Anti-inflammatory and hMSC combination therapy for traumatic brain injury

抗炎与hMSC联合治疗创伤性脑损伤

• 批准号: 10486391
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486391
• 关键词: Acute; Address; Anti-Inflammatory Agents; Anxiety; Astrocytes; Attenuated; Behavioral; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; CCL20 gene; CCR6 gene; Cause of Death; Cells; Clinical; Closed head injuries; Cognitive deficits; Collaborations; Combined Modality Therapy; Communication; Consensus; Data; Dendrimers; Dose; Drug Targeting; Encephalitis; Engraftment; FDA approved; Functional disorder; Funding; Future; Genes; Gliosis; Goals; Health; Human; Human Resources; Immune; Impaired cognition; Infiltration; Inflammasome; Inflammation; Inflammatory; Injury; Integral Membrane Protein; Interferons; Interleukin-1 beta; Intravenous; Lateral; Lesion; Ligands; Liquid substance; Long-Term Effects; Memory Loss; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Microglia; Military Personnel; Modeling; Mus; Nerve Degeneration; Nerve Regeneration; Nervous System Trauma; Neurogenic Inflammation; Neurologic; Neurons; Outcome; Pathogenesis; Pathology; Patients; Percussion; Peripheral; Pharmaceutical Preparations; Phase; Pioglitazone; Plasmids; Play; Population; Prevalence; Proteins; Rattus; Reagent; Regimen; Reporting; Research; Role; Severities; Signal Transduction; Spleen; Stimulus; Surrogate Markers; TBI treatment; Testing; Therapeutic; Therapeutic Agents; Translational Research; Traumatic Brain Injury; Uncertainty; Work; adult stem cell; anxiety reduction; anxiety-like behavior; astrogliosis; behavioral outcome; chemokine; chemokine therapy; clinical translation; combat; combinatorial; depressive behavior; disability; effective therapy; evidence base; glial activation; improved; inhibitor; innovation; learned behavior; motor behavior; mouse model; nano; nanoformulation; nanoparticle; neurogenesis; neuropathology; novel; novel therapeutics; pre-clinical research; programs; rational design; receptor; response; small hairpin RNA; stem cell therapy; systemic inflammatory response; targeted treatment; therapy outcome

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. The prevalence of TBI from all causes is estimated at ~2.5 to 3.7 million cases in the USA alone. Currently, there are no FDA- approved drugs available to treat TBI. While TBI illness ranges from mild to severe, moderate TBI is clinically most relevant, and If not treated immediately the secondary injury in these patients could spread quickly and may lead to long-term consequences including cognitive and memory loss. Mesenchymal stem cells (MSCs) transplantation has emerged as one of the major approaches to treat TBI. However, the viability of sole MSC therapy is being debated due to the uncertainty of variable engraftment in inflammatory state. Hence, there is a genuine unmet need to discover and develop new therapeutic agents for all forms of TBI, especially moderate TBI. It has been reported that adding an anti-inflammatory agent prior to MSC treatment increased the latter’s efficacy. During the last funding period, we have established an experimental mouse model to enable characterization of the consequences of repeated TBI (rTBI) in closed head injury, which shows extensive neuropathologic changes associated with the cognitive deficit, consistent with human TBI. We made the striking discovery that the expression of chemokine (C-C motif) ligand 20 (CCL20) (MIP3α) is pivotal to inflammation in TBI, implicating CCL20 as a potential TBI drug target. We have demonstrated that CCL20 inhibitor, pioglitazone (PG), played a key role in reducing astrogliosis, microglial activation and inflammasome activation in TBI. A combination of PG and hMSC treatment not only reduced inflammation but also improved behavioral outcomes by increasing the expression of brain-derived neurotrophic factor (BDNF). Because PG is not a specific CCL20 inhibitor and may have off-target effects, we have established and validated a nanoformulation of short hairpin RNA (shRNA) plasmids encoding CCL20 and its receptor CCR6 using dendrimer. A combination treatment involving shCCL20/shCCR6 (shCombo) and human MSC (hMSC) showed a significant reduction in inflammation, a concomitant increase in BDNF and neurogenesis in rTBI mouse model. Based on our preliminary data, we hypothesize that the shCombo dendriplex (DPX) or/and hMSC combination regimen will attenuate both acute brain- and systemic-inflammation by decreasing activation of glial cells and astrocytes in the brain, and secreting trophic factors over a prolonged period, which in turn promotes neuronal remodeling in the damaged brain and provides sustained relief from TBI-induced pathology. Three specific aims are proposed to test this hypothesis. In Aim #1, we will determine the optimal dose of pshCombo-DPX and the therapeutic window of treatment in rTBI mice. In Aim #2 we will examine the short-term and long-term effects of shCombo-DPX or/and hMSC therapy on pathophysiology and behavioral deficits in rTBI mice. In Aim #3, we will determine the mechanism of action of CCL20 in rTBI-induced pathogenesis and behavioral deficits. This highly innovative proposal aims to investigate whether shCombo-DPX as a single agent or in combination with hMSC will reduce acute brain- and systemic-inflammation and behavioral deficits, and plans to address the mechanism of action and surrogate markers of efficacy based on genes induced during acute inflammation. The proposed translational research based on a rationally designed better anti-inflammatory therapy is expected to increase our understanding of the long-term outcome of the therapy for mild to moderate TBI and pave the way for future clinical translation.

