Development and Treatment of Pre-Clinical EHEC Models with HUS

HUS 临床前 EHEC 模型的开发和治疗

• 批准号: 8889621
• 负责人: Shinichiro Kurosawa
• 金额: $ 40.93万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889621
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Anemia; Animal Model; Animals; Antibiotics; Antibodies; Bacteria; Bacterial Toxins; Biological Markers; Blood; Blood Circulation; Cardiac; Cells; Child; Clinical; Country; Critical Care; Custom; Cytoplasm; Data; Degradation Pathway; Development; Diarrhea; Disease Outbreaks; Dose; Eating; Elderly; Escherichia coli; Escherichia coli EHEC; Escherichia coli O157; Food; Funding; Goals; HMGB1 gene; Half-Life; Health; Heart; Hemolytic-Uremic Syndrome; Hemorrhagic colitis; Hour; Human; Infection; Injury; Intestines; Kidney; Legal patent; Lung; Mitochondrial DNA; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Neurologic; Organ; Outcome; Pain; Papio; Patients; Pattern; Peptides; Pharmaceutical Preparations; Protocols documentation; Relative (related person); Renal function; Reporting; Research Design; Risk; Septic Toxemia; Serotyping; Severities; Severity of illness; Spinach - dietary; Symptoms; Targeted Toxins; Testing; Therapeutic; Thrombocytopenia; Tissues; Toxin; Urine; Virulence Factors; base; bean; biodefense; cell injury; clinically relevant; cost; design; drug development; experience; foodborne illness; global health; high risk; infectious disease model; nonhuman primate; pathogen; phase I trial; pre-clinical; prevent; synthetic peptide; therapy development; treatment strategy

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.

描述(申请人提供)：肠出血性志贺毒素产毒大肠杆菌(EHEC)是NIAID生物防御优先B级病原体，是一个全球性的健康问题。E.Coli O157：H7菌株是最常见的，是最近汉堡、菠菜、豆芽和其他食品的污染物，导致多个州和多个国家爆发疫情。美国的负担是每年约176,000例感染(估计。全球有1.5亿人)，发病率很高，尤其是幼儿和老年人的急性肾损伤。出血性结肠炎通常会消失，但一些患者会进展为潜在的致命性溶血性尿毒症综合征(HUS)，以及神经、肺和心脏并发症。长期肾脏后遗症发生在25%-36%的腹泻相关HUS患者中。细菌毒素(STX1，STX2)可导致器官损伤，但毒素特异性治疗方法尚不可用，因为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HUS风险或报告早期肾脏损伤的生物标志物，阻碍了药物开发。我们已经建立了唯一的发生STX诱导的HUS的动物模型。使用救援方案，我们将使用这些模型来测试这样的假设，即通过辅助治疗针对血液中和已经在细胞内的毒素可以防止或缓解STX诱导的HUS的发展，并且STX诱导的生物标记物可以报告器官损伤以识别HUS的高危人群。我们预测，将毒素定位于一个或两个腔室将减少急性肾脏损伤，并将疾病严重程度降至最低。细胞内毒素将以定制设计的细胞通透性多肽(Aim1)为靶标，血管内毒素将以获得专利的人源化抗Stx2单抗(AIM2)为靶标。研究旨在最大限度地延迟给药，同时保持疗效。新的和已建立的生物标记物将与实验临床结果相关联，以识别报告早期和持续的分子。 肾脏损伤和HUS风险。我们将临床相关的动物模型与全身和细胞内毒素靶向化合物相结合，是将该领域向前推进到有针对性的患者治疗的有效方法。