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Novel cell therapy for sustained therapeutic protein delivery in vivo

用于体内持续治疗性蛋白质递送的新型细胞疗法

基本信息

批准号：
10011826
负责人：
MATTHEW H WILSON
金额：
$ 41.67万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011826
关键词：
Affect Alpha-galactosidase Anemia Animal Model Animals Antigens Autopsy Biological Models CAR T cell therapy Cell Therapy Cells Chronic Kidney Failure Clinical Data Communication Cytotoxic T-Lymphocytes Development Disease Disease model Engineering Engraftment Enzymes Erythropoietin Fabry Disease Fatty acid glycerol esters Future Gene-Modified Grant Half-Life Heart Diseases Hematocrit procedure Histology Human In Vitro Infusion procedures Kidney Kidney Diseases Knock-out Long-Term Effects Longevity Luciferases Mediating Modeling Morbidity - disease rate Mus Nature Organ Pathway interactions Patients Production Proteins Stroke System Systemic disease T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Tissues Toxic effect Toxicology Transgenic Organisms Translating Vaccination antigen-specific T cells cancer cell cancer therapy chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy cost enzyme replacement therapy experimental study globotriaosylceramide human disease human model in vivo in vivo Model in vivo imaging inducible gene expression innovation mouse model mouse perforin novel novel therapeutics perforin pre-clinical response therapeutic enzyme therapeutic protein vaccination strategy

项目摘要

A cell therapy capable of sustained therapeutic protein delivery in vivo has the potential to benefit both kidney disease and its complications. During our previous grant cycle, we developed and validated technology using transposon-modified antigen specific T cells for therapeutic protein delivery in vivo using erythropoietin (EPO) as a model system. We demonstrated delivery of murine EPO and therapy for anemia of chronic kidney disease in mice as a model system, and we demonstrated inducible human EPO expression from antigen-specific human T cells in vitro. We propose to significantly advance beyond our previous grant by extending our studies to human T cells in an in vivo context and testing an innovative approach to enhance long-term therapeutic enzyme delivery for Fabry disease that results from loss of -galactosidase A (-gal A). -gal A -/- mice represent an animal model of human Fabry disease, which results from lack of an enzyme needed to metabolize fats leading systemic disease including kidney disease. In aim 1, we will test transposon-modified antigen-specific T cells for expression of -gal A in a Fabry disease model. We will extend our mouse studies with EPO to -gal A in a Fabry disease model using antigen-specific mouse T cells and vaccination. We will gene modify human T cells to express a chimeric antigen receptor (CAR) along with luciferase or human -gal A. Cells will be infused into NOD/SCID/Fabry mice to evaluate the ability of engineered antigen-specific human T cells to engraft, respond to vaccination, and short-term expression -gal A in an in vivo model. Although perforin is important in T cells for clearance of malignant cells, the perforin pathway also contributes to clearance of antigen expressing cells post vaccination. In aim 2, we will test perforin knockout in T cells as a way of enhancing long-term therapeutic protein delivery from antigen-specific T cells. We propose to test perforin knockout in the setting of antigen- specific T cells to determine if it will boost long-term persistence of cells delivering therapeutic proteins. In aim 3, we will test transposon-modified antigen-specific T cells for long-term expression of -gal A in a mouse model of Fabry disease. We propose to deliver optimized human CAR-T cells expressing human -gal A in a NOD/SCID/Fabry mouse model. We will evaluate for engraftment, vaccination response, -gal A activity, and globotriaosylceramide levels in tissues. The proposed studies will lead to the development of new cell therapies for kidney disease and its complications and have the potential for therapeutic impact well beyond the kidney.

一种能够在体内持续递送治疗性蛋白质的细胞疗法有可能使双肾受益