Novel approaches to develop a treatment for cryptosporidiosis

开发隐孢子虫病治疗方法的新方法

基本信息

批准号：
8605836
负责人：
CHRISTOPHER D HUSTON
金额：
$ 22.88万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605836
关键词：
Accounting Acquired Immunodeficiency Syndrome Address Affect Biological Assay Biological Availability Cells Child Childhood Chronic Clinical Trials Collection Country Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Development Diarrhea Disease Disease Outbreaks Dose Drug Combinations Drug Kinetics Drug usage Economics Enteral Epithelial Cells FDA approved Goals Gold Growth Growth Inhibitors Histopathology Human Immunity Immunocompetent Immunocompromised Host In Vitro Infection Intestines Libraries Maintenance Microbe Modeling Mus Parasites Patients Pharmaceutical Preparations Pharmacodynamics Placebos Preclinical Drug Evaluation Publishing Safety Scheme Small Intestines System Testing Therapeutic Tissues Toxic effect United States Validation antimicrobial base biliary tract clinical efficacy combinatorial cost design drug development effective therapy efficacy trial follow-up high throughput screening in vitro Assay in vivo killings microbial microbicide nitazoxanide novel novel strategies public health relevance safety testing screening success tissue culture waterborne

项目摘要

DESCRIPTION (provided by applicant): Cryptosporidiosis, due to intestinal infection with the intracellular parasites Cryptosporidium parvum or C. hominis, is the leading cause of diarrhea resulting from waterborne outbreaks in the United States, and it is a major cause of pediatric infectious diarrhea in the developing world. The infection is chronic and often fatal for immunocompromised patients, and cryptosporidiosis causes as much as 50% of chronic diarrhea in AIDS patients. Unfortunately, nitazoxanide, the only drug with known efficacy, is only moderately effective for treatment of immunocompetent people, and it is equivalent to placebo in severely immunocompromised people. Cryptosporidiosis predominantly affects people in the developing world, and the high cost of de novo drug development is a major barrier to developing an effective treatment. Using a drug repurposing approach to address this economic barrier, the ultimate goal of this project is to develop an effective therapy for cryptosporidiosis The target product profile requires that the treatment be safe, low in cost, selectively toxic for Cryptosporidium at concentrations relevant within the small intestine and biliary tract, and capable of eliminating the parasite from patients in the absence of effective host immunity. Towards this end, preliminary data are presented documenting: 1) development and validation of a robust, cell-based, high-throughput screening (HTS) assay; 2) identification of FDA-approved drugs with selective anti-Cryptosporidium activity; and 3) an in vitro assay to compare the ability of different treatments to eliminate C. parvum from a cell-based tissue culture system. In aim 1, the abilities of the identified anti-Cryptosporidium drug leads to eliminate C. parvum will be determined in vitro, and then the drug leads will be tested in vivo using a model of cryptosporidiosis in severely immunocompromised mice. Synergistic drug combinations sometimes possess cidal antimicrobial activity (i.e., kill microbes rather than merely inhibit microbial growth) at achievable tissue concentrations despite static activity of each drug used alone, and, in some cases, drug combinations enable successful treatment of immunocompromised patients where either drug alone is ineffective. Therefore, in aim 2, combinatorial drug screens will be undertaken to identify drugs with synergistic anti-Cryptosporidium activity when used with nitazoxanide or the primary screening hits. As proof of concept, a screen was conducted in the presence of a sub-inhibitory concentration of nitazoxanide, which yielded five approved drugs with no anti-cryptosporidial activity when used alone that were strong C. parvum growth inhibitors in combination with low dose nitazoxanide. Synergy of promising drug combinations will be confirmed with checkerboard assays, and the most promising will be followed up in vitro and in vivo as in aim 1. Successful completion of these specific aims will result in identification of at least one FDA-approved drug or a combination of drugs that cures immunocompromised mice infected with C. parvum and is suitable for testing in human clinical trials.

描述（由申请人提供）：隐孢子虫病是由细胞内寄生虫小隐孢子虫或人隐孢子虫的肠道感染引起的，是美国水源性爆发腹泻的主要原因，也是美国小儿感染性腹泻的主要原因。发展中国家。这种感染是慢性的，对于免疫功能低下的患者来说通常是致命的，隐孢子虫病导致 50% 的艾滋病患者慢性腹泻。不幸的是，硝唑尼特作为唯一已知有效的药物，对于免疫功能正常的人的治疗只有中等程度的效果，对于免疫功能严重低下的人来说，它相当于安慰剂。隐孢子虫病主要影响发展中国家的人们，从头药物开发的高成本是开发有效治疗方法的主要障碍。使用药物再利用方法来解决这一经济障碍，该项目的最终目标是开发一种有效的隐孢子虫病治疗方法。目标产品概况要求该治疗方法安全、成本低、在小范围内相关浓度下对隐孢子虫具有选择性毒性。肠道和胆道，并且能够在缺乏有效宿主免疫力的情况下消除患者体内的寄生虫。为此，提供了初步数据，记录了：1）开发和验证了稳健的、基于细胞的高通量筛选（HTS）测定法； 2) 鉴定FDA批准的具有选择性抗隐孢子虫活性的药物； 3) 体外测定，比较不同处理方法从基于细胞的组织培养系统中消除微小念珠菌的能力。在目标 1 中，将在体外测定已鉴定的抗隐孢子虫药物线索消除微小隐孢子虫的能力，然后使用严重免疫功能低下的小鼠的隐孢子虫病模型对药物线索进行体内测试。尽管每种药物单独使用具有静态活性，但协同药物组合有时在可达到的组织浓度下具有杀灭微生物活性（即杀死微生物而不是仅仅抑制微生物生长），并且在某些情况下，药物组合能够成功治疗免疫功能低下患者，其中任一药物均有效单独是无效的。因此，在目标 2 中，将进行组合药物筛选，以确定与硝唑尼特或初步筛选命中药物一起使用时具有协同抗隐孢子虫活性的药物。作为概念证明，在亚抑制浓度的硝唑尼特存在下进行了筛选，产生了五种已批准的药物，单独使用时没有抗隐孢子虫活性，它们是与低剂量硝唑尼特联合使用的强小孢子虫生长抑制剂。有前途的药物组合的协同作用将通过棋盘试验得到证实，最有前途的药物组合将按照目标 1 进行体外和体内随访。成功完成这些具体目标将导致至少一种 FDA 批准的药物或一种药物的鉴定。药物组合可以治愈感染微小念珠菌的免疫功能低下的小鼠，并且适合在人体临床试验中进行测试。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.

来自 Medicines for Malaria Venture 开放式疟疾盒的一种基于哌嗪的新型药物先导物，用于治疗隐孢子虫病。

DOI：
发表时间：
2018-04
期刊：
影响因子：
4.9
作者：
Jumani, R S;Bessoff, K;Love, M S;Miller, P;Stebbins, E E;Teixeira, J E;Campbell, M A;Meyers, M J;Zambriski, J A;Nunez, V;Woods, A K;McNamara, C W;Huston, C D
通讯作者：
Huston, C D

A Proposed Target Product Profile and Developmental Cascade for New Cryptosporidiosis Treatments.

拟议的目标产品概况和新型隐孢子虫病治疗的开发级联。

DOI：
发表时间：
2015-10
期刊：
影响因子：
3.8
作者：
Huston, Christopher D;Spangenberg, Thomas;Burrows, Jeremy;Willis, Paul;Wells, Timothy N C;van Voorhis, Wesley
通讯作者：
van Voorhis, Wesley