Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, USA.
J Hepatol. 2017 Oct;67(4):818-828. doi: 10.1016/j.jhep.2017.05.012. Epub 2017 May 17.
The recent development of gene editing platforms enables making precise changes in the genome of eukaryotic cells. Programmable nucleases, such as meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-associated nucleases have revolutionized the way research is conducted as they facilitate the rapid production of mutant or knockout cellular and animal models. These same genetic tools can potentially be applied to cure or alleviate a variety of diseases, including genetic diseases that lack an efficient therapy. Thus, gene editing platforms could be used for correcting mutations that cause a disease, restoration of the expression of genes that are missing, or be used for the removal of deleterious genes or viral genomes. In the context of liver diseases, genome editing could be developed to treat not only hereditary monogenic liver diseases but also hepatitis B infection and diseases that have both genetic and non-genetic components. While the prospect of translating these therapeutic strategies to a clinical setting is highly appealing, there are numerous challenges that need to be addressed first. Safety, efficiency, specificity, and delivery are some of the obstacles that will need to be addressed before each specific gene treatment is safely used in patients. Here, we discuss the most used gene editing platforms, their mechanisms of action, their potential for liver disease treatment, the most pressing challenges, and future prospects.
近年来基因编辑平台的发展使得真核细胞基因组的精确改变成为可能。可编程核酸酶，如 meganucleases、锌指核酸酶 (ZFNs)、转录激活因子样效应核酸酶 (TALENs) 和成簇规律间隔短回文重复 (CRISPR)-相关核酸酶，极大地改变了研究的进行方式，因为它们促进了突变体或敲除细胞和动物模型的快速产生。这些相同的遗传工具也有可能应用于治疗或缓解各种疾病，包括缺乏有效治疗方法的遗传疾病。因此，基因编辑平台可用于纠正导致疾病的突变，恢复缺失的基因表达，或用于去除有害基因或病毒基因组。在肝脏疾病的背景下，基因组编辑可以开发用于治疗不仅是遗传性单基因肝脏疾病，还可以治疗乙型肝炎感染和具有遗传和非遗传成分的疾病。虽然将这些治疗策略转化为临床应用的前景极具吸引力，但首先需要解决许多挑战。安全性、效率、特异性和传递是在每种特定基因治疗在患者中安全使用之前需要解决的一些障碍。在这里，我们讨论了最常用的基因编辑平台、它们的作用机制、它们在肝脏疾病治疗中的潜力、最紧迫的挑战和未来前景。
