Developing Novel Therapeutics for Nephrotic Syndrome
Abstract
The proposed therapeutic development project addresses Nephrotic Syndrome (NS), one of the Department of Defense (DOD) FY22 Peer-Reviewed Medical Research Program (PRMRP) Topic Areas. Specifically, this therapeutic development project will address one DOD FY22 PRMRP Strategic Goal: Develop and test novel treatments for associated diseases and conditions, i.e., Nephrotic Syndrome. Nephrotic Syndrome (NS) is a disease attacking the kidney glomerular filtering system, causing the presence of large quantities of protein (mainly albumin) in the urine (i.e., proteinuria), body tissue swelling (i.e., edema), and low level of a protein called albumin in the blood (i.e., hypoalbuminemia). NS leads to severe complications such as high lipid levels in the blood (i.e., hyperlipidemia), an increased tendency of blood clot formation (i.e., thrombogenesis), infection, and kidney failure. About 661,000 Americans have kidney failure, which kills more people than breast or prostate cancer combined and costs the U.S. health care system at least $50 billion each year. Nearly 30,000 military personnel and Veterans suffer from kidney failure, and additional 3,000 Veterans are expected to reach kidney failure each year and require dialysis or a kidney transplant to survive. The current NS treatment only includes symptoms management (e.g., edema) and suppression of the patient s immune response (e.g., immunosuppressive therapy using steroids). However, immunosuppressive therapy (e.g., steroids) has no proven benefit for most adults with primary NS, and the potential risks of immunosuppressive/steroids treatment often outweigh any benefit. There is a significant unmet medical need for new non-steroid, non-immunosuppressive, kidney-specific therapies for NS. Primary NS is caused by injury to kidney glomerular podocytes, which are special neuron-like cells in the kidney filtering system that is critical in maintaining normal kidney function. NS can cause podocyte structure change (i.e., podocyte foot processes effacement), podocyte loss into the urine, and eventually scar formation in the kidney filtering system leading to blood protein (mainly albumin) leaking into the urine (i.e., proteinuria), edema, low level of albumin in the blood (i.e., hypoalbuminemia), and eventually kidney failure. Early treatment to reduce blood protein/albumin leaking into the urine and protect podocytes from injury and loss are novel kidney podocyte-specific, non-steroid, non-immunosuppressive therapies for NS patients. The primary goal of this DOD therapeutic development project is to test two new drugs we developed jointly with Pfizer in NS preclinical animal models. We have recently found that a gene called ROBO2 and its binding partner called SLIT are essential in maintaining the podocyte structure and population in the kidney filtering system. Interestingly, when we removed the ROBO2 gene from mice, we found that podocytes in these mice were protected from proteinuria and podocyte loss. In collaboration with Pfizer, we have generated several new drugs inhibiting the ROBO2/SLIT signaling pathway, and one of the drugs called PF-06730512 has recently entered a phase-2 clinical trial for NS patients. In this DOD therapeutic development project, we plan to treat NS preclinical animal models with two additional new drugs that we discovered jointly with Pfizer to inhibit the ROBO2/SLIT signaling pathway. After treatment with the two new drugs, we will analyze NS preclinical animal models and determine if they are protected from proteinuria and kidney failure. In addition, we will study the blood level of the two new drugs and analyze the gene and protein levels of ROBO2/SLIT in kidney tissue biopsy samples collected from NS patients. Research results generated in this DOD grant will help us prepare for future clinical trials to further test the two new drugs in healthy humans and NS patients, which are necessary steps before the U.S. Food and Drug
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311058
Entities
People
- Weining Lu
Organizations
- Boston Medical Center
- United States Army