Promoting adult hippocampal neurogenesis in Alzheimer's Disease using an antibody-based therapy

使用基于抗体的疗法促进阿尔茨海默病的成人海马神经发生

基本信息

批准号：
10325833
负责人：
Anne Valat
金额：
$ 50万
依托单位：
BOLDEN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325833
关键词：
3xTg-AD mouse Adult Aging Agrin Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Amyloid Animal Disease Models Antibodies Antibody Specificity Antibody Therapy Binding Binding Proteins Bone Morphogenetic Proteins Brain Caregivers Clinical Cognition Data Disease Dose Early Intervention Economic Burden Engineering Environment Exhibits Future Genetic study Goals Health Personnel Hippocampus (Brain)Human Immune response Immunize In Vitro Inflammation Injections Knock-in Mouse Lead Learning Life MUSK gene Memory Modality Molecular Target Monoclonal Antibodies Mus Neurologic Neuromuscular Junction Neurons Outcome Pathologic Pathology Pathway interactions Patients Phase Public Health Reporting Rodent Role Signal Transduction Signaling Protein Symptoms Testing Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Time Transgenic Mice United States Work adult neurogenesis aged base clinical development combat effective therapy efficacy testing experience experimental study healthy aging improved in vivo in vivo evaluation mouse model nerve stem cell nervous system disorder neurogenesis normal aging novel novel strategies novel therapeutics phase 2 study preclinical study prevent public health relevance receptor sex tau Proteins therapeutic target therapy development

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is a looming public health crisis that threatens millions of patients' ability to experience healthy aging. In addition to the challenges that AD poses to patients, healthcare providers and caregivers, there is also tremendous economic burden associated with AD and related dementias – estimated to be well over $200B/year in the United States alone. Hundreds of attempts to develop therapies to halt the progression of or reverse AD have been tried, but unfortunately none have been successful to date. The results of these studies strongly support the pursuit of new therapeutic modalities and molecular targets. Adult hippocampal neurogenesis (AHN) has long been appreciated as critical for normal learning and memory in rodents, however its role in humans has historically been less clear. Several preclinical studies have underscored the role of AHN in improving cognition in an AD environment. Critically, several recent studies have supported that AHN is also robust in humans and persists throughout life in healthy adults, but declines dramatically in AD patients. Thus, restoring AHN has emerged as an attractive target for early intervention, ameliorating or delaying the onset of AD symptoms. In the proposed experiments, Bolden Therapeutics will develop therapeutic monoclonal antibodies (mAbs) that reduce bone morphogenetic protein (BMP) signaling in neural stem cells in vivo to increase AHN via targeting a novel BMP co-receptor. BMP signaling is an important negative regulator of adult neurogenesis, and increases both in normal aging and in AD. Inhibiting BMP signaling has been shown to increase neurogenesis, and that is the expected outcome of our project. The mAbs will be generated by immunizing proprietary, knock- in mice, which are expected to have a more robust immunological response and will overcome tolerance. The most promising mAb candidate will be administered using both direct hippocampal stereotactic injection and systemic delivery in AD mice to provide proof of concept data for augmenting AHN in the setting of disease pathology. These studies will support future Phase II studies for further characterization of the mAb, including evaluating its effect on not only neurogenesis, but also cognition and additional pathological hallmarks (e.g., amyloid, tau, inflammation). Ultimately, our goal is that these studies will enable Bolden to generate the requisite data package to begin clinical development of a pro-neurogenic therapeutic antibody for improving the clinical course in MCI/AD, as well as potentially in other neurological indications.

项目摘要阿尔茨海默氏病（AD）是一种损失的公共卫生危机，威胁着数百万患者的能力体验健康的衰老。除了广告对患者，医疗保健提供者和照顾者，也有与AD和相关痴呆症相关的巨大经济伯恩（Burnen） - 估计仅在美国，就会超过$ 200B/年。数百种试图制定疗法以停止已经尝试过或反向广告的进展，但不幸的是，迄今为止没有成功。这这些研究的结果强烈支持追求新的治疗方式和分子靶标。成人长期以来，海马神经发生（AHN）对正常学习和记忆至关重要但是，啮齿动物在人类中的作用在历史上尚不清楚。一些临床前研究有强调了AHN在改善广告环境中认知方面的作用。至关重要的是最近的一些研究已经支持AHN对人类也很健壮，并且在健康的成年人中一生都持续存在，但下降在AD患者中动态。恢复AHN已成为早期干预的有吸引力的目标，改善或延迟AD症状的发作。在拟议的实验中，Bolden Therapeutics将开发理论单克隆抗体（mAb）减少体内神经元干细胞中骨形态发生蛋白（BMP）信号传导，以通过靶向增加AHN 一种新型的BMP共受体。 BMP信号传导是成人神经发生的重要负调节剂，在正常衰老和AD中都会增加。抑制BMP信号已显示会增加神经发生，这就是我们项目的预期结果。 MAB将通过免疫专有，敲击 - 在预计将具有更强的免疫反应并将克服耐受性的小鼠中。最有前途的mab候选者将使用直接海马立体定向注射和 AD小鼠的全身分娩，提供概念数据以增加疾病的环境病理。这些研究将支持未来的第二阶段研究，以进一步表征mab，包括评估其对神经发生的影响，还评估认知和其他病理标志（例如，淀粉样蛋白，tau，炎症）。最终，我们的目标是这些研究将使Bolden能够产生必不可少的数据包，以开始临床开发促进神经成分理论抗体以改善 MCI/AD的临床课程，以及其他神经系统迹象。