Inhibition of Complement Pathways with VCP As A Treatment For Alzheimer's Disease

VCP 抑制补体途径治疗阿尔茨海默病

• 批准号: 10602757
• 负责人: JIANHUA ZHOU
• 金额: $ 49.72万
• 依托单位: INFLAMED, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602757
• 关键词: APP-PS1; Achievement; Aducanumab; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Animal Disease Models; Animal Model; Animals; Apolipoprotein E; Award; Binding; Bone Marrow; Brain; Carcinogens; Cardiotoxicity; Cause of Death; Cells; Characteristics; Clinical Research; Clinical Trials; Collaborations; Complement; Complement Activation; Contractor; Data; Dementia; Deposition; Development; Disease; Disease Progression; Disease model; Effectiveness; Endotoxins; Event; FDA approved; Formulation; Funding; Genotype; Goals; Government; Grant; Heavy Metals; Hepatotoxicity; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Insurance; Intervention; Laboratories; Legal patent; Mediating; Memory Loss; Modeling; Mus; Mutagens; Nerve Degeneration; Nose; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; Population; Poxviridae; Privatization; Production; Proteins; Publishing; Qualifying; Regulation; Resources; Rodent; Role; Safety; Saline; Senile Plaques; Small Business Innovation Research Grant; Social Impacts; Spinal cord injury; Sterility; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Toxic effect; Toxin; Traumatic Brain Injury; Vaccinia Virus Study; Vaccinia virus; Vaccinia virus complement-control protein; Validation; aging population; clinically relevant; complement C3 precursor; complement pathway; complement system; cost; economic impact; efficacy evaluation; efficacy testing; efficacy validation; extracellular; genetic regulatory protein; improved; improved outcome; manufacture; mouse model; neuroinflammation; phase 1 study; phase 2 study; pre-clinical; preclinical study; prevent; safety assessment; safety study; stem cell derived tissues; synergism

Project Summary/Abstract Vaccinia virus complement control protein (VCP) has been shown to have structural and functional similarity to human complement control proteins. VCP modulates the human and rodent complement system. During the past two decades, we have studied VCP extensively in a number of preclinical inflammatory disease models including Alzheimer’s disease (AD) and spinal cord injury (SCI) and demonstrated that controlling complement mediated inflammation by VCP has significantly improved outcomes, leading to our hypothesis that VCP can be potentially used for therapeutic treatments of these diseases. AD is one of the most devastating diseases amongst the aging population in the world and the 6th leading cause of death in the US. It is well known that amyloid proteins and plaques are associated with activation of several proinflammatory mediators, especially complement components. Interestingly, ApoE genotypes that significantly facilitate A- deposit, are strongly involved in regulation of classical complement cascade. These pro-inflammatory mediators can cause damage on their own as well as working in synergy with each other, ultimately leading to neurodegeneration. Over time, the damaging role of complement components overpowers their beneficial effects as the disease progresses. As a result, complement pathways have become potential targets for developing treatments of diseases such as AD. To provide a proof of concept, we investigated the role of complement pathways regulated by VCP in AD mice model. In this model, VCP was shown to be effective in preventing memory loss. To further develop VCP as a potential treatment for AD, in this SBIR phase I study, we will aim at characterizing high qualify humanized recombinant VCP (hrVCP) and at the assessment of candidate hrVCP in animal models in a more clinical relevant manner by an independent CRO company with two specific aims: 1) To subject hrVCP to a full battery of in-house analytical characterization and stability profiling; ; Specific Aim 2: To validate our previous findings by testing efficacy of hrVCP in APP/PS1 AD models with collaboration of an independent CRO laboratory. Our milestone goals include development of active and stable hrVCP pre-formulation in Saline, production of more hrVCP if resources allow, and validation of efficacy data in AD models from a laboratory other than our own. If we are successful, PK/safety assessments and other preclinical studies of purified hrVCP protein will be the goal of Phase II studies, along with even more rigorous safety studies including in vitro cardiotoxicity, hepatotoxicity and bone marrow toxicity studies in stem cells derived tissue cells. We expect that the SBIR phase1 studies will lead to development of hrVCP for a commercial scale therapeutic approach to target the progression of neuroinflammation and neurodegeneration anticipated in AD patients.

项目概要/摘要 痘苗病毒补体控制蛋白 (VCP) 已被证明具有结构和功能相似性 VCP 调节人类和啮齿动物的补体系统。 在过去的二十年里，我们主要研究了一些临床前炎症性疾病的VCP 模型包括阿尔茨海默病（AD）和脊髓损伤（SCI），并证明控制 VCP 介导的炎症显着改善了结果，从而得出我们的补体假说 VCP 可用于治疗这些疾病，是最有潜力的疾病之一。 世界老龄化人口中的毁灭性疾病，是世界第六大死因 众所周知，淀粉样蛋白和斑块与多种激活相关。 促炎介质，尤其是补体成分。 显着促进 A- 沉积，强烈参与经典补体级联的调节。 这些促炎介质可以单独造成损害，也可以与每种促炎介质协同作用 随着时间的推移，补体成分的破坏作用最终会导致神经退行性变。 随着疾病的进展，补体途径会抵消其有益作用。 成为开发 AD 等疾病治疗方法的潜在目标 提供概念证明， 我们研究了 VCP 在 AD 小鼠模型中调节的补体途径的作用。 被证明可以有效预防记忆丧失，进一步开发 VCP 作为潜在的治疗方法。 AD，在这项 SBIR I 期研究中，我们的目标是表征高质量的人源化重组 VCP (hrVCP) 并以更具临床相关性的方式在动物模型中评估候选 hrVCP 一家独立的 CRO 公司，有两个具体目标：1) 让 hrVCP 接受全套内部研究 分析表征和稳定性分析；具体目标 2：验证我们之前的发现 与我们的独立 CRO 实验室合作测试 hrVCP 在 APP/PS1 AD 模型中的功效。 里程碑目标包括开发活性且稳定的 hrVCP 生理盐水预制剂、生产 如果资源允许，可以使用更多的 hrVCP，并验证来自实验室以外的 AD 模型中的功效数据 如果我们成功，我们将进行纯化 hrVCP 的 PK/安全性评估和其他临床前研究。 蛋白质将成为 II 期研究的目标，以及包括体外在内的更严格的安全性研究 我们期望对干细胞衍生的组织细胞进行心脏毒性、肝毒性和骨髓毒性研究。 SBIR 第一阶段研究将导致 hrVCP 的商业规模治疗的开发 针对 AD 患者预期的神经炎症和神经变性进展的方法。