Development of Novel Synthetic Triterpenoids for the Chemoprevention of Neurological Manifestations of Tuberous Sclerosis Complex
Abstract
Today, there is no cure for tuberous sclerosis complex (TSC), and neither the course nor the severity of the disorder can be predicted. Moreover, currently available treatments, largely designed to manage symptoms, are often ineffective or poorly tolerated by children. Therefore, there is an urgent need for safe, nontoxic drugs that are well tolerated and can be administered orally (by mouth), to prevent the development of the clinical manifestations or symptoms of TSC. Among the clinical manifestations or features of TSC, the overgrowth of normal tissue in the brain is often the most debilitating and life threatening, severely impacting the quality of life for children with TSC. These growths, which begin to form in the brain prior to birth, will interfere with brain function, causing seizures, delayed development, intellectual disability, and behavioral disorders. This proposal is focused on the development of a new class of drugs for use in the prevention of the neurological manifestations of TSC. This class of preventive drugs was specifically designed to modify disease processes to make them less aggressive and less malignant, enabling a new approach to preventive medicine. This class of drugs is known as synthetic oleanane triterpenoids or SOTs. Oleanane triterpenoids are abundant in nature, found in many plant species, and have known anti-inflammatory and anti-cancer properties. SOTs that have been designed by chemists have uniquely potent and safe ability to control inflammation and oxidative stress in almost every part of the body. Therefore, these agents now have the potential to significantly alter patterns of medical practice to a more preventive orientation. Lead molecules in the SOT family have now been safely administered to thousands of patients in clinical trials for cancer and chronic kidney disease, paving the way to developing their application for other diseases, including neurodegenerative diseases and conditions like TSC. This proposal is focused on a newly developed pyridyl derivative of the multifunctional SOT known as CDDO-Imidazolide. This derivative, known as CDOO-2P-Im (or 2P-Im), was designed to enhance the ability of the CDDO-Imidazolide to enter the brain, for use in treatment of brain diseases associated with chronic neuroinflammation and cancer. The studies outlined in this application will demonstrate the potential of 2P-Im to prevent neurological manifestations of the tuberous sclerosis complex (TSC) in validated preclinical (mouse) models of TSC. Therefore, the FY21 TSCRP Exploration – Hypothesis Development Award Focus Area(s) for this application include: Preventing epilepsy, improving treatment, and mitigating neurodevelopmental outcomes associated with TSC-related seizures. The potential for patient benefit is considered significant as there is now substantial evidence pointing to the important role of brain inflammation and increased expression of proinflammatory molecules or cytokines in mediating the neurological manifestations of TSC. These molecules, such as interleukine-1beta (IL-beta), and chemokines, such as monocyte chemoattractant protein-1 (MCP-1, also known as chemokine ligand 2 or CCL2), have been directly implicated in TSC-associated seizures and cognitive impairment, and 2P-Im suppresses the production of these molecules at extremely low levels that can be readily achieved by daily dosing of 2P-Im, when given orally (by mouth). The planned studies will help to answer important questions regarding how much of the drug (2P-Im) needs to reach the brain to be effective in preventing seizures or preserving cognitive function. The data generated will also provide important information regarding the dose of drug required to achieve clinical benefit. Success will open the door to clinical trials with SOTs currently in the clinic, and ultimately with 2P-Im. The principal hypothesis for this FY21 TSCRP EHDA application is that effective chemoprevention of the develo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210263
Entities
People
- John Letterio
Organizations
- Case Western Reserve University
- United States Army