肝脏是利用重组腺相关病毒载体的体内基因疗法的主要靶点。在过去的15年里，已经进行了多个临床试验，但我们仍然没有看到第一个基于肝靶向AAV基因疗法的市场批准。迄今为止，治疗基因的低效表达、载体引起的肝毒性和包膜以及大剂量下的基因载体介导的免疫反应是主要的挑战。尽管有高度鼓舞人心的临床前数据，但缺乏强大的、具有生物学和临床预测能力的临床前模型是不充足的临床结果的一个因素。为此，本研究报告了对六种AAV载体在人肝的十二个临床前模型中进行的功能评估的发现，目的是发现哪种模型组合最相关于识别AAV外壳变体用于安全有效地将基因载体递送至原代人肝细胞。结果是通过对从不死细胞、iPSC 衍生的和原代肝细胞、原代人肝组织到体内模型的模型进行研究所得，增加了我们对每个系统的优点和缺点的了解。这应该能够让我们开发针对人类肝脏的新型基因疗法。

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.