Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Brussels, Belgium.
PLoS One. 2010 Jan 21;5(1):e8825. doi: 10.1371/journal.pone.0008825.
Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics.
METHODOLOGY/PRINCIPAL FINDINGS: In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems.
CONCLUSIONS/SIGNIFICANCE: Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.
弗里德赖希共济失调（FRDA）是白种人中最常见的隐性共济失调，是由于在 FXN 基因的第一个内含子内的 frataxin 基因内的大量 GAA 三核苷酸重复扩展，导致 frataxin 水平严重降低。FRDA 患者细胞和小鼠模型中，靠近扩展的 GAA 重复序列的位置存在典型的异染色质标记。具有苯甲酰基二苯甲酰胺结构和 HDAC3 特异性的组蛋白去乙酰化酶抑制剂（HDACIs）可以使 FXN 基因的染色质结构解凝聚，并恢复 FRDA 患者细胞和基于 GAA 重复的 FRDA 小鼠模型 KIKI 中的 frataxin 水平，为 FRDA 的治疗提供了一种有吸引力的方法。
方法/主要发现：为了进一步改善苯甲酰基二苯甲酰胺 HDACIs 作为 FRDA 潜在治疗药物的药理学特性，我们用这种基本结构合成了其他化合物，并对其进行了 HDAC3 特异性筛选。我们在 FRDA 患者的外周血淋巴细胞和 KIKI 小鼠模型中对这两种化合物 136 和 109 进行了特征描述。我们测试了它们在一系列浓度下上调 frataxin 的能力，以确定最小有效剂量。然后，我们在这两个系统中确定了这些药物对 frataxin mRNA 和蛋白质以及总蛋白和局部组蛋白乙酰化的作用持续时间。这些化合物的作用在这两个系统中都超过了直接暴露的时间。
结论/意义：我们的结果支持基于苯甲酰基二苯甲酰胺 HDACIs 的治疗方法在 FRDA 中的临床前开发，并为这些药物的未来人体试验设计提供了信息，提示药物的间歇性给药。
