Preclinical Validation of Transglutaminase 2 as a Novel Target for Celiac Disease

转谷氨酰胺酶 2 作为乳糜泻新靶点的临床前验证

基本信息

批准号：
8767913
负责人：
CHAITAN KHOSLA
金额：
$ 48.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-10 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8767913
关键词：
Animal Model Animals Autoantibodies Biological Availability Celiac Disease Chemicals Clinical Protocols Data Development Diet Disease Disease Management Dose Drug Kinetics Drug Targeting Engineering Evaluation Gluten Goals HLA-DQ8 antigen In Vitro Inflammatory Interleukin-15 Intestines Knockout Mice Lead Life Lymphocyte Mouse Strains Mus Oral Patients Pharmacodynamics Phenotype Population Control Production Protein Isoforms Rest Role Schedule Series Small Intestines Solubility Specificity T-Cell Activation Testing Transgenic Mice Validation Villous Atrophy analog base clinically relevant drug candidate improved in vivo inhibitor/antagonist intestinal epithelium mouse model novel pre-clinical public health relevance research clinical testing response safety study small molecule therapeutic target transglutaminase 2

Animal Model Animals Autoantibodies Biological Availability Celiac Disease Chemicals Clinical Protocols Data Development Diet Disease Disease Management Dose Drug Kinetics Drug Targeting Engineering Evaluation Gluten Goals HLA-DQ8 antigen In Vitro Inflammatory Interleukin-15 Intestines Knockout Mice Lead Life Lymphocyte Mouse Strains Mus Oral Patients Pharmacodynamics Phenotype Population Control Production Protein Isoforms Rest Role Schedule Series Small Intestines Solubility Specificity T-Cell Activation Testing Transgenic Mice Validation Villous Atrophy analog base clinically relevant drug candidate improved in vivo inhibitor/antagonist intestinal epithelium mouse model novel pre-clinical public health relevance research clinical testing response safety study small molecule therapeutic target transglutaminase 2

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项目摘要

DESCRIPTION (provided by applicant): The overarching goal of the proposed studies is to preclinically validate transglutaminase 2 (TG2) as a drug target for celiac disease (CeD), using the most advanced small molecule leads and the most advanced animal models available to date. CeD is a life-long, gluten-induced inflammatory disorder of the small intestine for which no non-dietary therapy exists to date. Although TG2 is widely regarded as the most attractive small molecule drug target for CeD therapy, definitive support for this pharmacologic hypothesis remains elusive. In preliminary studies, we have studied a class of irreversible TG2 inhibitors based on the mildly electrophilic 3- bromo-4,5-dihydroisoxazole motif, and have identified a lead compound (ERW1041E) with good in vitro and in vivo activity. Importantly, ERW1041E is the only TG2 inhibitor to our knowledge that has been shown to block TG2 in vivo on a once-daily dosing schedule. Separately, by engineering double and triple transgenic mouse strains, we have established an animal model that shows all four hallmarks of CeD: (i) gluten-dependent T cell activation; (ii) gluten-dependent autoantibody production; (iii) gluten-dependent infiltrationof lymphocytes into the intestinal epithelium; and (iv) gluten-dependent villous atrophy. Last but not least, we have demonstrated that oral gluten exposure activates TG2 in the small intestine of this mouse model and can be blocked by our lead compound ERW1041E. Our plans for validation of TG2 as a therapeutic target for CeD are described under two Specific Aims: 1) We will identify improved analogs of ERW1041E through synthesis and in vitro evaluation of two focused compound series. The most promising analogs will be subjected to pharmacokinetic and preliminary toxicological analysis. In particular, we seek to improve the isoform specificity o ERW1041E without sacrificing its potency, tolerability, oral bioavailability, or solubility. 2) To validate TG2 as a CeD drug target, the pharmacodynamic relationship between inhibitor dose and intestinal TG2 activity will be defined for ERW1041E and up to four improved analogs. From this data, sub-maximal and maximal inhibitory doses of each compound will be selected, and used to interrogate the role of TG2 in different clinically relevant scenarios that can be accurately mimicked in our mouse models. Together, these studies will provide clear direction for clinical evaluation of the most promising drug candidate. If the above studies are successful, then the most promising TG2 inhibitor from this project may be a suitable candidate for testing in CeD patients. Notably, recent efforts have led to the development of a short (2-week), small (40-patient) clinical protocol for such proof-of-concept studies. Thus, pending appropriate non-clinical safety studies, a new target for CeD therapy could be clinically validated within the next 5 years.