Human Cell and Gene Therapy in Parkinsonian monkeys

帕金森猴的人类细胞和基因治疗

• 批准号: 8397422
• 负责人: Jeffrey H Kordower
• 金额: $ 22.95万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397422
• 关键词: Adverse effects; Animal Model; Behavioral; Brain; Cell Survival; Cell Therapy; Cells; Clinic; Clinical; Clinical Trials; Complement; Corpus striatum structure; Data; Development; Diagnosis; Disease; Dopamine; Embryo; Floor; Future; Goals; Gold; Growth; Health; Human; Image; Individual; Knowledge; MPTP Poisoning; Midbrain structure; Mission; Modeling; Monkeys; Motor; Neurodegenerative Disorders; Neurons; Outcome; Parkinson Disease; Parkinsonian Disorders; Patients; Physiological; Pluripotent Stem Cells; Population; Primates; Process; Public Health; Quality of life; Recovery; Recovery of Function; Research; Research Personnel; Rodent Model; Safety; Solutions; Source; Stem cell transplant; Stem cells; Structure; Symptoms; Testing; Therapeutic; Tissues; Translations; Transplantation; Treatment Efficacy; Undifferentiated; United States National Institutes of Health; Work; aging population; base; behavior test; body-mind; burden of illness; clinically relevant; disability; dopaminergic neuron; embryonic stem cell; fetal; gene therapy; human embryonic stem cell; human stem cells; in vivo; innovation; motor deficit; neurosurgery; neurturin; new technology; nonhuman primate; novel; pre-clinical; programs; progressive neurodegeneration; relating to nervous system; research clinical testing; research study; stem cell biology; stem cell therapy; success

DESCRIPTION (provided by applicant): Parkinson's disease is a devastating, universally fatal, incurable neurodegenerative disorder, which is debilitating and inflicts terrible suffering on the patient's mind and body. Human pluripotent cells, including embryonic 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 (MPTP lesioned monkeys). Our long-term goal is to assess the safety and temporal efficacy of HESC-DA cell therapy in PD patients. The current objective is to determine if grafted HESC-DA cells are a potent long-lasting therapy that structurally integrate within the dopamine depleted primate brain, as well as reverse functional deficits associated with PD. Our central hypothesis is that intrastriatal delivery of HESC-DA cells will reverse motor disability in MPTP treated monkeys and this effect will be potentiated by co-treating with AAV-neurturin. The rationale for the proposed research is if HESC-DA grafts ameliorate functional deficits in parkinsonian primates, we can pursue large-scale, long-term safety and tolerability studies as the next logical step for clinical translation. Guided by preliminary data, this hypothesis will test the following Specific Aim, that intrastriatal grafting of HESC-DA cells, or HESC-DA cells + AAV2-Neurturin will provide structural and functional recovery in MPTP monkeys. Utilizing a novel floor-plate based, dopaminergic neuralization paradigm that allows HESC to be efficiently differentiated into midbrain specific dopaminergic neurons, and we will determine the effects of grafted HESC-DA cells on host anatomical structure and function and correlate these results to overall quality of life (clinical rating scale). In the proposed Aim, immunohistochemical analysis and behavioral testing will be used to complement in vivo imaging in an effort to bridge a critical gap in knowledge for PD therapeutics. This research is innovative, as it 1) focuses on well characterized, functionally active, midbrain specific HESC- DA neurons as an alternative renewable source for cellular transplantation 2) advances our knowledge of the functional efficacy of this approach by utilizing a clinically relevant non-human primate model of PD, and 3) vertically advances and bridges our present studies with the addition of AAV-2 neurturin neurotrophic support. This proposal is significant as rigorously testing HESC-DA therapies in parkinsonian monkeys more accurately depicts human PD, 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 PD 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 enhance overall quality of life in PD. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health and the NIH-NINDS's mission because the discovery of human pluripotent stem cell based treatments that successfully slow or reverse progressive neurodegeneration and behavioral deficits will help develop a desperately needed treatment for PD patients. Furthermore, pre-clinical 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）：帕金森病是一种毁灭性的、普遍致命的、无法治愈的神经退行性疾病，它使患者衰弱，给患者的身心造成可怕的痛苦。人类多能细胞，包括胚胎干细胞，已被确定为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（MPTP 病变猴子）中测试长期治疗效果。我们的长期目标是评估 HESC-DA 细胞疗法对 PD 患者的安全性和暂时疗效。目前的目标是确定移植的 HESC-DA 细胞是否是一种有效的持久疗法，可以在结构上整合到多巴胺耗尽的灵长类动物大脑中，并逆转与 PD 相关的功能缺陷。我们的中心假设是，纹状体内输送 HESC-DA 细胞将逆转 MPTP 治疗猴子的运动障碍，并且通过与 AAV-neurturin 共同治疗将增强这种效果。拟议研究的基本原理是，如果 HESC-DA 移植物能够改善帕金森灵长类动物的功能缺陷，我们就可以进行大规模、长期的安全性和耐受性研究，作为临床转化的下一个合乎逻辑的步骤。在初步数据的指导下，该假设将测试以下具体目标，即纹状体内移植 HESC-DA 细胞或 HESC-DA 细胞 + AAV2-Neurturin 将为 MPTP 猴提供结构和功能恢复。利用基于新型底板的多巴胺能神经化范例，使 HESC 能够有效分化为中脑特异性多巴胺能神经元，我们将确定移植的 HESC-DA 细胞对宿主解剖结构和功能的影响，并将这些结果与整体生活质量（临床评分量表）相关联。在拟议的目标中，免疫组织化学分析和行为测试将用于补充体内成像，以努力弥合 PD 治疗知识的关键差距。这项研究具有创新性，因为它 1) 专注于特征明确、功能活跃、中脑特异性 HESC-DA 神经元，作为细胞移植的替代可再生来源 2) 通过利用临床相关的非人灵长类 PD 模型，增进了我们对这种方法功能功效的了解，3) 通过添加 AAV-2 神经营养因子神经营养因子，垂直推进和弥合了我们目前的研究 支持。该提案意义重大，因为在帕金森猴中严格测试 HESC-DA 疗法可以更准确地描述人类 PD，因此，所提出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帕金森病治疗领域。这里获得的知识有可能提供一种治疗选择，减少帕金森病的可怕症状并提高整体生活质量。 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，因为发现基于人类多能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 PD 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人类干细胞疗法的临床前开发。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。