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

优化和评估生物制剂以改善创伤性脑损伤后的认知功能

• 批准号: 9558098
• 负责人: Martin L Doughty
• 金额: $ 23.78万
• 依托单位: ALCAMENA STEM CELL THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9558098
• 关键词: Address; Affect; Affinity; American; Animal Model; Automobile Driving; Autopsy; Behavior; Binding; Biological Assay; Brain; Brain Injuries; C-terminal; Cell Death; Cell Membrane Permeability; Cell Nucleus; Cells; Cessation of life; Cognitive; Cytoplasm; Dose; Drug Controls; Drug Design; Engineering; Ensure; FDA approved; Failure; Family; Gene Expression; Genes; Genetic Transcription; Goals; Health Sciences; Human; In Vitro; Individual; Injury; International; Intracellular Transport; Investigational New Drug Application; Lead; Learning; Legal patent; Lesion; Libraries; Memory; Monitor; Motor; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Nervous System Physiology; Neuronal Dysfunction; Neuronal Injury; Neurons; Oligodendroglia; Oregon; Patients; Peptides; Permeability; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Plasmids; Protein Dephosphorylation; Publishing; Randomized; Rattus; Ribosomes; Rodent Model; Safety; Scientist; Site; Small Business Innovation Research Grant; Stem cells; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcription Repressor/Corepressor; Traumatic Brain Injury; United States National Academy of Sciences; Universities; University Health Services; Up-Regulation; Work; base; cognitive disability; cognitive function; cognitive recovery; combinatorial; design; drug candidate; economic cost; experience; experimental study; gene repression; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mimetics; mutant; nerve stem cell; neurogenesis; neuron loss; neuronal growth; novel; overexpression; pluripotency; prevent; relating to nervous system; restoration; screening; stem cell therapy; targeted treatment

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.

抽象的。中度和重度TBI会导致明显的神经元死亡和功能障碍，从而导致 认知障碍。恢复TBI患者神经功能功能的最佳策略是保留现有 神经元并刺激神经发生以替代丧失的神经组织。许多治疗学试图 实现这些目标，但没有成功，导致缺乏FDA批准的治疗方法 TBI导致的认知障碍的恢复。 失败的确切原因尚不清楚，但我们确实知道脑损伤会引起次要级联 升高神经基因的转录阻遏物的水平，称为REST。静止的上调成熟 神经元阻止它们正常运作，并最终以死亡和增加的水平结束 休息在干细胞和神经祖细胞中，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当前的方法都在休息的上游，不考虑 对于此转录块。 为了应对这一挑战，我们开发了一种铅生物学，可以促进休息降解并清除 损伤引起的神经元基因的转录抑制。将这种铅生物学设计成候选药物 对于FDA的研究新药（IND）应用，我们将实现以下目标： I.优化候选药物的活性，组织靶向和细胞内转运。 ii。评估人类诱导多能干（IPS）细胞的体外功效。 iii。使用TBI的啮齿动物模型评估体内功效。 为了实现这些目标，Alcamena干细胞疗法正在与领域领先的学术合作 约翰·霍普金斯大学（JHU）的科学家和统一的卫生科学服务大学 （USHS/DOD）。累积地，这些研究将告知我们我们的候选药物改善的程度 神经元和少突胶质细胞再生，生存和认知功能。另外，使用两个人 诱导多能干细胞和体内啮齿动物的脑损伤模型确保我们的结果是 可以转化为我们解决TBI患者未满足的治疗需求的长期目标。