Development of New Therapies for Huntington's Disease

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种进行性和致命性神经系统疾病，由功能未知的蛋白质亨廷顿基因编码CAG重复扩增引起。虽然在了解这种疾病的生物学方面取得了重大进展，但迄今为止还没有有效的治疗方法。许多不同的机制被认为有助于疾病的发病机制。已经确定了几种新的治疗药物，它们针对这些疾病的几种机制。这些药物包括调节基因转录、改善线粒体功能障碍、具有抗氧化和抗炎作用以及调节凋亡细胞死亡的药物。在目前的提案中，我们计划继续研究针对不同疾病机制的新型治疗剂，这可能会导致对可能被证明有效治疗HD患者的治疗化合物类别的新见解。在某些情况下，我们已经确定了这些靶点的治疗效果。在该项目的后期阶段，我们还将检查联合治疗的效果，这可能导致神经保护水平的提高。我们将在含有亨廷顿n端片段的转基因小鼠（R6/2）和全长转基因小鼠模型中研究治疗方法，其中人类全长亨廷顿基因已被纳入具有扩增226 CAG重复区域（BAC 226Q）的细菌人工染色体中。这些小鼠表现出强大的表型，以及细胞损失，因此似乎是筛选治疗剂非常有用的模型。因此，我们提出了一系列的实验来检验HD的一些治疗靶点。我们相信这些研究将提供关键的临床前数据，以确定哪些药物最有希望在HD患者的临床药物试验中用作神经保护剂。

DESCRIPTION (provided by applicant):Huntington's disease (HD) is progressive and fatal neurological disorder which is caused by a CAG repeat expansion in the gene coding for protein of unknown function, huntington. Although major advances have been made in understanding the biology of the illness, as yet there is no effective treatment. A number of different mechanisms are thought to contribute to disease pathogenesis. Several new therapeutic agents have been identified which target several of these disease mechanisms. These include agents, which modulate gene transcription, ameliorate mitochondrial dysfunction, which have anti oxidative and anti inflammatory effects and which modulate apoptic cell death. In the present proposal we plan to continue studies of novel therapeutic agents targeting different disease mechanism which may lead to new insights into classes of therapeutic compounds which may prove to effective in treating HD patients. In some cases we have previously identified therapeutic efficacy with these targets. In the latter stages of this project we will also examine the effects of combinations of therapies, which may result increased levels of neuroprotection. We will study therapies in both transgenic mice with an N-terminal fragment of huntington (R6/2), as well as a full-length transgenic mouse model in which the human full-length huntington gene has been incorporated into a bacterial artificial chromosome with an expanded 226 CAG repeat region (BAC 226Q). These mice show robust phenotype, as well as cell loss, and therefore appear to be a very useful model for screening therapeutic agents. We are therefore proposing a series of experiments that will examine a number of therapeutic targets for HD. We believe that these studies will provide critical pre-clinical data to determine the agents, which have the most promise for use as neuroprotective agents in clinical drug trials in HD patients.