Neural Stem Cell Transplantation: A Novel Cellular Therapy for Alzheimer's Disease

神经干细胞移植：阿尔茨海默病的新型细胞疗法

• 批准号: 9754727
• 负责人: Eva Lucille Feldman
• 金额: $ 103.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754727
• 关键词: APP-PS1; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Anatomy; Animals; Area; Autopsy; Behavior; Biochemical; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Brain; Cell Survival; Cell Therapy; Cells; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Coupled; Data; Dementia; Disease; Disease model; Dose; Drug Kinetics; Engraftment; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Designs; Feasibility Studies; Ferritin; Future; Goals; Growth Factor; Hippocampus (Brain); Histologic; Histology; Human; Inflammation; Injections; Intervention; Investigational Drugs; Investigational New Drug Application; Label; Laboratories; Learning; Magnetic Resonance Imaging; Maximum Tolerated Dose; Measures; Memory; Modeling; Mus; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Positron-Emission Tomography; Prevention; Preventive Intervention; Program Development; Receptor Activation; Research; Rodent Diseases; Route; Safety; Senile Plaques; Stem cell transplant; Stem cells; Structure; Synapses; Therapeutic; Time; Tissues; Translating; Transplantation; Treatment Efficacy; Tropism; age related neurodegeneration; base; clinical translation; design; effective therapy; efficacy testing; environmental enrichment for laboratory animals; imaging biomarker; improved; improved outcome; in vivo; longitudinal positron emission tomography; mouse model; nerve stem cell; neuronal circuitry; neurophysiology; neurotrophic factor; nonhuman primate; novel; paracrine; pre-clinical; preclinical development; programs; research clinical testing; response; safety and feasibility; stem cell therapy; targeted treatment; tissue tropism; translational impact; translational pipeline

Program Summary/Abstract This U01 proposal is designed to provide the preclinical framework required to advance a novel stem cell therapy to human clinical trials as an effective treatment for Alzheimer's disease (AD). AD is the most prevalent age-related neurodegenerative disorder and leading cause of dementia, affecting an estimated 5.3 million people in the U.S. There is no cure and no means of prevention. To date, a handful of traditional, single-target pharmacological approaches have produced only marginal clinical improvements - there is a critical need for more effective therapies. Therefore, the long-term goal of our research is to develop a disease-modifying cellular therapy for AD that will have a meaningful impact on patients' lives. Cellular therapies target multiple disease mechanisms and provide a multifaceted approach to treat the complex pathologies associated with AD. In collaboration with Neuralstem, Inc., we have developed a unique line of human cortex-derived neural stem cells (NSCs) that produce several neuroprotective growth factors. Our findings to date, as well as proof- of- concept studies by others, show the benefit of cell therapies in AD models and indicate that efficacy is enhanced when coupled with delivery of trophic factors. In our proposed approach, NSC transplantation will combine the multifactorial therapeutic potential of a cellular therapy with sustained and directed delivery of neurotrophic factors, providing increased benefit compared to traditional approaches and improving outcomes in AD. Our preliminary data in a mouse model demonstrate that NSC transplantation is safe and effective, significantly impacting cognition and reducing Aβ plaque burden. In this proposal, we will determine the maximum tolerated dose and assess NSC bio-distribution and tissue tropism in two well-established and highly relevant mouse models: 5XFAD and rTg4510. We will then perform large-scale efficacy testing of NSCs in these mouse models and complete a dose-response feasibility study in non-human primates, which are anatomically and cognitively more relevant to human clinical testing. Overall, our proposal will have a significant impact on AD by providing proof-of-concept efficacy data for a well-characterized cellular therapy in two relevant mouse models and safety data in a large animal with a brain structure that is more analogous to humans. Completion of our proposed IND-enabling studies, as well as our laboratory's unique track record of translating proof-of-principle animal studies to human trials, will enable this stem cell therapy to progress into an attainable disease-modifying intervention for AD patients.

程序摘要/摘要 该U01提案旨在提供推进新型干细胞所需的临床前框架 人类临床试验的治疗是对阿尔茨海默氏病（AD）的有效治疗方法。广告是最普遍的 与年龄相关的神经退行性障碍和痴呆的主要原因，估计有530万 美国的人们无法治愈，也没有预防手段。迄今为止，少数传统的单目标 药理学方法仅产生了边际临床改进 - 至关重要 更有效的疗法。因此，我们研究的长期目标是开发改良疾病 对AD的细胞疗法将对患者的生活产生有意义的影响。细胞疗法靶向多重 疾病机制，并提供了一种多方面的方法来治疗与 广告。与Neuralstem，Inc。合作，我们开发了独特的人类皮质衍生神经元系列 干细胞（NSC）产生多种神经保护生长因子。我们迄今为止的发现以及证明 - 关于其他人的概念研究，表明细胞疗法在AD模型中的好处，并表明有效性是 与营养因子的递送时，增强了。在我们提出的方法中，NSC移植将 将细胞疗法的多因素治疗潜力与持续和定向交付 与传统方法相比，神经营养因素提供了增加的收益并改善结果 在广告中。我们在鼠标模型中的初步数据表明，NSC移植是安全有效的， 显着影响认知并减轻Aβ斑块负担。在此提案中，我们将确定 在两个公认且高度的高度 相关的鼠标模型：5XFAD和RTG4510。然后，我们将对NSC进行大规模测试 这些鼠标模型并完成非人类隐私的剂量响应可行性研究 在解剖学和认知上与人类临床测试更相关。总体而言，我们的建议将有一个 通过为特征良好的细胞疗法提供概念概念的有效性数据，对AD的重大影响 大脑结构的两个相关的小鼠模型和安全数据，与大脑结构更类似 人类。完成我们提议的索引研究，以及我们实验室的独特记录 将原则动物研究转化为人类试验，将使这种干细胞疗法发展为 针对AD患者的可达到的疾病改良干预措施。