我们的研究计划的长期目标是为创伤性大脑开发安全有效的疗法 受伤（TBI），这是我们战斗中的军事人员的主要健康问题。 TBI的患病率 仅在美国，所有原因估计约为2.5至370万例。目前，没有FDA- 可用于治疗TBI的批准药物。虽然TBI疾病范围从轻度到重度，但中等TBI为 临床上最相关的，如果没有立即治疗，这些患者的继发损伤可能会扩散 很快，可能会导致长期后果，包括认知和记忆力丧失。间充质 干细胞（MSC）移植已成为治疗TBI的主要方法之一。然而， 由于可变植入的不确定性，唯一MSC治疗的生存能力正在争论 炎症状态。因此，发现和开发新疗法有真正的未满足需求。 所有形式的TBI的代理，尤其是中等TBI。 据报道，在MSC治疗之前添加抗炎剂增加了 后者的效率。在最后一个资金期间，我们建立了一个实验鼠标模型 能够表征闭合头部损伤中重复TBI（RTBI）的后果，这表明 与人类TBI一致的认知缺陷相关的广泛神经病理学变化。我们 惊人的发现是趋化因子（C-C基序）配体20（CCL20）（MIP3α）的表达 对于TBI的炎症至关重要，隐含的CCL20是潜在的TBI药物靶标。我们有 证明CCL20抑制剂Pioglitazone（PG）在减少星形胶质病中起着关键作用， TBI中的小胶质细胞激活和炎性体激活。 PG和HMSC处理的组合 不仅减少炎症，而且通过增加表达来改善行为结果 脑衍生的神经营养因子（BDNF）。因为PG不是特定的CCL20抑制剂，并且可以 具有脱离目标的效果，我们已经建立并验证了短发夹RNA的纳米制剂 （shRNA）使用树状聚合物编码CCL20及其接收器CCR6的质粒。组合处理 涉及SHCCL20/SHCCR6（SHCOMBO）和人类MSC（HMSC）显示出显着降低 RTBI小鼠模型中的炎症，BDNF的伴随增加和神经发生。 根据我们的初步数据，我们假设Shcombo DendRiplex（DPX）或/和 HMSC组合方案将通过 减少大脑中神经胶质细胞和星形胶质细胞的激活，并在A上分泌营养因子 延长时期，进而促进损害大脑中的神经元重塑，并提供 持续缓解TBI诱导的病理。提出了三个特定目标来检验这一假设。在 AIM＃1，我们将确定PSHCOMBO-DPX的最佳剂量和治疗窗口 在RTBI小鼠中。在AIM＃2中，我们将研究Shcombo-dpx或/and的短期和长期影响 关于病理生理和行为的HMSC治疗在RTBI小鼠中定义。在AIM＃3中，我们将确定 CCL20在RTBI诱导的发病机理和行为缺陷中的作用机理。 这项高度创新的建议旨在调查Shcombo-DPX是单一代理商还是 结合HMSC将减少急性脑和全身性炎症和行为缺陷， 并计划根据诱导的基因解决效率的作用机理和替代标记 在急性炎症期间。提议的基于理性设计的改善的翻译研究 预计抗炎疗法将增加我们对 用于轻度至中度TBI的治疗，为将来的临床翻译铺平了道路。