New Podocyte-Targeted Treatments for Focal Segmental Glomerulosclerosis (FSGS)
Abstract
Background: The human kidneys are a pair of organs that filter waste from the blood and regulate the amount of sugars, proteins, and other molecules in the blood. However, damage to the filtration units within the kidneys can lead to diminished kidney function. Continuous damage to the kidneys results in kidney failure, at which point the kidneys are no longer able to filter blood. Patients with kidney failure must undergo either transplantation surgery or dialysis to continue blood filtration. However, not all patients are able to receive a transplant due to a limited supply of donor kidneys, and dialysis imposes significant burdens on patient quality of life and health. Approximately 26 million Americans are afflicted with chronic kidney disease, and collectively these patients cost the U.S. healthcare system nearly $100 billion in 2011. Innovation is needed to address this growing patient population. A particular type of kidney disease, focal segmental glomerulosclerosis (FSGS), has emerged as a leading cause of kidney failure. FSGS is particularly difficult to treat as it is not a singular disease, but rather a pattern of kidney injury caused by primary factors such as viral infection and drug abuse. However, 80% of FSGS cases are of unknown cause, and despite this lack of evidence for an immune system-mediated cause of disease, the standard of FSGS treatment relies on drugs that suppress the immune system. Patients are given long-term doses of these drugs, which result in adverse side effects such as obesity, high blood pressure, and stunting of growth. Moreover, not all patients respond to treatment, and 70% of patients experience disease relapse after drug discontinuation. There is a critical clinical need to develop new treatments that (i) effectively halt and reverse FSGS from progressing to kidney failure with (ii) minimal side effects. A targeted drug delivery approach could address these needs by delivering drugs selectively to sites of disease, therefore enhancing beneficial drug effects while mitigating adverse side effects. FSGS is characterized by the loss of kidney cells called podocytes, key cells that facilitate filtration. Human and animal studies have shown that podocyte loss directly underlies FSGS and declining kidney function. As podocytes are the site of disease in FSGS, treatments should therefore protect these podocytes in order to halt and cure FSGS. Therefore, targeted drug delivery to podocytes could be a promising therapeutic avenue for FSGS. As there are currently no technologies to deliver drugs selectively to these cells, we aim to establish the proof-of-concept of such work. Hypothesis: We aim to develop nano-sized drug carriers for targeted drug delivery to kidney podocytes. These drug carriers will be engineered with properties to maximize accumulation in the kidney, and will be attached with a "recognition molecule" that enables targeted delivery to podocytes. We selected the molecule drug Bis-T-23 as a promising podocyte-stabilizing drug for these studies. This molecule was recently reported to effectively protect podocytes from injury in animals with FSGS, but may have adverse side effects when administered throughout the body in humans. We propose to deliver Bis-T-23 selectively to kidney podocytes using our engineered drug carriers. Once inside the podocytes, the carriers will release the drug Bis-T-23 into the cell for protection against disease. Using this drug carrier, we hypothesize that podocyte-specific delivery of drug will be an effective treatment strategy for FSGS. Innovation: The standard of FSGS treatment does not effectively address the fundamental problem of podocyte loss and disease advancement to kidney failure. The proposed work will introduce a novel drug carrier, engineered for podocyte-selective drug delivery. Targeted delivery of drugs to kidney podocytes has not been studied due to the lack of such targeting technologies, so
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610168
Entities
People
- Stuart Shankland
Organizations
- United States Army
- University of Washington