Development and Treatment of Pre-Clinical EHEC Models with HUS

描述（由申请人提供）：肠出血性产志贺毒素大肠杆菌（EHEC）细菌是NIAID生物防御优先级B病原体和全球健康问题。大肠杆菌O157:H7是最常见的菌株，是最近在汉堡、菠菜、豆芽和其他食品中引起多州和多国疫情的污染物。美国的负担是每年约17.6万例感染（全球估计为1.5亿例），发病率很高，特别是幼儿和老年人的急性肾损伤。出血性结肠炎通常会消退，但一些患者会发展为潜在致命的溶血性尿毒症综合征（HUS），以及神经系统、肺部和心脏并发症。25-36%的腹泻相关溶血性尿毒综合征患者存在长期肾脏后遗症。细菌毒素（Stx1,Stx2）会导致器官损伤，但由于缺乏概括人类症状的动物模型，缺乏中和细胞内毒素的药物，以及缺乏预测溶血性尿毒综合征风险或报告早期肾损伤的生物标志物，阻碍了药物的开发，目前还没有毒素特异性治疗方法。我们已经开发出了唯一一种能够产生stx诱导的溶血性尿毒综合征的动物模型。使用救援方案，我们将使用这些模型来测试假设，即靶向血液中的毒素和已经在细胞内的辅助治疗可以预防或减轻Stx诱导的溶血性尿毒综合征的发展，并且Stx诱导的生物标志物可以报告器官损伤以识别那些高风险的溶血性尿毒综合征。我们预测，靶向一个或两个隔室的毒素将减少急性肾损伤并将疾病严重程度降至最低。细胞内毒素将使用定制设计的细胞可渗透肽（Aim1）靶向，血管内毒素将使用获得专利的人源化抗stx2单克隆抗体（Aim2）靶向。研究的目的是在保持疗效的同时最大限度地延迟给药。新的和已建立的生物标志物将与实验临床结果相关联，以识别早期和持续报告的分子

DESCRIPTION (provided by applicant): Enterohemorrhagic Shiga toxin-producing E. Coli (EHEC) bacteria are NIAID Biodefense Priority B pathogens and a global health problem. The E. Coli O157:H7 strain is most common and is a recent contaminant of hamburger, spinach, bean sprouts and other foods causing multi-state and multi-country outbreaks. The US burden is ~176,000 infections annually (est. 150 million globally) with significant morbidity, particularl acute kidney injury in young children and the elderly. The hemorrhagic colitis usually resolves, but some patients progress to potentially lethal hemolytic uremic syndrome (HUS), as well as neurologic, pulmonary and cardiac complications. Long-term renal sequelae occur in 25-36% of patients who survive diarrhea- associated HUS. Bacterial toxins (Stx1,Stx2) drive organ damage, yet toxin-specific therapeutics are not available because drug development is hindered by lack of animal models that recapitulate human symptoms, lack of drugs that neutralize toxin within cells, and lack of biomarkers that predict HUS risk or report early renal injury. We have developed the only animal models that develop Stx-induced HUS. Using Rescue Protocols, we will use these models to test the hypothesis that targeting the toxins in the blood and already within cells with adjunctive therapeutics will prevent or mitigate development of Stx-induced HUS, and that Stx- induced biomarkers can report organ injury to identify those at high risk for HUS. We predict that targeting toxins in one or both compartments will reduce acute kidney injury and minimize disease severity. Intracellular toxins will be targeted with custom designed cell permeable peptides (Aim1) and intravascular toxin will be targeted with a patented humanized anti-Stx2 monoclonal antibody (Aim2). Studies are designed to maximize delayed administration of drug while maintaining efficacy. New and established biomarkers will be correlated with experimental clinical results to identify molecules that report early and sustained kidney injury, and HUS risk. Our combination of clinically relevant animal models with systemic and intracellular toxin targeting compounds is a powerful approach to move the field forward toward targeted patient treatment.