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

开发用于治疗神经退行性疾病的新型 C1q 抑制剂

基本信息

批准号：
9139157
负责人：
Sethu Sankaranarayanan
金额：
$ 121.39万
依托单位：
ANNEXON, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139157
关键词：
Abeta synthesis Affinity Age Aging-Related Process Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Animal Model Anti-Inflammatory Agents Antibodies Award Behavioral Biochemical Brain Brain region Chronic Clinic Clinical Research Clinical Trials Complement Complement 1q Complement Activation Country Data Dementia Dependence Deposition Development Disease Dose Economics Elderly Evaluation Event Excision Frequencies Funding Goals Grant Hippocampus (Brain)Histology Human Learning Measures Medical Medical Economics Memory Memory Loss Memory impairment Mus Nerve Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Outcome Pathology Pathway interactions Peripheral Phase Pilot Projects Population Preparation Primates Process Proteins Rattus Regimen Research Risk Risk Factors Role Safety Sampling Serum Small Business Innovation Research Grant Social Problems Staging Stroke Synapses Testing Therapeutic Agents Time Toxicology Vaccines Work aging population efficacy testing functional decline in vivo inhibitor/antagonist insight juvenile animal meetings morris water maze mouse model normal aging novel novel therapeutics preclinical study prevent public health relevance social

项目摘要

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.

描述（由申请人提供）：阿尔茨海默氏病（AD）是老龄化人群中痴呆症的最常见原因，并且是全球范围内未得到解决的严重的医疗、社会和经济问题，目前的治疗只能提供有限的症状缓解，这凸显了对更好的、更有效的治疗方法的需求。其目标是将新型治疗剂 ANX005 推向临床，作为 AD 的潜在治疗方法，ANX005 抑制经典补体级联的起始分子 C1q。 C1q 在发育过程中突触的物理修剪中发挥着关键作用。此外，在正常衰老过程中，C1q 在突触上的积累水平比年轻动物高 300 倍，C1q 的异常积累可能会使突触面临受损的风险。多种神经退行性疾病，导致突触损失和神经功能下降，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危险因素。建立概念证明，证明在 AD 动物模型中抑制 C1q 既可以防止突触损失，又可以防止功能衰退。我们将建立 ANX005 的适当给药方案，用于小鼠的慢性功效测试，以及两只大鼠的安全性评估的剂量选择。为了在研究过程中实现这些目标，ANX005 的给药剂量为 10-100 mg/Kg，每周一次，持续 1 至 6 个月。在AD小鼠模型中，测量学习和记忆的行为终点（例如莫里斯水迷宫）的功效将在给药期结束时进行评估，将收集血清、脑脊液和脑样本进行生化和组织学评估。将通过测量 CSF 以及海马和皮质大脑区域中的 C1q 水平来确定 ANX005 的目标参与度。通过突触前和突触后标记的定量组织学进行评估，以证明对突触保护以及小胶质细胞和星形细胞激活的影响，除了在未来两年内展示功效外，这项工作的成功将使 ANX005 进入早期临床研究。 AD小鼠模型中，这些临床前研究将从根本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。