Combined Nano and Cell therapy for the Treatment of TBI

纳米和细胞联合疗法治疗 TBI

• 批准号: 9206889
• 负责人: SUBHRA MOHAPATRA
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206889
• 关键词: Acute; Adverse event; Astrocytes; Attenuated; Brain; Brain Injuries; CCR6 gene; Cause of Death; Cell Therapy; Cells; Chitosan; Clinical; Collaborations; Consensus; Data; Development; Dose; Drug Targeting; Employee Strikes; Encephalitis; Engraftment; Freedom; Genes; Goals; Health; Human Resources; Immune; Infiltration; Inflammation; Inflammatory; Intravenous; Investigation; Lateral; Left; Ligands; Liquid substance; Magnetism; Memory Loss; Mesenchymal Stem Cells; Methods; Micelles; Military Personnel; Modeling; Nerve Degeneration; Nerve Regeneration; Nervous System Physiology; Nervous System Trauma; Neurologic; Neuronal Injury; Neurons; Pathology; Percussion; Pharmaceutical Preparations; Phase; Play; Polyethyleneimine; Population; Prevalence; Proteins; Rattus; Reactive Oxygen Species; Reagent; Research; Rodent; Role; Route; Severities; Signal Transduction; Small Interfering RNA; Spleen; Techniques; Testing; Therapeutic; Therapeutic Agents; Translational Research; Traumatic Brain Injury; Treatment Efficacy; Uncertainty; Vascular remodeling; adult stem cell; angiogenesis; astrogliosis; base; chemokine; combat; combinatorial; comparative efficacy; disability; effective therapy; fluid percussion injury; glial activation; in vivo; inhibitor/antagonist; innovation; intravenous administration; knock-down; nano; nanoparticle; nanotherapy; neurogenesis; neuroinflammation; neurovascular; new therapeutic target; novel; novel therapeutics; operation; pre-clinical research; programs; public health relevance; repaired; stem cell therapy; targeted treatment; therapeutic evaluation

 DESCRIPTION (provided by applicant): The long-term goal of our research program is to develop safe and effective therapies for traumatic brain injury (TBI), which is a major health issue with our military personnel in combat, with estimates of 150,000-300,000 military personnel from Operation Iraqi Freedom and Operation Enduring Freedom suffering some level of TBI. The prevalence of TBI from all causes has been estimated to be 2.5 to 3.7 millions in the USA alone. Currently, there are no drugs available to treat TBI. While TBI illness ranges from mild to severe, moderate TBI is clinically most relevant, and if left untreated it often progresses to severe TBI, which is difficult to treat Hence, there is a genuine need to discover new therapeutic agents for moderate TBI. Adult stem cell therapy including mesenchymal stem cells (MSCs), is under investigation, however, there remains a lack of consensus about the viability of this MSC therapy due to use of different models and techniques, uncertainty about routes of delivery, variable engraftment and the potential for adverse events. Thus, discovering and developing new therapeutic targets remains a major unmet need. We made the striking discovery that expression of chemokine (C-C motif) ligand 20 (CCL20) (MIP3α) is pivotal to inflammation following LFP-TBI (a lateral fluid percussion (LFP) injury model) in rodents, implicating CCL20 as a potential TBI drug target. Our data demonstrates that the acute phase of TBI involves an influx of CCL20-driven inflammatory cells from the periphery that appear to play a role in subsequent neuroinflammation and neurodegeneration. Toward developing a CCL20-based nanogene drug for TBI, we have synthesized multifunctional chitosan- polyethyleneimine (PEI) magnetic micelles (CPMMs) to deliver drugs and genes to the injured brain. In addition, we have found that intranasally delivered MSCs readily migrate to brain and spleen post TBI and reduce reactive astrogliosis in the injured brain. These results have led us to hypothesize that a combinatorial nano-cell therapy comprising intranasal/intravenous administration of CPMMs 1-2 days after TBI to deliver small interfering RNAs (siRNAs) against CCL20 followed by MSC therapy 3-10 days after TBI would respectively, ameliorate acute inflammation and secondary neuronal injury thus providing an effective treatment for moderate TBI. Three specific aims are proposed to test this hypothesis. In Aim #1, we will synthesize and characterize TRIC (targeted, reactive oxygen species-inducible CPMM) nanoparticles targeting CCL20 signaling and examine the effects of CCL20 inhibition on LFP-induced TBI pathology. In Aim #2, we will evaluate the route of delivery that provides a better therapeutic window for MSC delivery and the efficacy of MSC delivery in repairing neurological function deficits in the rat brain after LFP-induced moderate TBI. In Aim #3, we plan to evaluate therapeutic efficacy of a two-step nano-cell treatment approach for moderate TBI. We will compare the efficacy of TRIC NPs targeting CCL20/CCR6 followed by MSC therapy in ameliorating deficits following moderate TBI and determine mechanisms of action. This highly interdisciplinary and innovative approach of a two-step therapy involving NPs carrying the inhibitor(s) of CCL20 signaling and hMSC therapy for treatment of LFP-induced moderate TBI is highly innovative. We predict that the proposed research will increase our understanding of the potential and role of TRIC-siCCL20 for TBI. All the necessary reagents, methods and collaborations are in place and our investigative team is uniquely poised to conduct the proposed studies.

