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.

抽象的该项目的目标是将合成生物学、组织工程和昼夜节律原理结合起来生物学产生基于活干细胞的植入物，可以在规定的昼夜节律中输送生物药物用于治疗表现出昼夜节律的多种疾病过程的方式。在这个调控系统中，小鼠诱导多能干细胞（iPSC）的核心时钟基因电路将是这些细胞将被用于合成抗细胞因子生物药物。该项目的首要目标将集中于创建合成材料。具有规定的生物药物输送频率、相位和幅度的“时序发生”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这些细胞将被设计成可注射水凝胶载体中的稳定软骨结构。作为治疗实验性类风湿性关节炎（RA）的治疗方法在两种不同的情况下进行了测试这种疾病的小鼠模型是一种炎症性疾病，影响大约 1% 的普通患者。然而，目前有几种抗细胞因子生物制剂正在临床使用；我们认为高水平使用这些疗法可能会导致显着的副作用。与炎症细胞因子释放峰值的昼夜节律一致的递送将显着这些方法的有效性将通过临床、组织学、这种合成时间发生系统细胞的创建提供了分子和疼痛/行为测试。长期“时间疗法”或定时药物输送以治疗许多慢性病的可能性 RA 以外的炎症性疾病。