Ultrasound mediated targeted therapy for kidney disease

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.