Synthetic Chronogenetic Gene Circuits for Circadian Cell Therapies

用于昼夜节律细胞疗法的合成计时基因电路

基本信息

批准号：
10797183
负责人：
Farshid Guilak
金额：
$ 37.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-09-19
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10797183
关键词：
ARNTL gene Adverse effects Adverse event Affect Anti-Cytokine Therapy Autoimmune Diseases Basic Science Behavior Behavioral Biological Biological Products Cartilage Cell Therapy Cells Chondrocytes Chronotherapy Clinical Cues Custom Data Development Disease Disease model Dose Drug Controls Drug Delivery Systems Effectiveness Elements Engineering Exhibits Flare Frequencies General Population Genes Genetic Goals Histologic Hydrogels Implant In Vitro Infection Inflammation Inflammatory Injectable Injections Interleukin-1 Interleukin-6 K/BxN model Libraries Logic Luciferases Medicine Methods Modeling Molecular Mus Output Pain Patients Periodicity Pharmaceutical Preparations Phase Predisposition Process Reporter Research Rheumatoid Arthritis Risk Serum Severity of illness Symptoms Synthetic Genes System TNF gene TNFR-Fc fusion protein TNFRSF1A gene Testing Therapeutic Time Tissue Engineering Tissues Treatment Efficacy anakinra behavior test cancer type cartilage implant cellular engineering chronic inflammatory disease circadian circadian biology circadian pacemaker clinical practice cytokine design efficacy testing gene network improved in vivo in vivo evaluation induced pluripotent stem cell inhibitor mouse model novel programs promoter risk/benefit ratio stem cells synthetic biology therapy outcome

项目摘要

Abstract The goal of this project will be to combine principles of synthetic biology, tissue engineering, and circadian biology to generate living stem cell-based implants that can deliver biologic drugs in a prescribed circadian manner for the treatment of a wide range of disease processes that exhibit diurnal rhythmicity. To engineer this regulatory system, the core clock gene circuitry of murine induced pluripotent stem cells (iPSCs) will be engineered to synthesize anti-cytokine biologic drugs. These cells will be used to form tissue-engineered constructs for in vitro and in vivo testing. The first aim of this project will focus on the creation of synthetic “chronogenetic” gene circuits with prescribed frequency, phase, and amplitude of biologic drug delivery. More specifically, cells will be designed to synthesize inhibitors of either interleukin 1 or tumor necrosis factor alpha. These cells will be engineered into stable cartilage constructs in injectable hydrogel carriers that will be tested as a therapeutic approach for the treatment of experimental rheumatoid arthritis (RA) in two different mouse models of this disease. RA is an inflammatory disease that affects approximately 1% of the general population. Several anti-cytokine biologics are currently in clinical use; however, the continuous administration of these therapeutics at high level can lead to significant adverse effects. We posit that drug delivery that aligns with the circadian rhythmicity of peak inflammatory cytokine release will have significantly improved effectiveness. The efficacy of these approaches will be assessed using clinical, histologic, molecular, and pain/behavior testing. The creation of such synthetic chronogenetic systems cells provides the possibility for long-term “chronotherapy”, or timed drug delivery for the treatment of many chronic inflammatory diseases beyond RA.

抽象的该项目的目的是结合合成生物学，组织工程和昼夜节律原则生成活干细胞的生物学，可以在规定的昼夜节律中输送生物药物治疗暴露于昼夜节奏的广泛疾病过程的方式。到工程师这种调节系统，鼠诱导的多能干细胞（IPSC）的核心时钟基因电路将是设计为合成抗周期动物生物学药物。这些细胞将用于形成组织工程的体外和体内测试的构建体。该项目的第一个目的将集中于合成的创建具有规定的生物药物递送的频率，相位和放大器的“年代发育”基因回路。更具体地说，细胞将被设计为合成白介素1或肿瘤坏死因子的抑制剂阿尔法。这些细胞将在可注射水凝胶载体中设计成稳定的软骨构建体作为一种治疗实验性类风湿关节炎（RA）的治疗方法测试该疾病的小鼠模型。 RA是一种炎症性疾病，大约影响一般的1％人口。目前正在临床用途中，几种抗周期生物制剂正在使用。但是，连续高水平的这些治疗剂的给药会导致重大的不良影响。我们肯定该药物与峰值炎症细胞因子释放的昼夜节律有一致的交付将显着提高有效性。这些方法的效率将使用临床，组织学评估分子和疼痛/行为测试。这种合成的年代发育系统细胞的创建提供了长期“年级疗法”或定时提供许多慢性药物的可能性 RA以外的炎症性疾病。