Engineering smart cells for arthritis therapy

工程智能细胞用于关节炎治疗

• 批准号: 9912537
• 负责人: Farshid Guilak
• 金额: $ 39.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912537
• 关键词: Acute; Adverse event; Anti-Cytokine Therapy; Anti-inflammatory; Apoptosis; Autoimmune Diseases; Biological; Biological Response Modifier Therapy; Biology; Biomedical Engineering; CRISPR/Cas technology; Cartilage; Cell Differentiation process; Cell Therapy; Cell physiology; Cells; Chronic; Chronic Disease; Clinical; Complex; Computer Analysis; Cues; Custom; Decision Making; Development; Disease; Dose; Drug Delivery Systems; Encapsulated; Engineering; Environment; Exhibits; Feedback; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Engineering; Genome engineering; Goals; Growth Factor; IL6ST gene; Implant; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Arthritis; Injections; Interleukin-1; Interleukin-6; Logic; Measures; Modeling; Musculoskeletal; Pain; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pluripotent Stem Cells; Predisposition; Process; Production; Receptor Gene; Regenerative Medicine; Rheumatoid Arthritis; Risk; Sepharose; Signal Transduction; Stem cells; Stimulus; Suicide; Swelling; Synthetic Genes; System; TNF gene; TNFRSF1A gene; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissue Therapy; Tissues; Translations; Work; advanced system; anakinra; arthritis therapy; base; bone erosion; cancer type; clinical translation; cytokine; design; disability; gene therapy; genome editing; implantation; in vivo; in vivo evaluation; induced pluripotent stem cell; inhibitor/antagonist; innovation; joint destruction; mouse model; next generation; personalized medicine; response; safety engineering; scaffold; stem cell biology; success; synthetic biology; technology development; tool

Abstract The primary aim of this project will be to apply recent development of genome editing technologies to generate a highly advanced “smart” tissue-engineered construct featuring cell-based, feedback control of gene expression as a means of autoregulated drug or growth factor delivery. An important advance of this system is that cells will be programmed to automatically regulate their activity in response to environmental signals. To engineer this regulatory system, the gene regulation circuitry of stem cells (iPSCs) will be rewired to form controlled feedback loops that are activated by external stimuli, but then induce a controlled and autoregulated response. These cells will be used to form tissue-engineered constructs for in vitro and in vivo testing. The initial focus of the project will be on the creation of designer stem cells that contain artificial gene circuits that provide anti-inflammatory drug delivery in response to the environment. These cells will be engineered into stable cartilage constructs that will be implanted as a therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis. The creation of “smart” cells that provide automated, long-term, feedback-controlled drug therapy represents a transformative paradigm for regenerative medicine and arthritis therapy.

摘要 该项目的主要目的是应用基因组编辑技术的最新发展， 一种高度先进的“智能”组织工程构建体，具有基于细胞的基因反馈控制功能， 表达作为自动调节药物或生长因子递送的手段。该系统的一个重要进步是 细胞将被编程以自动调节其活动以响应环境信号。到 工程师这个调控系统，干细胞（iPSC）的基因调控电路将重新连接，形成 受控反馈回路由外部刺激激活，但随后诱导受控和自动调节 反应这些细胞将用于形成用于体外和体内测试的组织工程构建体。的 该项目最初的重点将是创造含有人工基因电路的设计干细胞， 响应环境提供抗炎药物递送。这些细胞将被改造成 将作为治疗方法植入用于治疗自身免疫性关节炎的稳定的软骨构建体， 类风湿性关节炎等疾病。创造“智能”细胞，提供自动化，长期， 反馈控制的药物治疗代表了再生医学和关节炎的一个变革性范例 疗法