A Novel Intervention Strategy for Stroke with RTL Therapy

劳逸结合治疗中风的新型干预策略

• 批准号: 8392585
• 负责人: Nabil J Alkayed
• 金额: $ 68.16万
• 依托单位: VIROGENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392585
• 关键词: Aftercare; Age-Months; Alleles; Alteplase; Brain; Brain Injuries; Cause of Death; Cells; Cerebral Ischemia; Clinical Trials; Cognitive deficits; Coupled; Data; Experimental Models; HLA-DR2 Antigen; Hour; Human; Immune; Immune response; Immune system; Immunosuppression; Immunotherapy; Infarction; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Ischemia; Ischemic Stroke; Left; Legal patent; Licensing; Ligands; MHC Class II Genes; Measurement; Middle Cerebral Artery Occlusion; Multiple Sclerosis; Mus; Myelin; Neurocognitive Deficit; Organ; Outcome; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Recombinants; Safety; Small Business Technology Transfer Research; Stroke; Systemic disease; T-Cell Immunologic Specificity; T-Cell Receptor; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Translating; United States; Wild Type Mouse; age effect; aged; base; central nervous system injury; design; disability; effective therapy; functional disability; improved; injured; middle age; mouse model; novel; novel strategies; novel therapeutic intervention; pre-clinical; receptor; research clinical testing; selective expression

DESCRIPTION (provided by applicant): This application is a Phase II STTR to further the study of a novel therapeutic intervention for ischemic stroke. Phase I investigated the mechanism of protection against ischemic stroke provided by the novel "designer" therapy, recombinant T cell receptor ligand (RTL), a selective modulator of the inflammatory function of myelin- reactive T cell specificities. Our findings suggest that RTL protects against ischemia-induced brain injury only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient. We demonstrate that RTL containing mouse MHC coupled to mouse myelin peptide is effective in reducing ischemic damage in mice (RTL551). Similarly, RTL1000 is a human MHC coupled to a human myelin peptide. RTL1000 is not effective in wild-type mice, but provides significant protection in 'humanized' HLA-DR2 mice that selectively express only this human MHC class II allele. As such, this treatment represents a new therapy targeting inflammatory immune cell populations specifically triggered by brain injury. This post-ischemic therapeutic approach is promising because it specifically suppresses brain targeted immune responses while leaving other portions of the immune system intact. The inflammatory response after ischemia in the brain has been studied extensively and modulation of this inflammatory response (immunotherapy) improves outcome in experimental models. However, these therapies have not translated successfully to patients in clinical trials. There is now support for the idea that stroke is a multi-organ systemic disease with interactions between the peripheral immune system and the injured and recovering brain. Many patients who survive the initial injury to the brain suffer CIDS, CNS injury-induced immunosuppression, resulting in fatal infection. Therefore, immunotherapy targeted towards minimizing brain damage following ischemia must minimize CNS inflammation while at the same time not exacerbating CIDS. This is a significant hurdle that our group is well poised to study. Our group has pioneered the study of cerebral ischemia-induced changes to peripheral immune organs using the middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke. This application will test three specific hypotheses 1) that RTL1000 has an extended therapeutic window and 2) that RTL1000 retains its protective potential in middle aged and old aged mice. Finally, 3) that RTL1000 is an effective therapy when combined with tissue plasminogen activator (tPA). Successful completion of the current proposal will determine the efficacy of RTL1000 in treatment of ischemic stroke, and its ability to be used in combination with tPA, ultimately providing a roadmap for designing pilot clinical trials. Upon completion of this Phase II STTR proposal, in partnership with Virogenomics, we will proceed to a Phase I safety trial in Stroke patients. PUBLIC HEALTH RELEVANCE: Stroke is one of the leading causes of death and the leading cause of disability in the United States. Unfortunately, there is currently only a single drug available to improve outcome following ischemic stroke, tissue plasminogen activator (tPA), with a limited therapeutic window of >4.5 hrs. The proposed studies will demonstrate the efficacy of RTL1000 in treatment of ischemic stroke, and its ability to be used in combination with tPA.

描述（由申请人提供）：此应用是II期STTR，可以进一步研究新型缺血性中风的治疗干预措施。第一阶段调查了针对新型“设计师”疗法，重组T细胞受体配体（RTL）提供的缺血性中风的机理，这是髓鞘反应性T细胞特异性的炎症功能的选择性调节剂。我们的发现表明，仅当RTL含有神经抗原肽和受体的II类MHC部分时，RTL才能预防缺血引起的脑损伤。我们证明，含有与小鼠髓磷脂肽偶联的小鼠MHC的RTL可有效减少小鼠的缺血性损伤（RTL551）。同样，RTL1000是与人髓磷脂肽结合的人类MHC。 RTL1000在野生型小鼠中无效，但在“人性化” HLA-DR2小鼠中提供了重要的保护，该小鼠仅有选择地表达该人类MHC II类等位基因。因此，这种治疗方法代表了一种针对脑损伤特异性触发的炎症性免疫细胞群体的新疗法。这种缺血后的治疗方法是有希望的，因为它专门抑制了大脑靶向的免疫反应，同时使免疫系统的其他部分完好无损。已经对脑缺血后的炎症反应进行了广泛的研究，对这种炎症反应（免疫疗法）的调节可改善实验模型的预后。但是，这些疗法尚未成功地转化为临床试验中的患者。现在有支持，即中风是一种多器官全身性疾病，在周围免疫系统与受伤和恢复大脑之间的相互作用。许多在最初对大脑受伤的患者患有CID，中枢神经系统损伤引起的免疫抑制，导致致命感染。因此，缺血后，旨在最大程度地减少脑损伤的免疫疗法必须最大程度地减少CNS炎症，同时又不加剧CID。这是我们小组准备学习的重大障碍。我们的小组率先研究了脑缺血诱导的缺血性中风中部动脉闭塞（MCAO）小鼠模型的外周免疫器官的变化。该应用程序将测试三个特定的假设1）RTL1000具有扩展的治疗窗口和2）RTL1000保留其在中年和旧老年小鼠中的保护潜力。最后，3）当与组织纤溶酶原激活剂（TPA）结合使用时，RTL1000是一种有效的疗法。当前建议的成功完成将确定RTL1000治疗缺血性中风的功效，以及与TPA结合使用的能力，最终为设计试验临床试验提供了路线图。在完成此II期STTR提案后，与病毒组学合作，我们将继续进行中风患者的I期安全试验。 公共卫生相关性：中风是美国的主要原因之一，是美国残疾的主要原因。不幸的是，目前只有一种药物可在缺血性中风，组织纤溶酶原激活剂（TPA）后改善预后，其治疗窗口> 4.5小时。拟议的研究将证明RTL1000治疗缺血性中风的功效，以及与TPA结合使用的能力。