IND-enabling studies for cell therapy in Parkinson's disease

帕金森病(PD)是一种进行性神经退行性疾病，目前无法治愈， 未得到满足的医疗需求。在美国，有100多万人患有这种疾病，估计成本为27美元 每年10亿美元。帕金森病治疗的主要手段是用增加多巴胺的药物进行对症治疗。 在纹状体。然而，这些药物的效用因药效减弱和虚弱而显著减少。 副作用。由于帕金森病源于单细胞类型的退化，因此多巴胺能神经元 将多巴胺供应到纹状体的特定位置，帕金森病患者一直被视为最佳细胞候选者 移植疗法。临床前和临床研究表明，原代胎儿移植 中脑DA神经元进入纹状体，提供显著和持续的功能恢复。然而， 使用胎儿流产组织的伦理、实践和安全问题以及人工流产的最新进展 多能干细胞(IPSCs)，帕金森病的移植试验开始在世界范围内重新出现，新的焦点是 多能干细胞技术。然而，到目前为止的临床研究表明， 细胞产品，在给药方法中，在临床方案中，通过考虑纳入 辅助治疗是实现细胞治疗在帕金森病中的潜力所必需的。NeoNeuron LLC已经开发出 关于可扩展和有效的技术以产生无限供应的DA神经元的知识产权 来自ipscs和一种图像引导的方法，将细胞输送到大脑的目标区域，使 帕金森病大鼠和非人灵长类动物模型的功能恢复。为我们的调查做准备 新药(IND)提交，NeoNeuron与美国食品和药物管理局(FDA)会面并收到 建议为细胞产品IPSC-DA神经元提供最佳剂量范围 免疫低下的帕金森病大鼠模型。该公司已经建立了标准的操作程序来 在当前良好的制造实践(CGMP)下扩展该产品，并生产将 以现成产品的形式出售。此功能适用于预期产品的开发 用于临床和商业化。在目标1中，我们将展示剂量反应和适当的证据 帕金森病偏侧模型大鼠DA细胞植入水平和6个月存活率。 目标2将评估辅助身体和认知训练对运动和认知功能的影响 移植的动物。我们将利用移植细胞的单细胞空间转录图谱来获得 对我们的产品和辅助培训干预的作用机制的见解 功能恢复。此阶段1将使我们能够通过确定 帕金森病模型中IPSC-DA细胞植入的最佳剂量水平和持久效应 计划中的第二阶段SBIR建议建立化学、制造和控制，增加安全 用于IND备案的非人类灵长类动物的毒理学研究和装置测试。

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is currently incurable with significant unmet medical needs. In the US, over a million people suffer from this disease with an estimated cost of $27 billion per year. The mainstay of PD management is symptomatic treatment with drugs that increase dopamine in the striatum. However, the utility of these drugs is significantly curtailed by waning efficacy and debilitating side effects. Since PD stems from the degeneration of a single cell type, dopaminergic (DA) neurons that supply dopamine to a defined location the striatum, PD patients have been viewed as optimal candidate for cell transplantation therapy. Preclinical and clinical studies have demonstrated that transplantation of primary fetal midbrain DA neurons into the striatum, provide significant and sustained restoration of function. However ethical, practical and safety issues with using fetal aborted tissue and the recent progress in induced pluripotent stem cells (iPSCs), grafting trials in PD are beginning to re-emerge world-wide with a new focus on pluripotent stem cell technologies. However, clinical studies to date suggest that critical refinements in the cellular product, in the delivery method, and in the clinical protocol by considering the incorporation of adjunctive therapies, are essential to realize the potential of cell therapy in PD. NeoNeuron LLC has developed intellectual property on scalable and effective technologies for generating an unlimited supply of DA neurons from iPSCs and an image-guided methodology for delivering the cells into the target area of the brain enabling functional recovery in the rat and in the nonhuman primate models of PD. In preparation for our Investigational New Drug (IND) submission, NeoNeuron met with the U.S. Food and Drug Administration (FDA) and received recommendations to conduct optimal dose range for the cellular product, iPSC-DA neurons, in the immunocompromised rat model of PD. The company has established standard operating procedures to expand this product under current good manufacturing practice (cGMP), and to produce DA neurons that will be available as an off-the-shelf product. This feature is desirable for the development of the intended product for clinical use and for commercialization. In Aim 1 we will show evidence of dose-response and adequate levels of DA cell engraftment and survival for a 6-month duration in the hemi- parkinsonian rat model of PD. Aim 2 will assess the impact of adjunctive physical and cognitive training on motor and cognitive functions in the grafted animals. We will leverage single cell spatial transcriptomics profiling of the grafted cells to gain insights into the mechanisms of actions of our product and of the adjunctive training intervention in enhancing functional recovery. This Phase 1 will enable us to respond to the FDA recommendations by identifying the optimal dose level of iPSC-DA cell engraftment and durable effects in the PD model and to proceed with our planned Phase II SBIR proposal to establish the chemistry, manufacturing and controls, additional safety toxicology studies and device testing in nonhuman primates for the IND filing.