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Bioengineering a Novel Therapeutic Transporter that Crosses the Blood Brain Barrier to Treat Brain Disorders

生物工程设计一种新型治疗转运蛋白，可跨越血脑屏障治疗脑部疾病

基本信息

批准号：
10324736
负责人：
Richard L. Klemke
金额：
$ 32.5万
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：
2021-08-20 至 2023-08-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324736
关键词：
Address Antibodies Antibody-drug conjugates Area Basement membrane Biodistribution Biological Bioluminescence Biomedical Engineering Blood - brain barrier anatomy Blood Circulation Blood Vessels Blood capillaries Brain Brain Diseases Brain Injuries Brain-Derived Neurotrophic Factor CCL2 gene CSF1 gene CXCR4 gene Cell Nucleus Cell Therapy Cells Chimeric Proteins Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex DNA Development Disease Doxorubicin Drug Kinetics Endothelium Engineering Extracellular Matrix Extravasation Face Fc Receptor Genetic Engineering Genetic Transcription Golgi Apparatus Home Homing Immune response Immunofluorescence Microscopy Immunooncology Immunotherapeutic agent In Situ In Vitro Inflammation Injectable Interleukin-10 Interleukin-12 Interleukin-15 Intravenous Invaded Ischemic Brain Injury Ischemic Stroke Kinetics Laboratories Longevity Lung Mediating Membrane Mesenchymal Stem Cells MicroRNAs Mitochondria Modeling Neurobiology Oncolytic viruses Organelles P-selectin ligand protein Patients Peptides Pharmaceutical Preparations Phase Physiological Production Proliferating Protein Secretion Proteins RNA Reperfusion Therapy Safety Simplexvirus Small Interfering RNA TFRC gene Technology Therapeutic Therapeutic Agents Tissues Toxic effect Vesicle Vesicular stomatitis Indiana virus Virus Work antibody engineering brain parenchyma cell type clinically relevant cytokine exosome fMet-Leu-Phe receptor gene therapy improved in vivo mesenchymal stromal cell migration mouse model nanobodies nanoparticle neurotrophic factor novel therapeutics nuclear transfer patient safety response senescence small hairpin RNA small molecule stroke model synthetic drug therapeutic protein tumorigenesis zinc finger nuclease

项目摘要

While the brain blood barrier (BBB) is an important physiological barrier that protects the brain, it is also represents a formable barrier to therapeutic delivery. Therefore, there is a critical need for therapeutic transporters that can be injected intravenously (i.v.), and effectively traverse the BBB and deliver therapeutic agents to the brain [1-8]. Cytonus Therapeutics has pioneered the development of a new bioinspired delivery agent (CargocytesTM) with potential to meet this critical need. Cargocytes are bioengineered enucleated mesenchymal stromal cells (MSCs) that specifically home to diseased tissues such as the brain and deliver therapeutic payloads following i.v. administration. Substantial work in our laboratory indicates that Cargocytes have potential to treat brain disorders as they readily extravasate through vascular barriers, invade endothelial basement membranes, and chemotax though complex extracellular matrices to target tissues deep within disease foci. Cargocytes can also be engineered to produce, secrete, and/or deliver a range of powerful therapeutics within the brain milieu including cytokines, neurotrophic factors, antibodies, nanobodies, RNAs, and even small molecule drugs. Overall, our findings demonstrate that Cargocytes are a new breakthrough technology platform for maximum local bioprotein delivery and production while minimizing systemic distribution. Cargocyte technology improves efficacy and reduces off-target toxicity, the “holy grail” of therapeutic delivery. The primary objective of this phase I application is to develop brain homing Cargocytes that cross the BBB using an established model of ischemic brain injury.

虽然脑血屏障（BBB）是保护脑的重要生理屏障，但它也代表了脑血管疾病的一个重要特征。可成形的屏障以提供治疗。因此，迫切需要可以注射的治疗性转运蛋白静脉内（i. v.），并有效地穿过BBB并将治疗剂递送至脑[1-8]。卡托努斯 Therapeutics率先开发了一种新的生物启发递送剂（CargocytesTM），这一关键需求。Cargocyte是生物工程化的去核间充质基质细胞（MSC），其特异性地归巢于患病组织如脑，并在静脉内给药后递送治疗有效载荷。我们的实质性工作实验室表明，Cargocytes具有治疗脑部疾病的潜力，因为它们容易通过血管外渗，屏障，侵入内皮基底膜，并通过复杂的细胞外基质向靶组织化学转运在疾病病灶的深处。货物细胞还可以被工程化以产生、分泌和/或递送一系列强大的免疫调节剂。脑环境内的治疗剂，包括细胞因子、神经营养因子、抗体、纳米抗体、RNA，甚至小分子药物。总的来说，我们的研究结果表明，Cargocytes是一个新的突破性技术平台，最大化局部生物蛋白递送和生产，同时最小化全身分布。Cargocyte技术提高疗效并降低脱靶毒性，这是治疗递送的“圣杯”。这项工作的主要目的是第一阶段应用是使用已建立的缺血模型开发穿过BBB的脑归巢胶质细胞脑损伤