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

项目摘要 阿尔茨海默病（AD）是一种迫在眉睫的公共卫生危机，威胁着数百万患者的能力， 体验健康的衰老。除了AD给患者、医疗保健提供者和 除了照顾者之外，还有与AD和相关痴呆症相关的巨大经济负担-估计 仅在美国就超过2000亿美元/年。数百次尝试开发治疗方法来阻止 已经尝试了AD的进展或逆转，但不幸的是，迄今为止没有一个成功。的 这些研究的结果有力地支持了对新的治疗方式和分子靶点的追求。成人 海马神经发生（AHN）长期以来被认为是正常学习和记忆的关键， 啮齿类动物，但它在人类中的作用历史上一直不太清楚。几项临床前研究已经 强调了AHN在AD环境中改善认知的作用。重要的是，最近的几项研究 我支持AHN在人类中也很强大，并在健康成年人的一生中持续存在， 在AD患者中非常明显。因此，恢复AHN已成为早期干预的一个有吸引力的目标， 改善或延迟AD症状的发作。 在拟议的实验中，Bolden Therapeutics将开发治疗性单克隆抗体（mAb）， 减少体内神经干细胞中的骨形态发生蛋白（BMP）信号传导，以通过靶向增加AHN 一种新的BMP共受体。BMP信号传导是成体神经发生的重要负调节因子， 在正常衰老和AD中均增加。抑制BMP信号传导已显示出增加神经发生， 这也是我们项目的预期结果。单克隆抗体将通过免疫专有的，敲- 在小鼠中，预期其具有更强的免疫应答并将克服耐受性。的 最有希望的mAb候选物将使用直接海马立体定向注射和 在AD小鼠中的全身递送，以提供在疾病背景下增强AHN的概念数据的证明 病理这些研究将支持进一步表征mAb的未来II期研究，包括 评价其不仅对神经发生，而且对认知和其他病理学标志（例如， 淀粉样蛋白、tau蛋白、炎症）。最终，我们的目标是这些研究将使博尔登能够产生 开始临床开发前神经源性治疗性抗体以改善 MCI/AD的临床过程，以及其他神经系统适应症的可能性。

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.