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

计划摘要/摘要 这项U01提案旨在提供推进新型干细胞所需的临床前框架 人类临床试验治疗阿尔茨海默病(AD)的有效方法。广告是最流行的 与年龄相关的神经退行性疾病和痴呆症的主要原因，估计影响530万人 美国人。没有治愈的方法，也没有预防的手段。到目前为止，一些传统的、单一目标的 药理学方法只产生了轻微的临床改善-迫切需要 更有效的治疗方法。因此，我们研究的长期目标是开发一种治疗疾病的药物 阿尔茨海默病的细胞治疗将对患者的生活产生重大影响。细胞疗法针对多个 疾病机制，并提供了一种多方面的方法来治疗与 广告。在与神经干细胞公司的合作中，我们开发了一种独特的人类皮质来源的神经 产生多种神经保护性生长因子的干细胞(NSCs)。我们迄今的发现，以及证据- 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 当与营养因子的输送相结合时，效果会得到增强。在我们建议的方法中，神经干细胞移植将 将细胞疗法的多因素治疗潜力与持续和定向的 神经营养因子，与传统方法相比提供更多的好处并改善结果 在公元后。我们在小鼠模型中的初步数据表明，神经干细胞移植是安全有效的， 显著影响认知和降低Aβ斑块负担。在这项提案中，我们将确定 最大耐受量并评估NSC在两个成熟和高度的组织中的生物分布和组织取向 相关小鼠模型：5XFAD和rTg4510。然后，我们将对NSCs进行大规模的疗效测试 并在非人类灵长类动物身上完成剂量反应可行性研究，这是 在解剖学和认知学上与人类临床测试更相关。总体而言，我们的提案将有一个 通过为一种具有良好特征的细胞疗法提供概念验证疗效数据对AD产生重大影响 两个相关的小鼠模型和大型动物的安全性数据，其大脑结构更类似于 人类。完成我们建议的支持IND的研究，以及我们实验室独特的 将动物试验转化为人体试验，将使干细胞疗法能够进展到 对阿尔茨海默病患者可实现的疾病修正干预。

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.