Stack Edward C, Ferrante Robert J
Boston University School of Medicine, Department of Neurology, Boston, Massachusetts, MA 20118, USA.
Expert Opin Investig Drugs. 2007 Dec;16(12):1933-53. doi: 10.1517/13543784.16.12.1933.
While the first description of Huntington's disease was reported over a century ago, no therapy exists that can halt or ameliorate the inexorable disease progression. Tremendous progress, however, has been made in significantly broadening the understanding of pathogenic mechanisms in this neurological disorder that may eventually lead to successful treatment strategies. Huntington's disease is caused by the expansion of a CAG repeat in the huntingtin gene, which results in the expression of a mutant form of the protein that is toxic to neurons. Several mechanisms have been identified in mediating this toxicity, such as protein aggregation, mitochondrial dysfunction, oxidative stress, transcriptional dysregulation, aberrant apoptosis, altered proteosomal function and excitotoxicity. With increasing understanding of each of these pathogenic mechanisms, therapeutic strategies have attempted to target specific aspects of each. There have been many encouraging reports of preclinical efficacy in transgenic Huntington's disease mice, from which a number have been extended to human clinical trials with some success. This review focuses on these studies and the compounds that hold promise for treating human Huntington's disease.
虽然亨廷顿舞蹈症的首次描述是在一个多世纪前报道的，但目前尚无能够阻止或改善这种不可阻挡的疾病进展的疗法。然而，在显著拓宽对这种神经疾病致病机制的理解方面已经取得了巨大进展，这最终可能会带来成功的治疗策略。亨廷顿舞蹈症是由亨廷顿基因中CAG重复序列的扩增引起的，这导致了一种对神经元有毒性的突变形式蛋白质的表达。在介导这种毒性方面已经确定了几种机制，如蛋白质聚集、线粒体功能障碍、氧化应激、转录失调、异常凋亡、蛋白酶体功能改变和兴奋性毒性。随着对这些致病机制中每一种的理解不断加深，治疗策略试图针对每一种机制的特定方面。在转基因亨廷顿舞蹈症小鼠的临床前疗效方面有许多令人鼓舞的报道，其中一些已经扩展到人体临床试验并取得了一定成功。这篇综述重点关注这些研究以及有望治疗人类亨廷顿舞蹈症的化合物。
