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: 8269640
• 负责人: Jeffrey H Kordower
• 金额: $ 22.5万
• 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/8269640
• 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.

描述（由申请人提供）：亨廷顿氏病是一种毁灭性的、普遍致命的、无法治愈的神经退行性疾病，使患者虚弱并对患者的身心造成可怕的痛苦。人神经干细胞已被鉴定为用于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）中测试长期治疗功效。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移植物是否是一种有效的持久疗法，在结构上保护神经元并逆转转基因小鼠中与HD相关的功能缺陷。我们的中心假设是，hNSC到先前的“脱敏”转基因HD小鼠的纹状体内递送将提供神经保护，改善结构神经解剖学的措施，以及减少运动和认知缺陷。拟议研究的基本原理是，一旦知道胎儿hNSC移植物是否改善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，并随后采用非人灵长类动物模型作为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特定目的：1）hNSC的纹状体内施用将预防HD病理和行为缺陷和2）延长HD转基因小鼠的存活。利用一种新的“脱敏”模式，允许移植的hNSC绕过免疫排斥，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，以弥补HD治疗知识的关键空白。这项研究是创新的，因为它1）专注于“脱敏”作为绕过移植物排斥反应的新手段，2）通过利用真正的疾病特异性遗传模型来提高我们对这种方法的功能功效的认识，以及3）将为HD中hNSC治疗的未来发展提供有价值的见解。这一提议是重要的，因为在转基因小鼠中严格测试hNSC疗法更准确地描述了人HD，因此，所提出的实验更有可能为临床提供高质量的可翻译结果。这些成果有望通过神经外科和干细胞生物学的融合，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，并防止某些死亡与HD。

项目成果

Neonatal immune-tolerance in mice does not prevent xenograft rejection.

• DOI: 10.1016/j.expneurol.2014.01.007
• 发表时间: 2014-04
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Mattis, Virginia B.;Wakeman, Dustin R.;Tom, Colton;Dodiya, Hemraj B.;Yeung, Sylvia Y.;Tran, Andrew H.;Bernau, Ksenija;Ornelas, Loren;Sahabian, Anais;Reidling, Jack;Sareen, Dhruv;Thompson, Leslie M.;Kordower, Jeffrey H.;Svendsen, Clive N.
• 通讯作者: Svendsen, Clive N.