Targeted therapeutic delivery to diseased lungs using enucleated mesenchymal stem cells

使用去核间充质干细胞向患病肺部进行靶向治疗

基本信息

批准号：
10156129
负责人：
HUAWEI WANG
金额：
$ 29.76万
依托单位：
CYTONUS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156129
关键词：
Acute Lung Injury Address Adult Respiratory Distress Syndrome Biodistribution Biological Bioluminescence Blood Vessels CXCR4 Receptors CXCR4 gene Cell Adhesion Molecules Cell Nucleus Cell Therapy Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Data Disease Doxorubicin Drug Delivery Systems Drug Kinetics Drug Transport Endothelium Engineering Environment Extracellular Matrix Proteins Extravasation Face Genetic Engineering Genetic Transcription Golgi Apparatus Grant Granulocyte-Macrophage Colony-Stimulating Factor Home Homing Immune response Immunofluorescence Microscopy Immunomodulators In Vitro Inflammation Institutes Interleukin-12 Interleukin-15 Intravenous Invaded Kinetics Legal patent Licensing Longevity Lung Lung Inflammation Lung diseases Mediating Medical center Mesenchymal Mesenchymal Stem Cells Mitochondria Modeling Nanotubes Organ Organelles P-selectin ligand protein Patients Peptides Pharmaceutical Preparations Phase Production Program Development Proliferating Protein Secretion Proteins RNA Resolution Respiratory System Risk Route Safety Site Small Interfering RNA Structure of parenchyma of lung System Testing Therapeutic Therapeutic Agents Vesicle Virus antibody engineering cell behavior cell type clinically relevant cytokine exosome extracellular vesicles fMet-Leu-Phe receptor gene therapy improved in vivo lung injury migration mouse model nanoparticle novel novel therapeutics nuclear transfer patient safety precision drugs preclinical study prevent prototype small hairpin RNA stem stem cells synthetic drug targeted delivery targeted treatment therapeutic protein tumorigenesis uptake zinc finger nuclease

项目摘要

There is critical need for cell-based therapeutics that can be administered intravenously (IV), and effectively home to and deliver therapeutics to the respiratory system, while maintaining patient safety. Cytonus Therapeutics and UC San Diego's Medical Center are co-developing enucleated mesenchymal stem cells with potential to deliver a wide range of biologics to treat respiratory diseases including acute respiratory distress syndrome (ARDS). Our novel platform for therapeutic delivery is to genetically engineer mesenchymal stem cells (MSCs) with inflammation homing proteins and then gently remove the nucleus, thereby providing a highly unique, viable, and safe cell therapeutic (CargocytesTM) with substantial lung homing potential. Enucleation grants the ability to genetically engineer Cargocytes with multiple lung targeting moieties and a wide range of biological payloads, while maintaining a clinically relevant safety profile. Our lung targeting strategy is built on the key potential of Cargocyte therapeutics to perform active-targeted delivery to the lungs via an intravenous route (i.v.). Nucleated MSCs will first be extensively engineered with established chemoattractant receptors CXCR4/CCR2 and inflamed endothelial adhesion molecule PSGL-1 and then enucleated prior to i.v. administration. Proof-of-concept preclinical studies will then be performed to determine whether Cargocytes engineered with lung trophic molecules home to inflamed lungs in a clinically relevant murine model of ARDS. Therefore, Aim 1 studies will determine if Cargocytes engineered with CCXCR4/CCR2 and PSGL-1 home to inflamed lung tissues and Aim 2 studies will determine if Cargocytes exit the vasculature and move into the inflamed/damaged lung parenchyma. If Cargocytes home to inflamed lung tissues and exit the vasculature, it could provide an effective means to treat a wide range of respiratory diseases.

迫切需要基于细胞的治疗方法，可以通过静脉注射 (IV) 给药，并有效地定位和治疗向呼吸系统提供治疗药物，同时维护患者安全。 Cytonus Therapeutics 和加州大学圣地亚哥分校医疗中心正在共同开发去核间充质干细胞，有潜力为患者提供多种生物制剂治疗呼吸系统疾病，包括急性呼吸窘迫综合征（ARDS）。我们新颖的治疗传递平台是用炎症归巢蛋白对间充质干细胞（MSC）进行基因改造，然后轻轻去除细胞核，从而提供一种高度独特、可行且安全的细胞治疗（CargologiesTM），具有显着的肺归巢作用潜在的。摘除细胞核赋予了对具有多个肺靶向部分和广泛的细胞的基因工程能力。范围的生物有效载荷，同时保持临床相关的安全性。我们的肺部靶向策略建立在 Cargcell 疗法的关键潜力是通过静脉内途径 (i.v.) 向肺部进行主动靶向递送。有核 MSC 将首先使用已建立的趋化受体 CXCR4/CCR2 进行广泛工程改造，发炎的内皮粘附分子 PSGL-1，然后在静脉注射之前去核。行政。概念验证然后将进行临床前研究，以确定用肺营养分子改造的 Carg cells 是否可以回家临床相关的 ARDS 小鼠模型中肺部发炎。因此，目标 1 研究将确定 Cargologies 是否用 CCXCR4/CCR2 和 PSGL-1 进行工程改造，成为发炎的肺组织，Aim 2 研究将确定 Cargologies 是否离开脉管系统并进入发炎/受损的肺实质。如果货物细胞是发炎的肺组织的家园并离开脉管系统，它可以提供治疗多种呼吸系统疾病的有效手段。