Identification and Cross-validation of Early Stage Phenotypes in Mouse Models of Huntington s disease

亨廷顿？帕金森病（HD）是一种遗传性神经退行性疾病，平均发病年龄为40岁。受影响的人失去控制运动的能力，出现精神问题，智力受损，体重减轻。这种疾病会持续15-20年，直到患者几乎没有运动，不能吞咽或说话。对于一些精神问题（例如抑郁症）有有效的治疗方法，但没有办法阻止或减缓精神衰退或疾病进展。欧洲的亨廷顿？欧洲疾病网络（EHDN）（由CHDI基金会资助）已经建立，以提供在欧洲进行HD临床试验所需的基础设施、工具和资源。不像老年痴呆症？s和帕金森？对于这种疾病，HD总是会遗传的，基因测试可用于诊断患有早期疾病和出现症状之前的个体。一旦开发出来，这群人将特别适合接受疾病修饰治疗。为了开发检测方法，监测这一群体的疾病出现和进展，CHDI基金会资助了TRACK-HD，这是一项始于2007年的为期三年的倡议，旨在开发临床、磁共振成像和血液检测，并比较其效用。HD的发病机制非常复杂，已经提出了许多潜在的治疗途径。然而，由于临床试验仍将是资源密集型和昂贵的，因此可以在临床上进行测试的药物数量将不可避免地受到限制。经过基因改造携带HD突变的小鼠是人类疾病的非常好的模型。因此，由于药物试验可以在小鼠中相对快速地进行，因此证明治疗在HD小鼠模型中具有有益效果是最有可能用于优先考虑药物进行临床试验的因素。因此，小鼠试验必须是严格的、受控的和可重复的，并且理想地包括与人类疾病相关的测试。我们将与CHDI基金会合作，对HD小鼠模型进行详细的比较评估，特别关注症状前和早期疾病，使用选择的测试来补充TRACK-HD临床研究。该项目将为小鼠试验的设计提供信息，这些试验被认为是临床评估中最有用的。这种协同作用将最大限度地提高使用经验证的HD小鼠模型将成功的HD治疗策略转化为临床的机会。

Huntington?s disease (HD) is an inherited neurodegenerative disorder with an average age of onset of 40 years. Affected individuals lose their ability to control movement, develop psychiatric problems, an impaired mental capacity and lose weight. The disease progresses for 15-20 years until patients have almost no movement and cannot swallow or speak. There are effective treatments for some psychiatric problems (e.g. depression) but there is no way to halt or slow the mental decline or disease progression. The European Huntington?s Disease Network (EHDN) (funded by the CHDI Foundation) has been established to provide the infrastructure, tools and resources necessary to perform clinical trials for HD in Europe. Unlike Alzheimer?s and Parkinson?s disease, HD is always inherited and a genetic test can be used to diagnose individuals with early stage disease and before symptoms develop. This group of people will be particularly suited to receive disease-modifying treatments once they are developed. To develop the tests to monitor the emergence and progression of disease in this group, the CHDI Foundation has funded TRACK-HD, a three year initiative that commenced in 2007 to develop clinical, magnetic resonance imaging and blood tests and compare their utility. The mechanisms that underlie HD are extremely complex and many potential therapeutic avenues have been proposed. However, because clinical trials will remain resource intensive and expensive, the number of drugs that can be tested in the clinic will inevitably be limited. Mice that have been genetically altered to carry the HD mutation are very good models of the human disease. Therefore, because drug trials can be performed relatively quickly in mice, the demonstration that a treatment has a beneficial effect in an HD mouse model is the factor most likely to be used to prioritise drugs for testing in clinical trials. Therefore, mouse trials must be rigorous, controlled and reproducible and ideally incorporate tests that are relevant to the human disease. In partnership with the CHDI Foundation, we shall conduct a detailed comparative evaluation of HD mouse models, with a particular focus on presymptomatic and early stage disease using tests chosen to complement the TRACK-HD clinical study. This project will inform the design of mouse trials using tests that emerge as being the most useful for clinical evaluation. This synergy will maximise the chance of translating successful therapeutic strategies for HD into the clinic using validated HD mouse models.