Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium, Gene Therapy Program, Department of Pathologyand Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Curr Pharm Des. 2011;17(24):2500-15. doi: 10.2174/138161211797247569.
Gene therapy holds great promise for the treatment of inherited metabolic disease. Among different vector systems used to date, vectors based on adeno-associated virus (AAV) have shown great potential for systemic expression of therapeutic transgenes. The main advantages of AAV are the beneficial safety profile and the possibility to generate long-term transgene expression without the necessity for chromosomal integration. Successful transduction of hepatocytes in the absence of immunological complications has been achieved in a number of animal species, including mice, dogs and nonhuman primates. Despite this plethora of successful studies, clinical applications have been lagging. Up to date, one clinical trial for liver-directed gene transfer has been performed and results underscored the important role of neutralizing antibodies towards the AAV capsid and the generation of cytotoxic T cell responses against transduced hepatocytes. Recently, a wide variation of novel AAV serotypes has emerged that shows great promise for improved gene transfer efficiency. However, one important factor hampering clinical progress has been the large degree of variability in terms of transduction efficiency and transgene expression levels of different AAV serotypes and the subsequent difficulties in the selection of a single serotype for clinical development. The aim of this review is to critically reevaluate pre-clinical data obtained in animal models of metabolic diseases in light of the progress that has been achieved in liver-directed gene transfer using AAV vectors. Using this evidence-based rationale, we have selected AAV8 as the serotype that combines the most favorable features for clinical applications of hepatic gene transfer.
基因治疗为遗传性代谢疾病的治疗带来了巨大的希望。在迄今为止使用的各种载体系统中，基于腺相关病毒（AAV）的载体在治疗性转基因的全身表达方面显示出了巨大的潜力。AAV 的主要优势在于有益的安全性特征，以及无需染色体整合即可产生长期转基因表达的可能性。在包括小鼠、狗和非人灵长类动物在内的多种动物物种中，已经成功地实现了肝细胞的无免疫并发症转导。尽管有大量成功的研究，但临床应用一直滞后。迄今为止，已经进行了一项针对肝脏定向基因转移的临床试验，结果强调了针对 AAV 衣壳的中和抗体和针对转导肝细胞的细胞毒性 T 细胞反应的重要作用。最近，出现了广泛的新型 AAV 血清型，为提高基因转移效率带来了巨大的希望。然而，一个重要的因素阻碍了临床进展，即不同 AAV 血清型的转导效率和转基因表达水平存在很大差异，随后在选择单一血清型用于临床开发方面存在困难。本综述的目的是根据使用 AAV 载体进行肝脏定向基因转移所取得的进展，批判性地重新评估代谢性疾病动物模型中的临床前数据。基于这一循证推理，我们选择了 AAV8，因为它结合了用于肝脏基因转移的临床应用的最有利特征。
