Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia.
Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia.
复制标题
DOI：
10.1111/jnc.12302
复制
发表时间：
2013-08
影响因子：
4.7
通讯作者：
Pandolfo M
中科院分区：
文献类型：
--
作者：
Gottesfeld JM;Rusche JR;Pandolfo M
弗里德赖希共济失调（FRDA）的遗传缺陷是FXN基因第一内含子中GAA·TCC三联体的扩增，该基因编码线粒体蛋白共济失调蛋白。先前的研究已经确定，重复序列减少了这一必需基因的转录，伴随着受影响个体中共济失调蛋白的减少。由于重复序列不改变FXN蛋白编码序列，一种治疗方法是增加致病性FXN基因的转录。组蛋白翻译后修饰附近的扩大重复是一致的异染色质形成和FXN基因沉默。为了寻找能够重新激活该沉默基因的小分子，筛选了组蛋白脱乙酰酶抑制剂在患者细胞中上调FXN基因表达的能力，并且I类组蛋白脱乙酰酶抑制剂的庚二酸2-氨基苯甲酰胺家族的成员被鉴定为FXN基因表达和共济失调蛋白的有效诱导剂。重要的是，这些分子在源自患者诱导的多能干细胞的人神经元细胞中以及在该疾病的两种小鼠模型中上调FXN表达。一种这样的化合物的安全性和毒性的临床前研究已经完成，并且已经开始在FRDA患者中进行I期临床试验。进一步的药物化学努力已经鉴定出具有上级药理学性质的改进的化合物。
The genetic defect in Friedreich's ataxia (FRDA) is the expansion of a GAA·TCC triplet in the first intron of the FXN ene, which encodes the mitochondrial protein frataxin. Previous studies have established that the repeats reduce transcription of this essential gene, with a concomitant decrease in frataxin protein in affected individuals. Since the repeats do not alter the FXN protein coding sequence, one therapeutic approach would be to increase transcription of pathogenic FXN genes. Histone posttranslational modifications near the expanded repeats are consistent with heterochromatin formation and FXN gene silencing. In an effort to find small molecules that would reactivate this silent gene, histone deacetylase inhibitors were screened for their ability to up-regulate FXN gene expression in patient cells and members of the pimelic 2-aminobenzamide family of class I histone deacetylase inhibitors were identified as potent inducers of FXN gene expression and frataxin protein. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound and a phase I clinical trial in FRDA patients has been initiated. Further medicinal chemistry efforts have identified improved compounds with superior pharmacological properties.
登录
查看更多内容
影响因子：
14.9
作者：
Greene E;Mahishi L;Entezam A;Kumari D;Usdin K
通讯作者：
Usdin K
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
9.8
作者：
Bidichandani, SI;Ashizawa, T;Patel, PI
通讯作者：
Patel, PI
影响因子：
4.8
作者：
Kumari, Daman;Biacsi, Rea Erika;Usdin, Karen
通讯作者：
Usdin, Karen
影响因子：
4.8
作者：
Chou, C. James;Herman, David;Gottesfeld, Joel M.
通讯作者：
Gottesfeld, Joel M.