Diversification of Glomerular Kidney Disease Treatments By Targeting Therapeutics to the Kidney

点击翻译按钮获取中文摘要

ABSTRACT Novel approaches to the treatment of glomerular kidney diseases are needed given that they represent the third most common cause of end stage renal disease. Systemic lupus erythematosus induced kidney disease (SLEN) is one glomerular disease where up to 60% of patients exhibit significant declines in kidney function, resulting in end stage renal disease in ~20%. Although novel treatments are being explored for lupus, they generally do not benefit the majority of patients and cause systemic immunosuppression, leaving the majority of the population with less effective treatment options. Additionally, neither new nor old treatments have been evaluated for their ability to target to the kidney and achieve sufficient exposure to influence the localized disease processes. The development of novel and effective renal targeted treatment approaches for glomerular kidney diseases, including SLEN, are needed to meet the clinical efficacy and safety needs of patients with these disorders. We have recently published research for enhanced kidney deposition of imatinib in a murine model of SLEN, when formulated in a nanoemulsion developed to optimize kidney exposure. Results from our studies showed three-fold higher kidney deposition of imatinib in MRL/MpJ-Faslpr mice that received our novel nanoformulation vs. free drug. We will now test the novel imatinib formulation after chronic dosing to evaluate efficacy and safety in two mouse models of SLEN. We will also modify this formulation by linking a relevant ligand or an antibody fragment to target a receptor and protein, respectively, that are upregulated in glomerular mesangial cells in SLEN. We will test whether these formulation techniques applied to the existing nanoemulsion will enhance imatinib glomerular deposition and retention, improve selectivity for targeting mesangial cells, improve therapeutic efficacy and provide relative safety, as compared to our primary formulation. The central hypotheses of our research are that 1) promising SLEN treatments can be formulated to enhance delivery to the diseased kidney and targeted structures, and 2) animal models that represent human SLEN will demonstrate favorable treatment responses, pharmacokinetics, and enhanced safety with imatinib nanoformulations vs. free drug. The research team comprised of scientists with diverse backgrounds in glomerular kidney diseases, drug development, nanoformulations, toxicology, and renal pathology across schools at the University of Colorado Anschutz Medical Center, will synergize their efforts to successfully develop novel strategies to enhance kidney delivery and accumulation of therapeutics for the treatment of glomerular kidney diseases.