Soragni Elisabetta, Xu Chunping, Plasterer Heather L, Jacques Vincent, Rusche James R, Gottesfeld Joel M
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Child Neurol. 2012 Sep;27(9):1164-73. doi: 10.1177/0883073812448533. Epub 2012 Jul 4.
Numerous studies have pointed to histone deacetylase inhibitors as potential therapeutics for various neurodegenerative diseases, and clinical trials with several histone deacetylase inhibitors have been performed or are under way. However, histone deacetylase inhibitors tested to date either are highly cytotoxic or have very low specificities for different histone deacetylase enzymes. The authors' laboratories have identified a novel class of histone deacetylase inhibitors (2-aminobenzamides) that reverses heterochromatin-mediated silencing of the frataxin (FXN) gene in Friedreich ataxia. The authors have identified the histone deacetylase enzyme isotype target of these compounds and present evidence that compounds that target this enzyme selectively increase FXN expression from pathogenic alleles. Studies with model compounds show that these histone deacetylase inhibitors increase FXN messenger RNA levels in the brain in mouse models for Friedreich ataxia and relieve neurological symptoms observed in mouse models and support the notion that this class of molecules may serve as therapeutics for the human disease.
大量研究表明，组蛋白去乙酰化酶抑制剂有望用于治疗多种神经退行性疾病，目前已有多种组蛋白去乙酰化酶抑制剂的临床试验正在进行或已经完成。然而，迄今为止所测试的组蛋白去乙酰化酶抑制剂要么具有高度细胞毒性，要么对不同的组蛋白去乙酰化酶的特异性很低。作者所在实验室已鉴定出一类新型组蛋白去乙酰化酶抑制剂（2-氨基苯甲酰胺），该抑制剂可逆转弗里德赖希共济失调中异染色质介导的frataxin（FXN）基因沉默。作者已经确定了这些化合物的组蛋白去乙酰化酶同工型靶点，并提供证据表明靶向该酶的化合物可选择性增加致病等位基因的FXN表达。对模型化合物的研究表明，这些组蛋白去乙酰化酶抑制剂可提高弗里德赖希共济失调小鼠模型大脑中的FXN信使核糖核酸水平，并缓解小鼠模型中观察到的神经症状，支持了这类分子可能作为人类疾病治疗药物的观点。
