Targeted therapeutic delivery to diseased lungs using enucleated mesenchymal stem cells

迫切需要基于细胞的治疗剂，其可以静脉内（IV）施用，并且有效地归巢和治疗。 将治疗药物输送到呼吸系统，同时保持患者安全。Cytonus Therapeutics和加州大学圣地亚哥分校 医学中心正在共同开发去核间充质干细胞，这些细胞有潜力为人类提供广泛的生物制剂。 治疗呼吸系统疾病，包括急性呼吸窘迫综合征（ARDS）。我们的新型治疗输送平台 是用炎症归巢蛋白对间充质干细胞（MSC）进行基因工程改造，然后轻轻地去除 细胞核，从而提供了一种高度独特的，可行的，安全的细胞治疗（CargocytesTM）与大量的肺归巢 潜力去核赠款用多个肺靶向部分和广泛的肺靶向部分基因工程化Cargocyte的能力。 生物有效载荷范围，同时保持临床相关的安全性特征。我们的肺部靶向策略建立在 Cargocyte治疗剂通过静脉途径（i. v.）向肺部进行活性靶向递送的关键潜力。 有核MSC将首先用已建立的趋化因子受体CXCR 4/CCR 2和CXCR 4/CCR 4广泛工程化。 发炎的内皮粘附分子PSGL-1，然后在静脉内给药前去核。概念验证 然后将进行临床前研究，以确定用肺营养分子工程化的Cargocytes是否能返回 在临床相关的ARDS小鼠模型中，因此，目标1研究将确定Cargocytes是否 用CCXCR 4/CCR 2和PSGL-1设计，使其回到发炎的肺组织，Aim 2研究将确定Cargocytes是否 离开脉管系统并进入发炎/受损的肺实质。如果Cargocytes回到发炎的肺组织 并排出脉管系统，它可以提供一种有效的手段来治疗各种呼吸系统疾病。

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.