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A non-viral gene editing platform for cell therapies and translational autoimmune disease modeling

用于细胞治疗和转化自身免疫性疾病建模的非病毒基因编辑平台

基本信息

批准号：
10376165
负责人：
Wesley Wierson
金额：
$ 33.74万
依托单位：
LIFENGINE ANIMAL HEALTH LABORATORIES INCORPORATED
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：
2022-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376165
关键词：
Address Advanced Development Allogenic Autoimmune Diseases Autologous B-Lymphocytes Base Pairing Binding Proteins Biological Models CD19 gene Canis familiaris Cell Therapy Cells Clinical Communities DNA DNA Repair DNA Repair Pathway Data Development Disease Disease model Engineering Failure Family suidae Frequencies Future Gene Delivery Genes Genetic Heterogeneity Goals Homologous Gene Homologous Transplantation Human Human Engineering In Vitro Insertional Mutagenesis K562 Cells Knock-in Knock-out Mediating Meiotic Recombination Messenger RNA Methods Modeling Mus Peripheral Blood Mononuclear Cell Phase Phenotype Plasmids Polymerase Population Production Proteins Reagent Reproducibility Resolution Retinoblastoma Site Southern Blotting T cell therapy T-Cell Receptor T-Lymphocyte Technology Therapeutic Time Transgenes Viral Work Zebrafish base cell type cellular engineering chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy cost cytotoxicity delivery vehicle engineered T cells gene function genome editing graft vs host disease human disease improved in vivo innovation novel nuclease overexpression prevent programs quantum repaired standard of care therapy outcome

项目摘要

SUMMARY Gene edited T lymphocytes hold promise as safe and effective living therapies for a wide range of human diseases, including autoimmune disease. However, viral methods currently employed to engineer cells for therapy are imprecise, exorbitantly expensive, and have high failure rates. These drawbacks limit development of cell therapies and prevent them from penetrating alternative markets, where natural, spontaneous disease can be addressed in pre-IND and IND-enabling studies to improve therapeutic outcomes. This proposal is focused on optimizing and advancing the development of a novel, non-viral method for highly efficient and precise engineering of human T cells. The innovation is a nanoplasmid-based, site-specific gene editing platform that enables tunable manufacturing of human cell therapeutics. Not only will this precise gene editing platform yield a quantum leap forward in cellular engineering, but the resultant product will also provide sustained clinical improvements over the standard of care for B cell–mediated autoimmune diseases, for which no current cell therapies exist. This Phase I proposal is focused on optimizing the efficiency of the GeneWeld site-specific gene editing platform and demonstrating the in vitro functionality of using GeneWeld to reprogram human Chimeric Antigen Receptor (CAR)-T cells for elimination of a targeted B cell population.

摘要基因编辑的T淋巴细胞有望成为广泛的人类安全有效的生活疗法疾病，包括自身免疫性疾病。然而，目前用于工程细胞的病毒方法治疗不精确，费用过高，失败率很高。这些缺点限制了发展并防止它们渗透到替代市场，在这些市场中，自然的、自发的疾病可以在IND前和IND使能研究中解决，以改善治疗结果。这项建议的重点是优化和推动一种新的、非病毒的方法的开发，以高度高效而精确的人类T细胞工程。这一创新是一种基于纳米质粒的、位置特异的基因编辑平台，支持人体细胞疗法的可调制造。不仅这种精确的基因编辑平台在细胞工程方面产生了巨大的飞跃，但由此产生的产品也将提供持续改善B细胞介导性自身免疫性疾病的护理标准目前还不存在细胞疗法。此第一阶段提案的重点是优化GeneWeld的效率位点特异性基因编辑平台和使用GeneWeld重新编程的体外功能演示人类嵌合抗原受体(CAR)-T细胞用于消除靶向B细胞群。