In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy
In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy
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DOI：
10.1111/j.1471-4159.2006.03868.x
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发表时间：
2006-07-01
影响因子：
4.7
通讯作者：
Blümcke, I
中科院分区：
文献类型：
--
作者：
Hahnen, E;Eyüpoglu, IY;Blümcke, I
在研究的组蛋白去乙酰化酶（HDAC）抑制剂中，辛二酰苯胺异羟肟酸（SAHA）发展为用于治疗脊髓性肌萎缩症（SMA）的有效且无毒的候选药物，脊髓性肌萎缩症是由运动神经元存活（SMN）蛋白水平不足引起的α-运动神经元疾病。SAHA在几种神经外胚层组织（包括大鼠海马脑切片和富含运动神经元的细胞组分）中以低微摩尔浓度增加SMN水平，并且使用新型人脑切片培养测定证实了其治疗能力。SAHA激活了SMA治疗的靶基因运动神经元存活基因2（SMN 2），并在亚微摩尔剂量下抑制HDAC，这提供了SAHA比HDAC抑制剂丙戊酸更有效的证据，丙戊酸正在SMA治疗的临床研究中。与SAHA相比，化合物间羧基肉桂酸双羟酰胺、辛二酰双羟肟酸和M344显示出不利的毒性特征，而MS-275未能增加SMN水平。临床试验表明，正在研究用于癌症治疗的SAHA具有良好的口服生物利用度，并且耐受性良好，允许实现显示增加SMN水平的体内浓度。由于SAHA穿过血脑屏障，口服给药可通过表观遗传SMN 2基因激活来减缓进行性α-运动神经元变性。
Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood-brain barrier, oral administration may allow deceleration of progressive alpha-motoneurone degeneration by epigenetic SMN2 gene activation.