Supported Research

Co-Applicant(s): Dylan Burger

Lay Abstract

BACKGROUND: “Acute Kidney Injury” describes a serious medical condition involving the sudden loss of kidney function, associated with impaired ability to remove toxins from the body and control fluid balance. This condition commonly follows loss of blood flow to the kidneys, which can occur after major surgery or trauma, with serious infections, or even immediately after kidney transplantation. Acute kidney injury affects up to half of the patients in intensive care units, and it carries a high death rate. Unfortunately, there are no treatments that can help the kidneys recover their function, and dialysis is often needed as a supportive therapy. Our laboratory has been studying the potential benefits of a small molecule called “microRNA-486-5p” (miR-486-5p) in experimental models of acute kidney injury. In mice and rats, miR-486-5p protects against acute kidney injury caused by loss of kidney blood supply and prevents inflammation and cell death. However, with intravenous administration of miR-486-5p, it can distribute to other organs besides the kidneys, potentially leading to undesirable “off-target” effects. Furthermore, miR-486-5p is subject to quick degradation when delivered into the blood, meaning that high doses are required to induce beneficial effects. Using chemical reagents, our colleague Dr. Gadde has developed small vesicles (“nanoparticles”, NPs) that can package microRNAs and thereby protect them from being degraded. Our research has also suggested that coating NPs with a specific substance called “CXCR4” may improve targeting to the injured kidneys, thereby allowing more efficient delivery of miR-486-5p. PURPOSE: Our main objective is to engineer NPs containing miR-486-5p for targeted kidney delivery in acute kidney injury. We will first develop a platform of NPs containing miR-486-5p, specifically targeted to the kidneys. Then, we will determine if NPs containing miR-486-5p, targeted to the kidneys, prevent acute kidney injury in mice. METHOD: First, we will create a library of about 50 different NP formulations, by mixing chemical reagents and miR-486-5p. We will generate NPs coated on the surface with CXCR4, to improve targeting to the kidneys. The NPs will be characterized via established methods in our lab, and we will select best candidates based on their effects in cells grown on dishes. Next, we will study the effects of the selected NPs (containing miR-486-5p and CXCR4) in mice with acute kidney injury, due to temporary blockage of blood supply. ANTICIPATED OUTCOMES: We expect to develop a refined selection of NPs containing miR-486-5p that selectively target the injured kidneys. We also expect that these NPs will prevent acute kidney injury in our mouse model, and will distribute to kidneys, but not other organs. PATIENT ENGAGEMENT: At this time, we have not engaged patients in this basic science project. However, members of the Nephrology Patient and Family Advisory Committee (PFAC) at The Ottawa Hospital have been informed of the progress of our research and have expressed interest in hearing regular updates. RELEVANCE TO PATIENTS/COMMUNITY: Despite many years of research, no treatments exist to prevent acute kidney injury or to accelerate recovery of kidney function. Mortality is high secondary to acute kidney injury, and patients who recover often develop chronic kidney disease. Accordingly, the overarching goal of this research is to improve outcomes for patients. CONCLUSION: Our lab has made considerable progress in studying the potential benefits of miR-486-5p in prevention of acute kidney injury. However, more work needs to be done. Demonstration of efficacy of targeted NP delivery in mice will represent a critical step in the pathway to first-in-human clinical trials adopting this promising new technology.