Engineering Technologies for Improved Treatment of 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 for survival. 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 2015. 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. The majority 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. The complexity of FSGS and its effect on different cell types in the kidney is becoming better understood and appreciated. 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. Downstream of podocytes are parietal epithelial cells (PECs) and tubular epithelial cells (TECs). Intriguingly, recent studies have revealed that PECs might contribute to regeneration of podocytes after injury. TECs have long been known to contribute toward FSGS disease progression by promoting scarring in the kidney. 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 these sites of disease, therefore enhancing beneficial drug effects while mitigating adverse side effects. Hypothesis: We hypothesize that new technologies that enable targeted drug delivery to each of the following three cell populations, podocytes, PECs, and TECs, will yield improved methods for coordinated treatment of FSGS, while reducing undesired side effects. Innovation: Targeted delivery of drugs to kidney podocytes, PECs, and TECs has not been significantly studied due to the lack of such targeting technologies, so this work will establish the foundations of this field. Impact: Many lines of evidence support the broad impact of kidney-targeting drug delivery technologies: • Broad patient applicability. The common theme across many kidney diseases is loss of podocyte function and fibrosis. Therefore, we anticipate that this technology will be broadly applicable. • Standard of care. This platform could lead to a shift in the standard of care, from long-term, nonspecific drugs that result in many side effects, to a more precise approach that targets the kidney. • Drug discovery. Kidney-targeting technologies could enable the discovery of new classes of drugs, such as proteins or DNA. This technology could also enable clinical use of drugs previously excluded due to toxicity when administered throughout the whole body. With advanced delivery technologies available, new drugs could be developed to better treat FSGS, and side effects from current drugs could be reduced through more kidn
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010440
Entities
People
- Suzie H. Pun
Organizations
- United States Army
- University of Washington