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.