Ultrasound mediated targeted therapy for kidney disease

超声介导的肾脏疾病靶向治疗

• 批准号: 8014605
• 负责人: Joshua J. Rychak
• 金额: $ 3.15万
• 依托单位: TARGESON, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8014605
• 关键词: Address; Adhesions; Adverse effects; Antibodies; Antibody Therapy; Binding; Biological Assay; Biotin; Blood Vessels; Cell Adhesion Molecules; Cell Line; Chemistry; Coupled; Coupling; Development; Diabetic Nephropathy; Diabetic mouse; Disorder by Site; Dose; Dot Immunoblotting; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Fibrosis; Flow Cytometry; Frequencies; Goals; Immunohistochemistry; Inflammation; Injury; Kidney; Kidney Diseases; Laser Scanning Confocal Microscopy; Lead; Ligands; Mediating; Methods; Microbubbles; Microbubbles Ultrasound Contrast Medium; Modality; Molecular Target; Monitor; Monoclonal Antibodies; Mus; Organ; P-Selectin; Play; Proteins; Rattus; Recombinants; Relative (related person); Renal Tissue; Reporter Genes; Role; Signal Transduction; Site; Specificity; Streptavidin; Surface; Testing; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Time; Tissues; Transforming Growth Factor beta; Translating; Ultrasonography; Vascular Endothelium; Viral; Work; cytokine; density; diabetic; gel electrophoresis; in vivo; kidney cell; kidney cortex; mesangial cell; molecular imaging; molecular marker; mouse model; novel; pre-clinical research; public health relevance; shear stress; targeted delivery; tool

DESCRIPTION (provided by applicant): Antibodies can be used diagnostically as ligands for molecular imaging, and also as therapeutic to neutralize factors involved in the development of kidney disease. However, the systemic administration of many relevant antibodies may lead to serious side-effects in other organs. To minimize systemic exposure and concentrate efficacy to the target organ we propose to develop a novel acoustically activated therapeutic antibody delivery vehicle for local treatment of experimental diabetic nephropathy. Simultaneous targeted accumulation and therapy is accomplished by utilizing antibodies able to 1) mediate targeted microbubble adhesion to sites of inflammation and fibrosis, and 2) produce therapeutic effects by neutralizing molecular targets. Microbubble ultrasound contrast agents will be targeted to relevant molecular markers of kidney disease by monoclonal antibodies immobilized to the surface of the agent. Antibodies against two targets will be investigated: P-selectin and TGF-beta. Antibody-bearing microbubbles will be administered intravenously and accumulate at sites of intravascular expression of TGF-beta and P-selectin. Low-power (non-destructive) contrast ultrasound imaging will be used to visualize and quantify retention of antibody-coated microbubbles within the kidney. Antibodies will then be released from the microbubbles by high power ultrasound, via ultrasound mediated microbubble destruction. This method has shown efficacy for delivering reporter genes to perivascular tissue in mice and rats, although targeted accumulation of the therapeutic microbubble at the target site has not been demonstrated. We propose quantify the payload of antibody-bearing microbubbles and verify targeted adhesion to recombinant target proteins. The ability of these microbubbles to selectively deliver antibodies to renal tissue, and specifically glomeruli, will be examined using immunohistochemistry and contrast-enhanced ultrasound imaging in a mouse model of diabetic kidney disease. This project will result in the development of a novel and efficient targeted antibody delivery tool for pre-clinical research. Additionally, this work has the potential to translate into a clinically viable method of treatment for diabetic nephropathy. Public Health Relevance: Antibody therapy offers a treatment modality for advanced kidney disease, for which only symptomatic treatment is currently available. Ultrasound-mediated microbubble antibody delivery is a safe, non-viral, non- invasive and high-efficiency method of drug-delivery. This approach would reduce the amount of antibody needed and target the site of injury, while the specific retention of microbubbles in the kidney would allow for monitoring the progression of diabetic kidney disease using ultrasound imaging.

描述（由申请人提供）：抗体可在诊断上用作分子成像的配体，也可用作治疗剂以中和参与肾脏疾病发展的因素。然而，许多相关抗体的全身给药可能导致其他器官的严重副作用。为了最大限度地减少全身暴露并将疗效集中到靶器官，我们建议开发一种新型的声学激活治疗性抗体递送载体，用于实验性糖尿病肾病的局部治疗。通过利用能够1）介导靶向微泡粘附至炎症和纤维化部位和2）通过中和分子靶标产生治疗效果的抗体来实现同时靶向积聚和治疗。微泡超声造影剂将通过固定在造影剂表面的单克隆抗体靶向肾脏疾病的相关分子标志物。将研究针对两个靶点的抗体：P-选择素和TGF-β。携带抗体的微泡将静脉内施用，并在TGF-β和P-选择素的血管内表达部位累积。低功率（非破坏性）超声造影成像将用于可视化和量化肾脏内抗体包被微泡的保留。然后通过高功率超声，经由超声介导的微泡破坏，将抗体从微泡中释放。该方法已显示出将报告基因递送至小鼠和大鼠血管周围组织的功效，尽管尚未证明治疗性微泡在靶位点的靶向累积。我们建议量化的抗体承载微泡的有效载荷，并验证有针对性的粘附重组靶蛋白。将在糖尿病肾病小鼠模型中使用免疫组织化学和对比增强超声成像来检查这些微泡选择性地将抗体递送至肾组织，特别是肾小球的能力。该项目将导致开发一种用于临床前研究的新型高效靶向抗体递送工具。此外，这项工作有可能转化为临床上可行的糖尿病肾病治疗方法。 公共卫生相关性：抗体疗法为晚期肾脏疾病提供了一种治疗方式，目前只能对症治疗。超声介导的微泡抗体给药是一种安全、无病毒、无创、高效的给药方法。这种方法将减少所需的抗体量并靶向损伤部位，而微泡在肾脏中的特异性保留将允许使用超声成像监测糖尿病肾病的进展。