Rapid, single-step precision engineering and pre-clinical evaluation of chimeric antigen receptor Regulatory T cells for Type 1 diabetes

嵌合抗原受体调节性 T 细胞治疗 1 型糖尿病的快速、单步精密工程和临床前评估

基本信息

批准号：
10477106
负责人：
Ryan Pawell
金额：
$ 30.96万
依托单位：
INDEE, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477106
关键词：
Address Adoption Advanced Development Animal Model Antigens Biological CD3 Antigens CRISPR/Cas technology Cell Survival Cell Therapy Cell membrane Cell physiology Cells Clinical Complex Consumption Cyclic GMP Data Diabetes Mellitus Diet Dose Economic Burden Electroporation Engineering Evaluation Studies FOXP3 gene Genes Genetic Glycemic Index Gold HLA-A2 Antigen Healthcare Human Immune In Vitro Injections Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Kidney Legal patent Lipid Bilayers Liquid substance Luciferases Measurement Measures Mediating Medical Methods Microfluidics Patients Performance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Population Process Proteins Protocols documentation Regulatory T-Lymphocyte Ribonucleoproteins Right kidney Safety South Carolina Specificity Spleen T cell therapy T-Cell Development T-Cell Proliferation T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Technology Therapeutic Time Transfection Treg therapy Universities Viral Virus adeno-associated viral vector base capsule cellular engineering chimeric antigen receptor chimeric antigen receptor T cells cost efficient diabetes mellitus therapy effector T cell engineered T cells improved in vivo islet meetings mouse model next generation novel nucleic acid delivery peer phase 2 study pre-clinical preclinical evaluation preclinical study prevent professor success trafficking

项目摘要

Ex vivo engineering of patient-derived regulatory T (Treg) cells holds promise as a safe and effective approach for treating type 1 diabetes (T1D). Despite promising preclinical studies, considerable biological and technical hurdles must be addressed before this therapeutic strategy can be realized. First, Treg cells must be engineered to optimally enhance their specificity, stability, and functionality. Second, scalability issues – or generating sufficient yield of patient-derived, ex vivo engineered cells to constitute a therapeutic dose – must be overcome. Indee. Inc. is addressing all of these challenges with their Hydropore™ platform. Hydropore™ uses a naturally occurring fluid dynamics phenomenon – vortex shedding – to enable Treg cell engineering that enhances the stability, functionality, and scalability issues in less time than the current gold standards that use virus-based methods and electroporation. HydroporeTM ultimately results in more effective engineered T cells such as Tregs. In this proposal, Indee. Inc. will demonstrate the technical performance of Hydropore™ in engineering the next generation of chimeric antigen receptor regulatory T cells (CAR-Tregs) for T1D. Studies will also focus on demonstrating the superior in vitro and in vivo biological activity of CAR-Tregs engineered using HydroporeTM relative to those engineered using traditional methods. Pending the successful completion of these objectives, CAR-Tregs will be engineered using Treg cells isolated from T1D patients and demonstrate clinical- and commercial-scale processing and enrichment of sufficient CAR-Tregs cells for human trials.

患者衍生的调节t（Treg）细胞的体内工程有望成为一种安全有效的方法用于治疗1型糖尿病（T1D）。尽管有希望的临床前研究，但大量的生物学和技术在实现这种理论策略之前，必须解决障碍。首先，必须设计Treg单元格最佳增强其特异性，稳定性和功能。其次，可伸缩性问题或生成必须克服构成治疗剂量的患者衍生的，离体工程细胞的足够产率 - 必须克服。 Indee。 Inc.通过其Hydropore™平台解决所有这些挑战。 Hydropore™自然使用发生的流体动力学现象 - 涡流脱落 - 使Treg细胞工程能够增强稳定性，功能和可伸缩性问题比当前使用基于病毒的黄金标准的时间少方法和电穿孔。 HydroPoretm最终导致更有效的工程T细胞（例如Tregs）。在此提案中，Indee。 Inc.将展示下一个工程中Hydropore™的技术性能 T1D的嵌合抗原受体调节T细胞（CAR-Tregs）的生成。研究也将关注展示了使用Hydroporetm设计的CAR-Treg的优质体外和体内生物学活性相对于使用传统方法设计的那些。等待这些目标的成功完成， Car-Treg将使用从T1D患者分离的Treg细胞进行设计，并证明临床和用于人类试验的足够的CAR-Tregs细胞的商业规模加工和富集。