Department of Pharmacology and the National Research Centre for Growth and Development, The University of Auckland, Auckland, New Zealand.
Br J Pharmacol. 2010 Jan 1;159(2):285-303. doi: 10.1111/j.1476-5381.2009.00526.x. Epub 2009 Dec 15.
Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome.
表观遗传学是一个快速发展的领域，在治疗包括雷特综合征、焦虑和抑郁障碍、精神分裂症、阿尔茨海默病和亨廷顿病等脑部疾病方面具有广阔的前景。本综述主要关注表观遗传学的药理学，以治疗表观基因组的疾病，无论这些疾病是在发育过程中诱导产生的，还是在生命后期表现或获得的。特别是，我们将集中讨论治疗脑部疾病的药物，这些药物可以修饰表观基因组。虽然在体外和体内模型中使用 DNA 甲基转移酶抑制剂和组蛋白去乙酰化酶抑制剂已经证明可以改善与疾病相关的缺陷，但在人类中的临床试验却不太成功。我们将讨论在理解具有许多分子成分的表观基因组的复杂性方面的最新进展，并讨论在衰老或患病的大脑中，表观基因组受损的证据。我们还将借鉴人类和模型系统之间可能存在的物种差异的例子，强调需要更有力的临床前测试。最后，我们将讨论在针对表观基因组进行研究设计时需要考虑的基本问题。
