Development of Novel Podocyte Endoplasmic Reticulum Calcium Stabilizers to Treat Focal Segmental Glomerulosclerosis
Abstract
Background: Focal segmental glomerulosclerosis (FSGS) is an important kidney disease characterized by damage of the kidney filtering unit resulting in leakage of blood proteins in the urine and progressive loss of kidney function, leading to chronic kidney disease and kidney failure. Approximately 26 million Americans suffer from chronic kidney disease and cost the U.S. healthcare system nearly $100 billion in 2011. Once kidneys stop working, patients must undergo either kidney transplantation or dialysis to filter out toxins from the blood. However, not all patients are able to receive a new kidney due to a limited supply of donor kidneys, and dialysis imposes significant burdens on patient quality of life and health. In addition, primary FSGS (around 80% of FSGS) is most common in 18-45 year-old males and the incidence is 3-7 times higher in African Americans compared to whites, a population that is highly concentrated among our military personnel and Veterans. The standard of FSGS treatment relies on drugs that suppress the immune system, despite the lack of evidence for an immune system-mediated cause of the disease. These drugs are oftentimes ineffective and have significant adverse effects such as obesity, hypertension, infection, and kidney toxicity. Thus, there is an urgent need to develop mechanism-based and highly targeted therapies for FSGS patients. Rationale: The hallmark of FSGS is injury and loss of podocytes, key cells involved in kidney filtration. Moreover, human and animal studies have highlighted that podocyte endoplasmic reticulum (ER) stress, which is caused by accumulation of abnormally folded proteins in the ER due to a number of pathophysiological insults including genetic mutations, plays an important role in FSGS. For the first time, we demonstrate that the podocyte ER calcium release channel, type 2 ryanodine receptor (RyR2), becomes leaky under ER stress, leading to podocyte injury. Most importantly, we have identified a chemical compound through collaboration with the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) and a novel biotherapeutic protein, which can fix leaky RyR2 and inhibit podocyte injury. As currently there are no drugs targeting podocyte ER, we aim to develop a new class of drugs – podocyte ER calcium stabilizers to treat FSGS. Hypothesis: We hypothesize that podocyte ER stress-induced ER calcium leak is an important mechanism leading to podocyte injury in FSGS and that our newly identified podocyte ER calcium stabilizers are effective treatments for FSGS. We will inject the chemical compound, overexpress the therapeutic protein in podocytes by mouse transgenic approach, and deplete an ER calcium leak-activated death molecule to determine whether podocyte injury, protein leak in the urine, and kidney failure will be mitigated in our preclinical FSGS mouse model. Innovation: The standard of the current FSGS treatment does not effectively resolve the underlying problem of podocyte injury and loss. Our proposed work is a first-of-its-kind FSGS therapy based on normalizing the aberrant ER calcium homeostasis in podocytes undergoing ER stress. Based on our strong preliminary data, our drug candidates hold promise for halting or delaying the progression of FSGS. Impact: • Drug discovery: Our study could enable the discovery of a new class of drugs – podocyte ER calcium stabilizers in the treatment of FSGS. • Shift in the standard of care: Our work could lead to a shift from nonspecific drugs that cause many side effects to a precise approach that targets podocyte ER calcium depletion. • Broad patient applicability: Most FSGS patients carrying genetic mutations do not respond to the current treatment. Our innovative mechanistic approach could enable treatment for genetic causes of FSGS. In addition, development of podocyte ER calcium stabilizers may have wide clinical applications in the treatment of va
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910320
Entities
People
- Ying Chen
Organizations
- United States Army
- Washington University in St. Louis