脏嗜性的最新知识以及血液成分对肝脏摄取腺病毒载体的影响。最后，将总结为尽量减少腺病毒载体毒性、优化递送并增加转基因表达而开发的不同方法。只有消除腺病毒载体的免疫原性并实现肝细胞特异性转导，才能充分发挥其潜力。
