Human Neural Stem Cells for HD: Technical and Empirical Advances

描述（由申请人提供）：亨廷顿舞蹈病是一种毁灭性的、普遍致命的、无法治愈的神经退行性疾病，它使人衰弱，并对患者的身心造成可怕的痛苦。人类神经干细胞已被确定为治疗的潜在替代细胞基质，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hNSC移植在HD患者中的安全性和暂时有效性。目前的目标是确定hNSC移植是否是一种有效的长期治疗方法，可以在结构上保护神经元并逆转与HD相关的转基因小鼠的功能缺陷。我们的中心假设是，将hNSC注入先前“脱敏”的转基因HD小鼠，将提供神经保护，改善神经结构解剖措施，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，随后在临床转化之前采用非人类灵长类动物模型作为逻辑的下一步。在初步数据的指导下，这一假设将检验以下两个具体目标：1)在肠内给药hNSC可以预防HD的病理和行为缺陷；2)延长HD转基因小鼠的生存时间。利用一种新的“脱敏”模式，允许移植的hNSC绕过免疫排斥反应，我们将确定移植的hNSC对宿主解剖结构和功能的影响，并将这些结果与总体寿命联系起来。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，以弥合HD治疗学知识的关键空白。这项研究具有创新性，因为它1)将“脱敏”作为一种绕过移植排斥反应的新手段，2)通过利用真正的疾病特异性遗传模型，提高了我们对该方法功能功效的认识，3)将为hNSC治疗HD的未来进展提供有价值的见解。这一提议意义重大，因为在转基因小鼠中严格测试hNSC疗法更准确地描述了人类HD，因此，提议的实验更有可能为临床提供高质量的可翻译结果。这一结果将通过神经外科和干细胞生物学的结合，垂直推进HD治疗领域。在这里获得的知识有可能提供一种治疗选择，将减少可怕的症状，并防止与HD相关的某些死亡。

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.