Immunotherapy targeting the HPA axis in Alzheimer's disease

总结 心理应激和下丘脑-垂体-肾上腺（HPA）轴功能障碍在许多疾病中发挥作用，包括 阿尔茨海默病（AD）、重度抑郁症、代谢综合征和肌肉减少症。长期的高度压力和 还假设升高的皮质类固醇充当许多年龄相关疾病和表型的“促进剂”。 此外，许多研究报告了压力增加和HPA轴功能障碍之间的关联， 老年痴呆症患者认知能力下降、海马体和脑萎缩。我们对HPA轴的兴趣源于 涉及心理应激、促肾上腺皮质激素释放激素/因子（CRH/CRF）和 皮质酮，作为影响淀粉样蛋白和tau病理学以及与年龄相关的认知功能下降的因素。 事实上，HPA轴的抑制理论上代表了AD的独特治疗策略，因为它已经被证明是一种有效的治疗方法。 调节潜在的Aβ和tau蛋白病，并独立影响，可能是通过皮质类固醇 过量，脑萎缩和认知能力下降。不幸的是，测试HPA轴在AD和认知老化中的作用， 由于缺乏有效抑制人类HPA轴活化的小分子治疗剂而受阻。作为 作为小分子方法的替代，我们成功地开发了皮摩尔亲和力的IgG 1单克隆抗体， (mAb)靶向CRF（抗CRF mAb，CTRND 05），其剂量依赖性地阻断应激诱导的皮质酮增加， 并且可以在过表达CRF的小鼠中快速逆转选择性库欣样蛋白表型。代谢和免疫学研究 揭示了与HPA轴的长期抑制一致的许多效应;多器官转录组学研究 显示了对许多可能介导CTRND 05生理效应的基因的稳健调节。我们假设 针对CRF的被动免疫疗法代表了一种新的、可转化的治疗AD的方法， 其他疾病。通过多效性作用，抗CRF免疫治疗可减缓Aβ和tau蛋白的发展。 病理学以及脑萎缩和认知能力下降。在这份提案中，我们将系统地、严格地评估 这种抗CRF免疫疗法在适当的临床前模型中的治疗潜力， 诊断学生物标志物。由于CRF在人类和小鼠之间完全保守，并且以相似的浓度存在， 这些研究的阳性结果将为测试人源化高亲和力抗- CRF mAb用于人类治疗获益。

Summary Psychological stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction play a role in many disorders including Alzheimer’s disease (AD), major depression, metabolic syndrome, and sarcopenia. Chronic high levels of stress and elevated corticosteroids are also hypothesized to act as “accelerants” of many age-associated diseases and phenotypes. Further, numerous studies report an association between increased stress and HPA axis dysfunction with increased rates of cognitive decline and hippocampal and brain atrophy in late-life dementia. Our interest in the HPA axis stemmed from rodent model data implicating psychological stress, corticotropin-releasing hormone/factor (CRH/CRF), and corticosterone, as factors that impact amyloid and tau pathology and age-associated declines in cognitive function. Indeed, suppression of the HPA axis theoretically represents a unique therapeutic strategy in AD, as it has been implicated in regulating the underlying Aβ and tau proteinopathies and independently affecting, presumably through corticosteroid excess, brain atrophy and cognitive decline. Unfortunately, testing the role of HPA axis in AD and cognitive aging, has been hindered by the lack of small molecule therapeutics that effectively suppress HPA axis activation in humans. As an alternative to small molecule approaches, we have successfully developed a picomolar affinity IgG1 monoclonal antibody (mAb) targeting CRF (anti-CRF mAb, CTRND05) that dose-dependently blocks stress-induced increases in corticosterone, and can rapidly reverse select Cushingoid phenotypes in mice overexpressing CRF. Metabolic and immunologic studies reveal numerous effects consistent with long-lasting suppression of the HPA-axis; multi-organ transcriptomic studies shows robust regulation of numerous genes that may mediate the physiologic effects of CTRND05. We hypothesize that passive immunotherapy targeting CRF represents a novel, translatable, therapeutic approach to AD and possibly many other disorders. Through pleiotropic actions, anti-CRF immunotherapy may slow the development of Aβ and tau pathologies as well as brain atrophy and cognitive decline. In this proposal, we will systematically and rigorously evaluate the therapeutic potential of this anti-CRF immunotherapy in appropriate preclinical models and develop companion theragnostic biomarkers. As CRF is completely conserved between humans and mice, and is present at similar concentrations, positive results from these studies will provide the rationale for testing of a humanized high affinity anti- CRF mAb for therapeutic benefit in humans.