Development of Novel, Highly mTORC1 Selective Inhibitors for the Treatment of Tuberous Sclerosis
Abstract
Tuberous sclerosis complex (TSC) is a disease that is caused by specific gene mutations. Patients with TSC suffer from a variety of different types of tumors and also have significant neurological problems such as seizures, mental retardation, and autism. Unfortunately, current treatment options for TSC are inadequate. Although a medicine called Everolimus has been approved to treat some aspects of the disease, it has a number of side effects that can limit its utility. It can suppress the immune system, making people who take it more susceptible to serious infections. It can also affect metabolism, altering levels of glucose and cholesterol in the blood. Because of these side effects, many people with TSC cannot take Everolimus consistently and at a high enough doses to treat the disease symptoms. Recently, scientists have discovered that Everolimus and other similar drugs inhibit two different protein complexes in the cells of the body. Inhibition of one of these complexes (called “mTORC1”) causes the beneficial effects of Everolimus on TSC, while inhibition of the other complex (called “mTORC2”) causes the undesired side effects. This has led to the idea that if new medicines could be developed that target mTORC1 exclusively, they would have many fewer side effects, while still being effective against the disease symptoms and thus be a better treatment option for TSC patients. Aeonian Pharmaceuticals, Inc. is a leader in developing new medicines that specifically target mTORC1. Aeonian has developed a set of five new molecules that may represent superior treatments for TSC. However, more research is now required to identify which of these is the best drug candidate to test in patients with TSC. In this project, Aeonian will first evaluate these five new drugs in normal mice and in cells derived from patients with TSC to identify the three best drug candidates. Next, Aeonian will test the three drugs in normal mice to determine which ones cause the fewest side effects and will identify the drug with the fewest side effects. This optimal drug will finally be tested in mice that have a gene mutation that mimics the disease in human patients with TSC. This experiment will allow Aeonian to determine whether the drug can reduce the number of seizures that TSC mice experience. Together, the evidence gathered from this project will allow Aeonian to advance its new, optimal drug to a clinical trial in patients with TSC. Because this project involves developing a new and better medicine for TSC, it addresses a significant unmet need in TSC patient care. It also addresses the focus area of “Facilitating therapeutics, biomarkers, and clinical trials research.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910224
Entities
People
- Stelios Tzannis
Organizations
- United States Army