Chopra Vanita, Quinti Luisa, Khanna Prarthana, Paganetti Paolo, Kuhn Rainer, Young Anne B, Kazantsev Aleksey G, Hersch Steven
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
Novartis Institutes for Biomedical Research, Basel, Switzerland.
J Huntingtons Dis. 2016 Dec 15;5(4):347-355. doi: 10.3233/JHD-160226.
Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington's disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability.
In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD.
The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures.
We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy.
Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates.
在亨廷顿舞蹈症（HD）的细胞、无脊椎动物和啮齿动物模型中，组蛋白去乙酰化酶（HDAC）抑制剂对基因转录的调节作用已被反复证明具有神经保护作用。然而，由于现有化合物的效力或脑生物利用度有限，将这些治疗方法应用于临床一直很困难。
在本研究中，我们评估了LBH589（一种口服生物可利用的异羟肟酸衍生的非选择性HDAC抑制剂）在HD小鼠模型中的治疗潜力。
使用各种生化、行为和神经病理学结果指标，在两种HD小鼠模型中测试LBH589的疗效。
我们发现LBH589可穿过血脑屏障；诱导组蛋白高度乙酰化，并防止R6/2 HD小鼠纹状体神经元萎缩。在全长敲入HD小鼠中，LBH589治疗可改善运动性能并减少神经元萎缩。
我们在HD片段和全长小鼠模型中获得的LBH589有效结果表明，LBH589是HD患者临床评估的一个有前景的候选药物，并证实非选择性HDAC抑制剂可以成为可行的临床候选药物。
