Vascular injury and disease during diabetes lead to end-organ dysfunction (kidney failure, blindness, amputation) and cardiovascular disease that profoundly reduces patient quality of life and life expectancy. The proposed work seeks to develop new therapeutics to prevent and arrest diabetic vascular disease, by engineering nanoparticles to enable efficient delivery of a protein therapeutic. A major cause of vascular injury is protein glycation, the covalent attachment of glucose to proteins that leads to advanced glycation end- products and protein inactivation. In particular, the protein CD59, the key regulator of the membrane attack complex (MAC), is ubiquitously expressed, and human CD59 is uniquely susceptible to glycation-inactivation during diabetes. Human and experimental studies underscore the connection between CD59 glycation- inactivation, complement dysregulation, and MAC deposition in tissues. Therefore, delivery of exogenous, glycation-resistant CD59 could rescue complement regulation and mitigate complement-mediated vascular injury in diabetes, but is challenging due to rapid clearance and non-specific serum-binding of this protein. Moreover, a delivery strategy would need to achieve broad cell tropism (red blood cells, endothelial and epithelial cells) and high delivery efficiency. The goal of this work is to engineer nanoparticles (NPs) to enable efficient intravenous delivery of mouse CD59 in vivo using lipid-based NPs to improve protein pharmacokinetics. We hypothesize that nanoparticle delivery of CD59 will mitigate cardiovascular disease and endothelial dysfunction in diabetic mice with CD59 deficiency.
In Aim 1, NPs will be optimized for biocompatibility, protein loading, minimal non-specific uptake, and delivery in vitro. Optimized NPs will then be evaluated in Aim 2 for biodistribution and therapeutic efficacy in preventing atherosclerosis, endothelial dysfunction, and tissue complement deposition in diabetic, CD59-deficient animals. Successful completion of this work could validate CD59 delivery as a clinical strategy to halt and prevent diabetic vascular complications. The applicant, Gary Liu, aims to lead a lab as a principal investigator. One of his future research aims is to develop new therapies for diabetic microvascular complications. This postdoctoral fellowship includes (1) didactic training in diabetes, its complications, endocrinology, and bioinformatics; (2) scientific training in diabetic animal models and methods for quantifying cardiovascular disease and endothelial dysfunction, and (3) professional development and training in the responsible conduct of research in preparation for a career as a principal investigator. Training will occur at the Koch Institute of MIT in Dr. Robert Langer?s lab, which will provide the materials, equipment, and intellectual expertise necessary to carry out the proposed work.
The global diabetes crisis demands urgency for new therapies to halt and prevent diabetic complications. The proposed work will engineer nanotechnology to enable delivery of a protein drug, which may lead to new treatments to mitigate diabetic vascular injury and complications.