Human Neural Stem Cells for HD: Technical and Empirical Advances

描述(申请人提供)：亨廷顿病是一种毁灭性的、普遍致命的、无法治愈的神经退行性疾病，它使人虚弱，给患者的身心造成可怕的痛苦。人类神经干细胞已经被确定为治疗的潜在替代细胞基质，但到目前为止，还没有在与疾病相关的动物模型(转基因HD小鼠)中测试长期疗效。我们的长期目标是评估hNSC移植在HD患者中的安全性和短期疗效。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，在转基因小鼠中从结构上保护神经元并逆转与HD相关的功能缺陷。我们的中心假设是，在纹状体内将hNSC注射到先前“脱敏”的转基因HD小鼠体内将提供神经保护，改善结构神经解剖学的措施，以及减少运动和认知障碍。这项拟议研究的基本原理是，一旦知道胎儿hNSC移植是否改善了HD小鼠的进行性缺陷，我们就可以在这个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临床移植前的合乎逻辑的下一步。在初步数据的指导下，这一假说将检验以下两个具体目标：1)纹状体内注射hNSC可防止HD病理和行为缺陷；2)延长HD转基因小鼠的存活时间。利用一种新的允许移植的hNSC绕过免疫排斥的“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，并将这些结果与总体寿命相关联。在AIM#1中，免疫组织化学分析和行为测试将用于补充AIM#2中的生存研究，以努力弥合HD疗法知识的关键差距。这项研究具有创新性，因为它1)将“脱敏”作为一种绕过移植物排斥反应的新方法，2)利用真正的疾病特异性遗传模型，加深了我们对这一方法的功能有效性的认识，3)将为hNSC治疗HD的未来发展提供有价值的见解。这一建议具有重要意义，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，拟议的实验更有可能为临床提供高质量的可翻译结果。这一成果有望通过神经外科和干细胞生物学的融合在垂直方向上推进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.