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Ultrasound-triggered delivery of siRNA as treatment for diabetic kidney disease

超声波触发 siRNA 治疗糖尿病肾病

基本信息

批准号：
8328778
负责人：
Joshua J. Rychak
金额：
$ 55.13万
依托单位：
TARGESON, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328778
关键词：
Acoustics Acute Aftercare Animal Disease Models Animal Model Benchmarking Binding Biodistribution Biological Assay Blinded Blocking Antibodies Blood Cell Death Cells Chronic Clinical Collagen Data Development Diabetic Nephropathy Diabetic mouse Disease Dose Drug Formulations Electroporation Employee Strikes Endothelial Cells Enzyme-Linked Immunosorbent Assay Evaluation Exhibits Exposure to Fibrinogen Fibrosis Flow Cytometry Fluorescence Growth Factor Hour Human Image Immunohistochemistry In Situ Hybridization In Vitro Incubated Industry Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Label Ligands Liver Lung Measures Mediating Methods Microbubbles Modeling Molecular Target Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nucleic Acids Pathologist Perfusion Plasma Plasmids Play Process Production Proteins Proteinuria Residual state Resistance Ribonucleases Rodent Role Schedule Selectins Small Interfering RNA Spleen Staging Staining method Stains Surface Techniques Technology Therapeutic Time Tissues Toxic effect Transforming Growth Factor beta Treatment Protocols Ultrasonic Therapy Ultrasonography Validation Work base cell type clinically relevant cytotoxicity diabetic gel electrophoresis gene therapy head-to-head comparison in vivo kidney vascular structure knock-down mesangial cell neutralizing antibody non-invasive monitor novel nuclease research study small hairpin RNA sonoporation success targeted delivery terthienyl zeta potential

项目摘要

DESCRIPTION (provided by applicant): Gene therapy in the context of diabetic kidney disease holds tremendous promise, although concrete progress in the field has been difficult to achieve. Specifically, the growth factor TGF-2 is known to play a critical role in glomerular matrix expansion and progression of glomerular fibrosis, and inhibition of TGF-2 activity by neutralizing antibodies has shown striking efficacy in several animal models of diabetic kidney disease. However, as is the case with many targets of molecular therapy, TGF-2 is strongly implicated in numerous somatic processes, and off-target inhibition may pose severe detrimental effects. Means by which TGF-2 therapy could be targeted specifically to the impaired kidney could offer a critical breakthrough in making gene therapy for kidney disease a reality. In the current proposal, we aim to develop a novel microbubble-based delivery vehicle for targeted TGF-2 gene therapy. We have developed a microbubble that can be conjugated with a payload of plasmid or siRNA, and targeted to the diabetic kidney by means of a selectin-binding targeting ligand. These agents can be administered intravenously, and their accumulation within the kidney monitored by non-invasive ultrasound imaging. Release of the siRNA payload and transfer into the targeted glomerular cells is mediated by application of high-power ultrasound energy specifically to the kidneys, which causes rapid destruction of the microbubbles and a transient poration of the adjacent cells. Remaining untargeted agents are cleared to the liver, spleen, and lung, where agent destruction by deflation exposes any residual siRNA to endogenous nucleases, thus potentially reducing off-target effects. We aim to evaluate this targeted siRNA delivery strategy in several clinically-relevant mouse models of diabetes. TGF-2 knock-down, and reduction in mesangial matrix expansion, will be assessed longitudinally. We will also systematically assess the payload capacity and stability of the agent, and evaluate toxicity and biodistribution in rodents. We anticipate that successful completion of the proposed aims will demonstrate efficacy of this targeted delivery technology for treatment of diabetic kidney disease, and provide Targeson with critical data needed to advance to the next stage of development for clinical use.

描述（由申请人提供）：基因治疗在糖尿病肾病的背景下拥有巨大的希望，尽管该领域的具体进展一直难以实现。具体地，已知生长因子TGF-2在肾小球基质扩张和肾小球纤维化进展中起关键作用，并且通过中和抗体抑制TGF-2活性在几种糖尿病肾病动物模型中显示出显著的功效。然而，与分子治疗的许多靶点一样，TGF-2与许多体细胞过程密切相关，并且脱靶抑制可能造成严重的有害影响。TGF-2治疗可以特异性靶向受损肾脏的方法可以为肾脏疾病的基因治疗提供关键突破。在目前的提案中，我们的目标是开发一种新的基于微泡的载体靶向TGF-2基因治疗。我们已经开发了一种微泡，它可以与质粒或siRNA的有效载荷缀合，并通过选择素结合靶向配体靶向糖尿病肾脏。这些药物可以静脉内给药，并通过非侵入性超声成像监测其在肾脏内的积聚。siRNA有效载荷的释放和转移到靶向肾小球细胞中是通过将高功率超声能量特异性地应用于肾脏来介导的，这导致微泡的快速破坏和相邻细胞的瞬时穿孔。剩余的非靶向试剂被清除到肝、脾和肺，其中通过放气的试剂破坏将任何残留的siRNA暴露于内源性核酸酶，从而潜在地减少脱靶效应。我们的目标是在几种临床相关的糖尿病小鼠模型中评估这种靶向siRNA递送策略。将纵向评估TGF-2敲低和系膜基质扩张的减少。我们还将系统地评估该药剂的有效载荷能力和稳定性，并评估啮齿动物中的毒性和生物分布。我们预计，成功完成拟议目标将证明这种靶向给药技术治疗糖尿病肾病的有效性，并为Targeson提供进入下一阶段临床应用开发所需的关键数据。