Development of novel inhibitors of C1q for the treatment of Neurodegenerative diseases

 描述（由申请人提供）：阿尔茨海默病（AD）是老年人群中痴呆症的最常见原因，是全球范围内严重的未解决的医学、社会和经济问题。目前的治疗方法只能提供适度的症状缓解，突出了对更好的疾病改善治疗的需求。我们的目标是推进一种新的治疗药物，ANX 005，走向临床作为一个潜在的治疗AD。ANX 005抑制经典补体级联反应的起始分子C1 q。C1 q在发育过程中突触的物理修剪中起着关键作用。此外，在正常衰老过程中，C1 q在突触上积累，其水平比年轻动物高300倍。C1 q的异常积累可能使突触在各种神经退行性疾病中处于损伤的风险中，导致突触丢失和神经功能下降。这也可能有助于解释为什么年龄是神经退行性疾病最重要的风险因素。这项工作将寻求建立概念证据，即抑制C1 q既能防止突触丢失，又能防止AD动物模型的功能下降。我们将建立适当的ANX 005给药方案，用于小鼠的慢性疗效试验，以及用于大鼠和灵长类动物安全性评价的剂量选择。为了在研究过程中实现这些目标，ANX 005将在AD小鼠模型中以10-100 mg/Kg的范围肠胃外给药，每周一次，持续1至6个月。将在给药期结束时评价测量学习和记忆的行为终点（如Morris水迷宫）的疗效。将收集血清、CSF和脑样品用于生物化学和组织学评价，并将测定血清和CSF中ANX 005的水平。将通过测量CSF以及海马和皮质脑区域中的C1 q水平来评价ANX 005的靶向结合。将通过突触前和突触后标志物的定量组织学评价疗效，以证明对突触保护以及小胶质细胞和星形胶质细胞活化的影响。这项工作的成功结果将使ANX 005在未来两年内进入早期临床研究。除了在AD小鼠模型中证明疗效外，这些临床前研究还将在基础水平上测试预防突触丢失可以减缓神经退行性疾病进展的假设，并为神经退行性疾病的过程提供新的见解。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the aging population and is a serious unmet medical, social and economic problem worldwide. Current therapies provide only modest symptomatic relief, highlighting the need for better, disease-modifying treatments. The goal is to advance a novel therapeutic agent, ANX005, toward the clinic as a potential treatment for AD. ANX005 inhibits C1q, the initiating molecule of the classical complement cascade. C1q has a critical role in the physical pruning of synapses during development. In addition, C1q accumulates on synapses during normal aging - at levels 300-fold higher than those in younger animals. Abnormal accumulation of C1q may put synapses at risk of damage in a variety of neurodegenerative diseases, leading to synapse loss and a decline in neurologic function. It may also help to explain why age is the most important risk factor for neurodegenerative disease. This work will seek to establish proof of concept that inhibition of C1q will both protect against synapse loss and prevent functional decline in animal models of AD. We will establish appropriate dosing regimens with ANX005 for chronic efficacy testing in mice, as well as dose selection for safety evaluation in both rats and primates. In order to achieve these goals over the course of studies, ANX005 will be dosed in the range of 10-100 mg/Kg, parenterally, once weekly for durations of 1 to 6 months in a mouse models of AD. Efficacy in behavioral endpoints that measure learning and memory, such as the Morris water maze, will be evaluated at the end of the dosing period. Serum, CSF and brain samples will be collected for biochemical and histological evaluation, and levels of ANX005 in serum and CSF will be determined. Target engagement of ANX005 will be evaluated by measuring C1q levels in CSF and in hippocampal and cortical brain regions. Efficacy will be evaluated by quantitative histology of pre and post synaptic markers to demonstrate impact on synapse protection and microglial and astrocytic activation. Successful outcome of this work will allow advancement of ANX005 into early phase clinical studies within the next two years. In addition to demonstration of efficacy in AD mouse models, these preclinical studies will test, on a fundamental level, the hypothesis that preventing synapse loss can slow the progression of neurodegenerative disease, and provide novel insights into the process of neurodegeneration.