Nephritis, a chronic inflammatory kidney disease, is a leading cause of mortality in lupus patients. Current therapy for lupus nephritis includes corticosteroids, such as dexamethasone (Dex), which are often associated with significant toxicity that results from systemic exposure to the drugs and off target effects. To address this problem, we propose to develop kidney-targeted corticosteroid therapy, which will allow sufficient Dex concentration in the kidney for inflammation resolution, while limiting systemic exposure to corticosteroids. Our long-term goal is to develop novel therapies for lupus. The objective of this application is to demonstrate that molecularly targeted copolymer-conjugated Dex will provide safe but effective therapy for lupus by targeted delivery and local retention of the anti-inflammatory drug Dex to the kidney. Our central hypothesis is that molecularly targeted copolymer conjugated Dex will be nephrotropic to lupus-affected kidneys with limited systemic distribution and will ameliorate renal dysfunction and increase lifespan of lupusprone mice. This hypothesis is based upon our initial studies showing that copolymer conjugated Dex shows enhanced uptake by the inflamed kidney, particularly in the proximal tubule epithelial cells. Furthermore, we have strong preliminary data that demonstrate that copolymer conjugated Dex reduces nephritis and extends lifespan in lupus mice without inducing loss of bone mineral density. However, some side effects remain and thus further refinement of this kidney targeted therapy is needed to maximize therapeutic benefits and eliminate residual off target effects. However, our lack of knowledge about the cellular mechanisms involved in renal uptake of copolymer conjugated Dex hampers our progress toward this goal. Therefore, we propose in vitro and in vivo studies to determine the mechanisms involved in cellular uptake and processing of copolymer conjugated Dex in the kidney. We will also use peptides to more effectively target copolymer conjugated Dex to the proximal tubule epithelial cells and to promote more efficient cellular uptake. The impact of peptide targeting on the safety and efficacy of copolymer conjugated Dex will also be examined.
There is a need for improved therapy for nephritis, the leading cause of renal failure and mortality in lupus patients. Current therapy involves corticosteroids, which cause major toxicity due to systemic exposure. Our development of kidney-targeted corticosteroid therapy, which effectively treat nephritis while limiting systemic exposure to corticosteroids, represents a major leap forward in the treatment of lupus nephritis.
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