Enhanced Neural Stem Cell Production in the Aging Brain

描述（由申请人提供）：NewNeural，Inc.正在计划开发一种小分子药物（MS-818），该药物将显着促进脑细胞和脑细胞功能丧失的患者产生新的脑细胞。我们的长期战略是为患有中风、阿尔茨海默病、帕金森病和与年龄相关的记忆障碍等疾病的患者开发细胞替代疗法--脑细胞的丧失与疾病进展有关。我们以前报道过，移植的神经干细胞在24个月大的大鼠脑中显示出广泛的迁移和位置整合，并且那些记忆受损的大鼠在移植后四周认知功能有显著改善。最近，我们发现杂环嘧啶化合物MS-818，当注射到老年大鼠（27个月大），诱导神经干细胞增殖7倍。该化合物还增加了培养中人类神经干细胞的增殖。我们的假设部分得到了初步观察的支持，即MS-818直接诱导内源性神经干细胞的增殖，然后这些细胞可以迁移到并重新填充大脑的受疾病影响的区域。如果这一假设被证明是正确的，MS-818将为治疗神经退行性疾病患者提供一种强大的新方法，其中新神经细胞的加速产生可能有助于改善认知和其他神经功能。我们在第一阶段提案中的目标是确认使用MS-818在细胞培养和动物模型中促进剂量依赖性神经发生的可行性。我们计划通过以下三个具体目标来验证我们的假设并实现我们的目标：目标1。确认MS-818通过特异性诱导培养的人NSC增殖来增强神经发生。目标二。确认MS-818处理的人神经干细胞能够增殖并分化为神经元和神经胶质细胞，目的3。证明MS-818可以剂量依赖性方式增强老年大鼠的神经发生。在第二阶段，我们的目标是评估MS-818对疾病动物模型认知功能的药理学作用。将监测和量化功能改善的程度和持续时间，并在动物中进行药代动力学和毒性研究。在完成这些研究后，我们预计将产生数据，以支持进一步的研究性新药（IND）在动物模型中的研究，为人类临床试验做准备。

DESCRIPTION (provided by applicant): NewNeural, Inc. is proposing to develop a small molecule drug (MS-818) that will significantly boost the production of new brain cells in patients who have suffered debilitating loss of brain cells and brain cell function. Our long-term strategy is to develop cell replacement therapies for patients with diseases such as stroke, Alzheimer's disease, Parkinson's disease, and age-associated memory impairment-- where loss of brain cells is associated with disease progression. We previously reported that transplanted neural stem cells display extensive migration and positional incorporation in the 24-month old rat brains, and those memory-impaired rats had significant improvement in cognitive function four weeks after transplantation. Recently, we discovered that the heterocyclic pyfimidine compound MS-818, when injected into aged rats (27 months old), induced the proliferation of neural stem cells by 7-fold. The compound also increased the proliferation of human neural stem cells in culture. Our hypothesis, supported in part by preliminary observations, is that MS-818 directly induces the proliferation of endogenous neural stem cells, which can then migrate to and repopulate the disease-affected regions of the brain. If this hypothesis is proven correct, MS-818 will offer a powerful new approach for treating patients with neurodegenerative conditions where the accelerated production of new neural cells may help improve cognitive and other neural functions. Our objective in this Phase I proposal is to confirm the feasibility of using MS-818 to promote dose-dependent neurogenesis in cell culture and animal models. We plan to test our hypothesis and accomplish our objectives with the following three specific aims: Aim 1. Confirm that MS-818 enhances neurogenesis by specifically inducing the proliferation of human NSCs in culture. Aim 2. Confirm that the MS-818-treated human neural stem cells are able to multiply and differentiate into neurons and glial cells and Aim 3. Demonstrate that MS-818 can enhance neurogenesis in aged rats in a dose-dependent manner. In Phase II, our objective will be to evaluate pharmacological effects of MS-818 on cognitive functions in animal models of disease. The extent and duration of functional improvement will be monitored and quantified, and pharmacokinetics and toxicity studies will be conducted in animals. Upon the completion of these studies, we expect to generate data to support further investigational new drug (IND)-enabling studies in animal models, in preparation for human clinical trials.