Development of Aptamer-Based Therapy Against HUS

基于适体的 HUS 疗法的开发

基本信息

批准号：
7929518
负责人：
SAUL r TZIPORI
金额：
$ 66.47万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929518
关键词：
Acute Adverse effects Affinity Animals Antibiotics Aptamer Technology Binding Biochemical Biological Assay Bioterrorism Blood Circulation Categories Cells Child Childhood Clinical Complication DNA Development Dialysis procedure Diarrhea Disease Disease Outbreaks Dose Drug Kinetics Drug toxicity Elderly Enzyme-Linked Immunosorbent Assay Escherichia coli Escherichia coli EHEC Escherichia coli O157 Evaluation Event Generations Gnotobiotic Goals Half-Life Hela Cells Hemolytic-Uremic Syndrome Human Immunoglobulin Variable Region In Vitro Infection Instruction Intensive Care Intoxication Kidney Lead Life Measures Modeling Morbidity - disease rate Mus Mutagenesis Oligonucleotides Oliguria Oral Pallor Penetration Polymers Prevention Protein Biosynthesis Protein Synthesis Inhibition Receptor Cell Screening procedure Serotyping Serum Shiga Toxin Spinach - dietary Systemic disease Systemic infection Testing Therapeutic Therapeutic Agents Tissues Toxic effect Toxin Variant Virulence Vulnerable Populations adverse outcome aptamer base cytotoxicity design foodborne foodborne illness foot improved in vitro Assay in vivo molecular size mortality pathogen preclinical evaluation prevent protective efficacy response therapy development uptake waterborne

项目摘要

DESCRIPTION (provided by applicant): This proposal is submitted in response to RFA-AI-08-001. Our proposal targets the development of therapy against hemolytic uremic syndrome (HUS) caused by Shiga toxin (Stx)-producing E. coli (STEC). STEC strains are serious Category B pathogens associated primarily with food and waterborne acquired disease. They represent an important global emerging infection with relevance to foodborne illness and potential bioterrorism. The virulence of STEC is underscored by the very low infectious dose required to produce clinical disease. The treatment of STEC infection is complicated by potentially adverse consequences of routine administration of antibiotics. Diarrhea-associated (HUS) is a life-threatening complication of STEC infection, primarily the O157:H7 serotype, in children and the elderly that is heralded by the sudden onset of pallor and oliguria. It is associated with significant morbidity and, despite improvements in pediatric intensive care; the mortality rate from this disease remains 3-5%. There is no proven therapy for HUS that reduces mortality, the need for acute dialysis, or the occurrence of serious extra-renal events. The recent outbreaks, the spinach outbreak in particular, showed how vulnerable the population is to accidental contamination, and how urgently protective or therapeutic measure are needed. In this application we propose to use the newly developed aptamer technology which has gained foot as potential therapeutic agents in several systemic diseases in humans. In this application two teams have come together to achieve the goals of this application. They include a team with expertise in the design, synthesis and application of aptamer technology, and a team with expertise on STEC disease and the development screening and in vitro and in vivo evaluation of therapeutic agents against HUS. Consequently: Specific Aim 1 focuses on the design, synthesis and optimization of aptamers, Specific Aim 2 will apply ELISA and cell-based assays for screening of aptamers. Specific Aim 3 will evaluate in the mouse toxicity model selected aptamers generated from the cell based screening, including drug toxicity and pharmacokinetics, while Specific Aim 4 will perform preclinical evaluation and pharmacokinetics in the well-established piglet model of E. co//O157:H7 infection/systemic intoxication model. RELEVANCE (See instructions): Infection of children with Shiga toxin (Stx) producing Escherichia coli (STEC), primarily a food and waterborne acquired disease, is the leading cause of hemolytic-uremic syndrome (HUS) in the US. There is no specific treatment to prevent or ameliorate HUS. In this proposal, we propose to develop aptamer-based therapeutic agents for prevention or treatment of HUS.

描述（由申请人提供）：该提案是针对RFA-AI-08-001提交的。我们的提议针对的是针对由Shiga毒素（STX）引起的溶血性尿毒症综合征（HUS）的疗法的发展。 STEC菌株是严重的B类病原体，主要与食物和水生成的疾病相关。它们代表着与食源性疾病和潜在生物恐怖主义有关的重要全球新兴感染。 STEC的毒力由产生临床疾病所需的非常低的感染剂量强调。常规抗生素给药的潜在不利后果使STEC感染的治疗变得复杂。腹泻相关（HUS）是STEC感染的一种威胁生命的并发症，主要是O157：H7血清型，在儿童和老年人中因苍白和寡头突然发作而预示着。它与大量发病率有关，尽管小儿重症监护术改善；该疾病的死亡率仍然是3-5％。没有可靠的HUS疗法可以降低死亡率，急性透析或严重的肾上腺外事件的发生。最近的爆发尤其是菠菜爆发，表明人口对偶然污染的脆弱性以及如何紧急保护性或治疗方法。在此应用程序中，我们建议使用新开发的适应性技术，该技术已成为人类几种全身性疾病的潜在治疗剂。在此应用程序中，两个团队聚集在一起，以实现该应用程序的目标。它们包括一个在适体技术的设计，合成和应用方面具有专业知识的团队，以及一支在STEC疾病和开发筛查以及对HUS治疗剂的体外和体外评估方面具有专业知识的团队。因此：特定目标1专注于适体的设计，合成和优化，特定的目标2将应用ELISA和基于细胞的测定法以筛选适体。特定的目标3将在小鼠毒性模型中评估从基于细胞的筛选（包括药物毒性和药代动力学）中产生的适合学剂，而特定的AIM 4将在E. CO // O157的E. CO // O157：piplinical IAM 4中进行临床前评估和药代动力学。 H7感染/全身中毒模型。相关性（请参见说明）：产生大肠杆菌（STEC）的志贺毒素（STX）的感染，主要是一种食物和水生成的疾病，是美国溶血性尿毒症综合征（HUS）的主要原因。没有特定的治疗方法可以预防或改善HUS。在此提案中，我们建议开发基于适体的治疗剂来预防或治疗HUS。