Development of Cell Therapies for FSGS
Abstract
Background: The human kidneys are a pair of bean-shaped organs that filter, or remove, waste from the blood and regulate the amount of nutrients, sugars, proteins, and other molecules within the blood. However, damage to the filtration units within the kidneys can lead to chronic kidney disease (CKD), which diminishes kidney function. Approximately 26 million Americans are afflicted with CKD, and continuous damage to the kidneys can result in kidney failure, also known as end stage renal disease (ESRD), at which point the kidneys are no longer able to filter blood. ESRD requires patients to undergo transplantation or dialysis to continue blood filtration; however, these patients continue to face high death rates and poor health, and place a tremendous burden (nearly $100 billion in 2011) on the healthcare system. The Veteran population is particularly vulnerable to CKD (34% higher than the general population), with over 600,000 patients currently under the care of the Department of Veterans Affairs. Innovation is needed to address this growing patient population. A leading cause of CKD and ESRD in the United States, focal segmental glomerulosclerosis (FSGS), is characterized by the loss of kidney cells called podocytes. Podocytes are key cells that facilitate filtration. Because podocytes cannot multiply, podocyte loss in FSGS leads to disease advancement to ESRD. The treatment goal should therefore be regeneration of these lost podocytes in order to halt and cure FSGS. However, the standard FSGS drug treatment only delays or prevents podocyte loss and is therefore unable to halt advancement to ESRD in all patients. There is therefore a critically unmet clinical need to change the current treatment strategy toward one that restores podocyte number. Cell therapy is an approach to regenerate diseased or damaged cells and tissues where patient cells are engineered for enhanced function and then re-introduced to patients. Recent disease applications of promising preclinical and clinical cell therapies have included heart attack and cancer. However, cell therapy has not been developed for kidney diseases. Within the kidneys are renal progenitor cells (RPCs) that have the potential to multiply and turn into podocytes. While RPCs are thought to naturally replenish lost podocytes, this replenishment is not able to keep up with the number of podocytes lost in disease. Recent studies have shown that these RPCs can be recovered from the urine of kidney disease patients. These urine-derived RPCs (uRPCs), when injected into the blood of mice with FSGS, are able to "home" into the kidney, turn into podocytes, and improve kidney health. Since uRPCs can be easily isolated and multiplied from patient urine, uRPCs can be isolated, modified, and injected into patients as a strategy to regenerate lost podocytes. Hypothesis: We aim to develop uRPCs enhanced with nanoparticle "survival backpacks" attached to the cell surface (NP-uRPCs) for podocyte regeneration. These nanoparticle backpacks will be loaded with a drug known to improve RPC function and survival. We hypothesize that this system will (1) regenerate podocytes due to uRPCs turning into podocytes and (2) exhibit enhanced uRPC performance, as prednisone enhances uPRC survival as well as their ability to multiply and turn into podocytes. Innovation: The standard of FSGS treatment does not address the underlying podocyte loss and disease advancement to ESRD. The proposed work will introduce a novel, reparative therapy that can regenerate podocytes using uRPCs with minimal side effects. Nanoparticle-enhanced cells have not been used for kidney disease treatment before, so this work will be the first of its kind to do so. Moreover, given the easy access and supply of uRPCs from urine, this strategy would be easy to implement in the clinic. Here, we will also establish methods to genetically engineer uRPCs, which may present a cure for patients with genet
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610248
Entities
People
- Suzie H. Pun
Organizations
- United States Army
- University of Washington