 描述（由申请人提供）： 我们研究计划的长期目标是开发安全有效的治疗创伤性脑损伤 (TBI) 的方法，这是我们在战斗中的军事人员面临的一个主要健康问题，估计有 150,000-300,000 名军事人员参与了伊拉克自由行动和据估计，仅在美国就有 2.5 至 370 万人患有某种程度的 TBI。 TBI疾病范围从轻度到重度，中度TBI在临床上最为相关，如果不及时治疗，通常会进展为难以治疗的重度TBI。因此，确实需要发现新的中度TBI治疗剂。包括间充质干细胞（MSC）在内的疗法正在研究中，然而，由于使用不同的模型和技术、输送途径的不确定性、植入的可变性以及潜在的不良反应，对于这种 MSC 疗法的可行性仍缺乏共识。事件。因此，发现新的治疗靶点仍然是一个未满足的主要需求，我们发现趋化因子（C-C 基序）配体 20 (CCL20) (MIP3α) 的表达对于 LFP-TBI（横向液体冲击 (LFP)）后炎症的发生至关重要。 ））损伤模型），表明 CCL20 作为潜在的 TBI 药物靶点。我们的数据表明，TBI 的急性期涉及 CCL20 驱动的炎症细胞的涌入。为了开发一种基于 CCL20 的纳米基因药物治疗 TBI，我们合成了多功能壳聚糖-聚乙烯亚胺 (PEI) 磁性胶束 (CPMM)，将药物和基因输送到受伤的大脑。此外，我们发现鼻内递送的 MSC 很容易在 TBI 后迁移到大脑和脾脏，并减少受伤大脑中的反应性星形胶质细胞增生。使我们认为，组合纳米细胞疗法包括在 TBI 后 1-2 天鼻内/静脉内施用 CPMM，以递送针对 CCL20 的小干扰 RNA (siRNA)，然后在 TBI 后 3-10 天进行 MSC 治疗，将分别改善急性炎症和继发性神经元损伤，从而为中度 TBI 提供有效的治疗方法。在目标 1 中，我们将综合并描述 TRIC。 （靶向活性氧诱导型 CPMM）纳米颗粒靶向 CCL20 信号传导，并检查 CCL20 抑制对 LFP 诱导的 TBI 病理的影响。在目标 #2 中，我们将评估为 MSC 递送提供更好的治疗窗口的递送途径。 MSC 递送在修复 LFP 诱导的中度 TBI 后大鼠大脑神经功能缺陷中的功效在目标 3 中，我们计划评估两步纳米细胞治疗方法对中度 TBI 的治疗效果。我们将比较针对 CCL20/CCR6 的 TRIC NP 和 MSC 治疗在改善中度 TBI 后的缺陷方面的功效，并确定这种携带 TBI 抑制剂的两步治疗 NP 的作用机制。 CCL20 信号传导和 hMSC 疗法治疗 LFP 诱导的中度 TBI 具有高度创新性，我们预测拟议的研究将增加我们对 TRIC-siCCL20 的潜力和作用的理解。 TBI。所有必要的试剂、方法和合作都已到位，我们的研究团队已准备好进行拟议的研究。