OPTIMIZATION AND ASSESSMENT OF A BIOLOGIC TO IMPROVE COGNITIVE FUNCTION AFTER TRAUMATIC BRAIN INJURY

抽象的。中、重度颅脑损伤可导致严重的神经元死亡和功能障碍，导致 认知障碍。恢复颅脑损伤患者神经功能的最好策略是保留现有的 并刺激神经再生，以取代丢失的神经组织。许多治疗师都试图 实现了这些目标，但都没有成功，导致缺乏FDA批准的治疗方法 脑外伤所致的认知功能障碍的恢复。 失败的确切原因尚不清楚，但我们知道，脑损伤会导致继发性级联反应 提高一种称为REST的神经基因转录抑制因子的水平。成熟期休息时间的上调 神经元阻止它们正常运作，最终导致它们死亡和水平升高。 干细胞和神经前体细胞中的休息阻止它们成为新的神经元或少突胶质细胞。 以前的治疗策略以及目前的方法都是在休息的上游奏效，并没有考虑到 为了这个转录区块。 为了应对这一挑战，我们开发了一种铅生物，它可以促进休息时间的降解，并清除 损伤诱导神经基因转录抑制。将这一先导生物改造成候选药物 对于FDA的研究性新药(IND)申请，我们将实现以下目标： 优化我们候选药物的活性、组织靶向性和细胞内转运。 评估人类诱导的多能干细胞(IPS)的体外效果。 使用脑外伤啮齿动物模型评估体内疗效。 为了实现这些目标，阿尔卡米纳干细胞治疗公司正在与领域领先的学术机构合作 约翰霍普金斯大学(JHU)和健康科学统一服务大学的科学家 (USHS/DoD)。累积起来，这些研究将告诉我们我们的候选药物改善的程度 神经元和少突胶质细胞的再生、存活和认知功能。此外，使用两个人 诱导多能干细胞和脑损伤的活体啮齿动物模型确保了我们的结果是 可翻译为我们的长期目标，即解决脑外伤患者未得到满足的治疗需求。

Abstract. Moderate and severe TBI can cause significant neuronal death and dysfunction, resulting in cognitive disability. The best strategy to restore neurologic function in TBI patients is to preserve existing neurons and to stimulate neurogenesis to replace lost neural tissue. Many therapeutics have sought to accomplish these goals, but none have succeeded, resulting in a lack of FDA-approved treatments for the restoration of cognitive disabilities that result from TBI. The exact cause of failure is not known, but we do know that brain injury induces secondary cascades that elevate levels of a transcriptional repressor of neural genes known as REST. Upregulation of REST in mature neurons prevents them from functioning properly and eventually ends in their death and increased levels of REST in stem cells and neural progenitor cells prevent them from becoming new neurons or oligodendrocytes. Previous therapeutic strategies as well as current approaches all work upstream of REST and do not account for this transcriptional block. To address this challenge, we have developed a lead biologic that promotes REST degradation and clears the injury induced transcriptional repression of neuronal genes. To engineer this lead biologic into a drug candidate for an Investigational New Drug (IND) application with the FDA we will carry out the following objectives: I. Optimize the activity, tissue targeting and intracellular transport of our drug candidate. II. Assess in vitro efficacy in human induced pluripotent stem (iPS) cells. III. Assess in vivo efficacy using a rodent model of TBI. To accomplish these objectives, Alcamena Stem Cell Therapeutics is collaborating with field leading academic scientists at Johns Hopkins University (JHU), and the Uniformed Services University of the Health Sciences (USHS/DoD). Cumulatively, these studies will inform us on the degree to which our drug candidate improves neuron and oligodendrocyte regeneration, survival and cognitive function. Additionally, the use of both human induced pluripotent stem cells and an in vivo rodent model of brain injury ensure that our results are translatable towards our long-term goal of addressing the unmet therapeutic needs of TBI patients.