Mussolino Claudio
Medical Center - University of Freiburg, Institute for Transfusion Medicine and Gene Therapy, Freiburg, Germany.
Epigenet Insights. 2018 Dec 13;11:2516865718818838. doi: 10.1177/2516865718818838. eCollection 2018.
In the last decades, a better understanding of human pathologies has revealed that genetic alterations as well as epigenetic aberrations can be drivers of a disease or exacerbate its manifestation. The availability of customizable platforms that allow precise genomic targeting has opened the possibility to cure genetic disorders by tackling directly the origin of the disease. Indeed, tethering of different effectors to a DNA-binding moiety grants precise alterations of the genome, transcriptome, or epigenome with the aim of normalizing disease-causing aberrations. The use of designer nucleases for therapeutic genome editing is currently approaching the clinics, and safety concerns arise with respect to off-target effects. Epigenome editing might be a valuable alternative, as it does not rely on DNA double-strand breaks, one of the most deleterious form of DNA damage, to exert its function. We have recently described designer epigenome modifier (DEM), a novel platform for achieving precise epigenome editing in clinically relevant primary human cells. We discuss the efficiency of DEM and highlight their remarkable safety profile, which certainly makes this platform a valuable candidate for future clinical translation.
在过去几十年中，对人类病理学的更深入了解表明，基因改变以及表观遗传异常可能是疾病的驱动因素或加剧其表现。可定制平台的出现使得能够进行精确的基因组靶向，这为通过直接解决疾病根源来治愈遗传疾病开辟了可能性。事实上，将不同的效应物与DNA结合部分相连可实现基因组、转录组或表观基因组的精确改变，目的是使致病异常正常化。用于治疗性基因组编辑的设计核酸酶目前正走向临床，并且出现了对脱靶效应的安全担忧。表观基因组编辑可能是一种有价值的替代方法，因为它不依赖于DNA双链断裂（DNA损伤最有害的形式之一）来发挥其功能。我们最近描述了设计表观基因组修饰剂（DEM），这是一种在临床相关的原代人类细胞中实现精确表观基因组编辑的新型平台。我们讨论了DEM的效率，并强调了它们卓越的安全性，这无疑使该平台成为未来临床转化的有价值候选者。
