Optimizing Small Molecule Therapeutics to Treat Focal Segmental Glomerulosclerosis
Abstract
Focal segmental glomerulosclerosis (FSGS) is a debilitating kidney disease characterized by the abnormal leak of blood proteins into the urine (proteinuria). This disease causes fluid accumulation and swelling, high blood pressure, and high cholesterol, and patients have a high risk of developing complete kidney failure, which requires kidney dialysis or transplantation for survival. FSGS is much more common in African Americans, a population that is highly represented among military personnel and Veterans, than Caucasians. African Americans also have more severe disease and a four-fold higher risk of developing complete kidney failure due to FSGS. There are very few treatment options for FSGS, and those that do exist often result in severe side effects and exhibit limited improvement. Even kidney transplantation is associated with a 30%-40% recurrence of FSGS in the transplanted organ. Thus, there is an urgent need to develop better treatments for FSGS. Our preliminary research showed that modulating the activity of the protein HDAC8 with certain small molecules shows very promising results in an animal model of FSGS. Importantly, these molecules are effective after the onset of disease, a critical factor in treating human FSGS which occurs without warning. However, the currently available compounds have significant liabilities that preclude translation to a human therapeutic. Based on compelling data, we hypothesize that by careful medicinal chemistry design, we can generate small molecules that will be efficacious in models of FSGS, and be appropriate, after key drug development studies, for advancement to clinical trials. Therefore, the objective is to develop novel therapeutics that will prevent the progression of FSGS in military patients. This application is in response to the Peer Reviewed Medical Research Program Portfolio, Internal Medicine, with the Topic Area FSGS, and the Strategic Goal for Treatment to Develop and test novel treatments, and/or improve upon existing treatments for associated diseases and conditions. These models were selected and designed to reflect the same types of kidney injury that would affect combat and retired military personnel. Therefore, these studies will identify candidate drugs that can be quickly translated into human clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310480
Entities
People
- Neil A Hukriede
Organizations
- United States Army