Human Neural Stem Cells for HD: Technical and Empirical Advances

人类神经干细胞治疗 HD：技术和经验进展

• 批准号: 8095989
• 负责人: Jeffrey H Kordower
• 金额: $ 18.75万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095989
• 关键词: Adverse effects; Affect; Animal Model; Area; Behavioral; Bypass; Cell Death; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Cognitive deficits; Complement; Data; Development; Disease; Disease Progression; Disease model; Embryo; Future; Genes; Genetic; Genetic Models; Goals; Graft Rejection; Graft Survival; Growth Factor; Health; Human; Huntington Disease; Immunosuppression; Knowledge; Laboratories; Lead; Lesion; Longevity; Measures; Mission; Modality; Modeling; Motor; Mus; Neonatal; Neuroanatomy; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Outcome; Pathology; Patients; Production; Proteins; Public Health; Quinolinic Acid; Rattus; Recovery; Regimen; Research; Research Personnel; Rodent; Safety; Structure; Symptoms; Techniques; Testing; Therapeutic; Tissues; Toxin; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translations; Transplantation; Treatment Efficacy; Triplet Multiple Birth; United States National Institutes of Health; Work; Xenograft procedure; base; behavior test; body-mind; burden of illness; desensitization; disease phenotype; embryonic stem cell; fetal; human Huntingtin protein; human stem cells; improved; innovation; insight; motor deficit; nerve stem cell; neuropathology; neuroprotection; neurosurgery; new technology; nonhuman primate; novel; pre-clinical; prevent; programs; progressive neurodegeneration; research clinical testing; research study; stem cell biology; stem cell therapy; success

DESCRIPTION (provided by applicant): Huntington's disease is a devastating, universally fatal, untreatable neurodegenerative disorder, which is debilitating and inflicts terrible suffering on the patient's mind and body. Human neural stem cells have been identified as a potential alternative cellular substrate for treatment, but to date, have not been tested for long- term therapeutic efficacy in disease relevant animal models (transgenic HD-mice). Our long-term goal is to assess the safety and temporal efficacy of hNSC transplantation in HD patients. The current objective is to determine if hNSC grafts are a potent long-lasting therapy that structurally protect neurons and reverse functional deficits associated with HD in transgenic mice. Our central hypothesis is that intrastriatal delivery of hNSC into previously "desensitized" transgenic HD mice will provide neuroprotection, improving measures in structural neuroanatomy, as well as reduce motor and cognitive deficits. The rationale for the proposed research is that once it is known if fetal hNSC grafts ameliorate progressive deficits in HD mice, we can pursue safety and tolerability studies in this most relevant animal model and subsequently employ a non-human primate model for HD as a logical next-step before clinical translation. Guided by preliminary data, this hypothesis will test the following two Specific Aims, that: 1) intrastriatal administration of hNSC will prevent HD pathology and behavioral deficits and 2) prolong the survival of HD transgenic mice. Utilizing a novel "desensitization" paradigm that allows grafted hNSC to bypass immunorejection, we will determine the effects of grafted hNSC on host anatomical structure and function and correlate these results to overall lifespan. In aim#1, immunohistochemical analysis and behavioral testing will be used to complement survival studies in Aim#2, in an effort to bridge a critical gap in knowledge for HD therapeutics. This research is innovative, as it 1) focuses on "desensitization" as a novel means to bypass graft rejection, 2) advances our knowledge of the functional efficacy of this approach by utilizing a true disease specific genetic model, and 3) will shed valuable insight for the future advancement of hNSC therapy in HD. This proposal is significant as rigorously testing hNSC therapies in transgenic mice more accurately depicts human HD, and therefore, the proposed experiments are more likely to provide quality translatable results to the clinic. The outcomes are expected to vertically advance the field of HD therapy through the blending of neurosurgery and stem cell biology. The knowledge obtained here has the potential to provide a therapeutic option that will reduce the terrible symptoms and prevent certain death associated with HD. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health and the NIH-NINDS's mission because the discovery of human stem cell based treatments that successfully slow or reverse progressive neurodegeneration and behavioral deficits will help develop a desperately needed treatment for HD patients. Furthermore, development of human stem cell therapies are needed now more than ever with the advent of exciting new technologies centered on patient-derived induced neural cells. Thus, the proposed research is relevant to the part of NIH's mission that pertains to the application of knowledge that enhances health and reduces the overall burden of illness.

描述（由申请人提供）：亨廷顿舞蹈症是一种毁灭性的、普遍致命的、无法治疗的神经退行性疾病，它使患者衰弱，给患者的身心造成可怕的痛苦。人类神经干细胞已被确定为一种潜在的替代治疗细胞基质，但迄今为止，尚未在疾病相关动物模型（转基因 HD 小鼠）中测试长期治疗效果。我们的长期目标是评估 HD 患者 hNSC 移植的安全性和暂时疗效。目前的目标是确定 hNSC 移植物是否是一种有效的持久疗法，可以在结构上保护神经元并逆转与转基因小鼠 HD 相关的功能缺陷。我们的中心假设是，向先前“脱敏”的转基因 HD 小鼠纹状体内输送 hNSC 将提供神经保护，改善结构神经解剖学措施，并减少运动和认知缺陷。这项研究的基本原理是，一旦知道胎儿 hNSC 移植是否能改善 HD 小鼠的进行性缺陷，我们就可以在这种最相关的动物模型中进行安全性和耐受性研究，并随后采用非人类灵长类动物模型作为 HD 临床转化之前的逻辑下一步。在初步数据的指导下，该假设将测试以下两个具体目标，即：1）纹状体内给予 hNSC 将预防 HD 病理和行为缺陷，2）延长 HD 转基因小鼠的存活时间。利用允许移植的 hNSC 绕过免疫排斥的新型“脱敏”范例，我们将确定移植的 hNSC 对宿主解剖结构和功能的影响，并将这些结果与整体寿命相关联。在目标#1 中，免疫组织化学分析和行为测试将用于补充目标#2 中的生存研究，以努力弥合 HD 治疗知识方面的关键差距。这项研究具有创新性，因为它 1) 专注于“脱敏”作为绕过移植排斥的新方法，2) 通过利用真正的疾病特异性遗传模型，增进了我们对该方法功能功效的了解，3) 将为 HD 中 hNSC 治疗的未来发展提供宝贵的见解。这项提议意义重大，因为在转基因小鼠中严格测试 hNSC 疗法可以更准确地描述人类 HD，因此，所提议的实验更有可能为临床提供高质量的可转化结果。通过神经外科和干细胞生物学的融合，研究结果预计将垂直推进 HD 治疗领域。这里获得的知识有可能提供一种治疗选择，减少与 HD 相关的可怕症状并预防某些死亡。 公共健康相关性：拟议的研究与公共健康和 NIH-NINDS 的使命相关，因为发现基于人类干细胞的治疗方法能够成功减缓或逆转进行性神经退行性变和行为缺陷，将有助于为 HD 患者开发急需的治疗方法。此外，随着以患者衍生的诱导神经细胞为中心的令人兴奋的新技术的出现，现在比以往任何时候都更需要开发人类干细胞疗法。因此，拟议的研究与 NIH 使命的一部分相关，即应用知识来增强健康并减少疾病的总体负担。