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.
Few techniques for targeted gene therapy are available, especially in deep tissues such as the kidney. This project will examine the ability of a targeted ultrasound-based technique to deliver a therapeutic siRNA to diabetic kidney, and determine whether this strategy is able to ameliorate glomerular fibrosis in animal models of the disease.
| Zhao, Jinghong; Miyamoto, Satoshi; You, Young-Hyun et al. (2015) AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. Am J Physiol Renal Physiol 308:F1167-77 |
| Declèves, Anne-Emilie; Sharma, Kumar; Satriano, Joseph (2014) Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia-Reperfusion: Autophagy and Cellular Stress Markers. Nephron Exp Nephrol : |
| Rychak, Joshua J; Klibanov, Alexander L (2014) Nucleic acid delivery with microbubbles and ultrasound. Adv Drug Deliv Rev 72:82-93 |
| Declèves, Anne-Emilie; Zolkipli, Zarazuela; Satriano, Joseph et al. (2014) Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int 85:611-23 |
| Sweiss, Natalie; Sharma, Kumar (2014) Adiponectin effects on the kidney. Best Pract Res Clin Endocrinol Metab 28:71-9 |
| Börgeson, Emma; Sharma, Kumar (2013) Obesity, immunomodulation and chronic kidney disease. Curr Opin Pharmacol 13:618-24 |
| Miyamoto, Satoshi; Sharma, Kumar (2013) Adipokines protecting CKD. Nephrol Dial Transplant 28 Suppl 4:iv15-22 |
| Declèves, Anne-Emilie; Rychak, Joshua J; Smith, Dan J et al. (2013) Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging. Am J Physiol Renal Physiol 305:F1343-51 |
| Satriano, Joseph; Sharma, Kumar (2013) Autophagy and metabolic changes in obesity-related chronic kidney disease. Nephrol Dial Transplant 28 Suppl 4:iv29-36 |
