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， 未满足的医疗需求。在美国，超过一百万人患有这种疾病，估计费用为27美元。 每年10亿。PD管理的主要方法是使用增加多巴胺的药物进行对症治疗 在纹状体。然而，这些药物的效用由于功效减弱和使人衰弱而显著减少。 副作用.由于PD源于单细胞类型的退化，因此， 供应多巴胺到纹状体的确定位置，PD患者已被视为细胞移植的最佳候选人。 移植治疗临床前和临床研究表明，移植原代胎儿 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、实践和安全性问题以及诱导流产的最新进展 多能干细胞（iPSC），PD移植试验开始重新出现在世界各地，新的重点是 多能干细胞技术。然而，迄今为止的临床研究表明， 细胞产品、递送方法和临床方案， 持续治疗对于实现PD细胞治疗的潜力至关重要。NeoNeuron LLC开发了 关于可扩展和有效技术的知识产权，用于产生无限供应的DA神经元 从iPSC和图像引导的方法，用于将细胞输送到大脑的目标区域， 在大鼠和非人灵长类PD模型中的功能恢复。为了准备我们的研究 新药（IND）提交，NeoNeuron会见了美国食品药品监督管理局（FDA），并收到 建议进行最佳剂量范围的细胞产品，iPSC-DA神经元，在 免疫受损大鼠模型。公司已建立标准操作程序， 根据当前的良好生产规范（cGMP）扩展该产品，并生产DA神经元， 可以作为现成的产品。该特征对于预期产品的开发是理想的 用于临床应用和商业化。在目标1中，我们将显示剂量反应和充分的证据 在PD的偏侧帕金森病大鼠模型中DA细胞植入和存活6个月的水平。 目标2将评估连续性身体和认知训练对运动和认知功能的影响， 被移植的动物我们将利用移植细胞的单细胞空间转录组学分析， 深入了解我们的产品的作用机制和持续培训干预， 功能恢复第一阶段将使我们能够通过识别 iPSC-DA细胞植入的最佳剂量水平和PD模型中的持久效应，并继续我们的研究。 计划的第二阶段SBIR提案，以建立化学、制造和控制，以及额外的安全性 用于IND申报的非人灵长类动物毒理学研究和器械试验。

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.