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.

源自患者的调节性 T (Treg) 细胞的离体工程有望成为一种安全有效的方法尽管临床前研究有希望，但仍需要大量的生物学和技术研究。在实现这一治疗策略之前，必须解决一些障碍。首先，必须对 Treg 细胞进行改造。最佳地增强其特异性、稳定性和功能性。其次，可扩展性问题——或生成。必须克服来自患者的离体工程细胞产量不足以构成治疗剂量的问题。 Indee. Inc. 正在通过其 Hydropore™ 平台解决所有这些挑战。发生的流体动力学现象——涡流脱落——使 Treg 细胞工程能够增强与使用基于病毒的当前黄金标准相比，在更短的时间内解决了稳定性、功能性和可扩展性问题方法和 HydroporeTM 最终产生更有效的工程 T 细胞，如 Tregs。在此提案中，Indee Inc. 将展示 Hydropore™ 在未来工程中的技术性能。用于 T1D 的嵌合抗原受体调节性 T 细胞 (CAR-Treg) 的产生也将重点关注。证明使用 HydroporeTM 工程设计的 CAR-Treg 具有卓越的体外和体内生物活性相对于那些使用传统方法设计的项目，在成功完成这些目标之前， CAR-Tregs 将使用从 T1D 患者分离的 Treg 细胞进行工程设计，并证明临床和商业规模的加工和富集足够的 CAR-Treg 细胞用于人体试验。