Genetically-engineered stem cells for self-regulating arthritis therapy

用于自我调节关节炎治疗的基因工程干细胞

基本信息

批准号：
10598619
负责人：
Farshid Guilak
金额：
$ 55.51万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598619
关键词：
Acute Adult Adverse effects Adverse event Amplifiers Anti-Cytokine Therapy Anti-Inflammatory Agents Arthritis Autoimmune Diseases Biological Biological Products Biological Response Modifier Therapy CRISPR/Cas technology Cell Therapy Cell physiology Cells Chemical Dynamics Chronic Chronic Disease Clinical Collagen Arthritis Complex Cues Custom Development Disease Dose Drug Delivery Systems Encapsulated Engineering Environment Exhibits Feedback Genes Genetic Genetic Engineering Genetic Transcription Genome engineering Goals Histologic IL6ST gene Implant In Vitro Induction of Apoptosis Infection Inflammation Inflammation Mediators Inflammatory Injections Interleukin-1 Interleukin-6 K/BxN model Measures Methods Modeling Molecular Mus Musculoskeletal Output Pain Patients Pharmaceutical Preparations Predisposition Prevalence Process Production Regenerative Medicine Rheumatoid Arthritis Risk Safety Sensitivity and Specificity Sepharose Serum Severities Suicide Swelling Synthetic Genes System TNF gene TNFRSF1A gene Testing Therapeutic Time Tissue Engineering Tissues Translations Treatment Efficacy Work anakinra arthritis therapy behavior test biomaterial compatibility bone erosion cancer type chronic inflammatory disease clinical translation collagen antibody induced arthritis cytokine design disability drug production efficacy testing engineered stem cells implantation in vivo in vivo evaluation inhibitor innovation joint destruction mouse model next generation personalized medicine prevent programs receptor response safety engineering scaffold stem cell based approach stem cell biology stem cells subcutaneous success synthetic biology systemic inflammatory response

项目摘要

Abstract Arthritis-related conditions occur in over 1 in 5 adults, and the prevalence is increasing. Current approaches to modulate endogenous inflammatory mediators in rheumatoid arthritis (RA) predispose patients to significant adverse effects (AEs), such as infection, when anti-cytokine biologic drugs are delivered continually at fixed doses. As the severity of RA fluctuates over time, development of specific therapeutic strategies that can sense and respond to varying levels of endogenous inflammatory mediators by producing correspondingly appropriate levels of anti-cytokine drugs represents an attractive alternative approach that may mitigate AEs induced by continuous biologic administration. The goal of this project is to used genetically engineered stem cells to create bioartificial implants for biologic drug delivery as a therapy for RA. By combining principles of synthetic biology and tissue engineering, we will develop stem cells that respond to specific pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alpha by producing targeted anti-cytokine drugs in a feedback-controlled, self-regulating, and multiplexed manner. A primary focus of this study is to fine-tune these reprogrammed anti-inflammatory cells to enhance the sensitivity and specificity of cell-based drug delivery in response to low-level systemic inflammation. Synthetic gene circuits will also be introduced in these cells to allow for exogenously-controlled tunable and inducible safety switches that can temporarily or permanently disable anti-cytokine drug production. These engineered cells will be encapsulated in agarose-based implants that will be placed subcutaneously in mice induced with experimental RA, and the long-term safety and efficacy of these approaches will be assessed using clinical, histologic, molecular, and pain/behavior testing. The creation of such “designer” cells provides the possibility for long-term, feedback-controlled drug delivery for the treatment of chronic inflammatory diseases.

抽象的与关节炎相关的疾病发生在超过1个成年人中，并且患病率正在增加。当前的方法调节类风湿关节炎（RA）患者的内源性炎症介质当抗周期动物生物学药物递送时，明显的不良反应（AES），例如感染（AES）继续以固定剂量进行。随着RA的严重程度随着时间的流逝而波动，特定疗法的发展可以通过生产来感知和响应不同水平的内源性炎症介体的策略相应适当水平的抗伴侣药物代表了一种有吸引力的替代方法可以减轻由连续生物给药引起的AE。该项目的目的是普遍使用设计的干细胞以生物人工为生物赋予生物肉体，作为RA的一种疗法。经过结合合成生物学和组织工程的原理，我们将开发出对的干细胞特定的促炎细胞因子，例如白介素-1，白介素6和肿瘤坏死因子α通过以反馈控制，自我调节和多路复用方式产生靶向抗周期药物。一个这项研究的主要重点是微调这些重编程的抗炎细胞，以增强响应低级全身注射的基于细胞药物的敏感性和特异性。合成的这些细胞还将引入基因回路，以允许外源控制和诱导性。安全开关可以暂时或永久禁用抗周期药物的生产。这些设计细胞将封装在基于琼脂糖的叶片中，将其皮下置于与实验性RA以及这些方法的长期安全性和效率将使用临床评估组织学，分子和疼痛/行为测试。这种“设计师”细胞的创建提供了可能性长期，反馈控制的药物输送，用于治疗慢性炎症性疾病。