Optimization of a Selective Calpain-2 Inhibitor for prolonged field care in Traumatic Brain Injury
Abstract
Objective and Theoretical Reasoning: Traumatic brain injury (TBI) is a major cause of death and disability in the United States. Consequences of TBI can last a few days or for the remaining of the lives of the persons who survive and can affect cognitive, emotional, and motor functions. Currently, there are no treatments targeting the major feature of TBI, which is neuronal damage and neuronal death that take place in the hours/days following the injury. If such a treatment were to be available, it could save many lives, as well as improve the outcomes of TBI by limiting the amount of brain damage resulting from the injury. We have identified a mechanism that is activated in the hours following TBI, lasts for many days, and is directly related to the extent of cell damage. We have also tested the effects of an inhibitor of this process in a mouse model of TBI and showed that this compound limits the extent of cell death and prevents the impairment of cognitive and motor function when injected after TBI for a few days. This molecule needs to be optimized by using medicinal chemistry to produce a new therapeutic treatment for TBI. The overall objectives of our project are to identify a suitable inhibitor that can be administered intravenously in the hours/days following TBI, to perform the studies required by the Food and Drug Administration (FDA) in order to plan for clinical trials, and to validate a blood biomarker that can be used to rapidly determine the effectiveness of the treatment. Problem, Question, Impact: We have put together an outstanding team of chemists, biologists, and pharmacologists with the required expertise to successfully identify a new molecule with the appropriate features to be developed as a new treatment. Successful completion of the proposed studies will provide the necessary information to initiate clinical trials in TBI/repeated concussions. Types of Patients It Will Help: An estimated 2.5 million Americans experience some form of TBI/repeated concussions every year. Of these, at least 50,000 do not survive, and 90-100,000 have long-term disabilities. Since 2000, only about 10% of head injuries sustained by military personnel are classified as mild to severe TBI. Nevertheless, Veterans who experienced TBI complain of headaches, loss of memory, and other symptoms, which are the results of the injury. Treating all forms of TBI in both civilian and military populations with the proposed therapeutic will provide significant health benefits. Repeated concussion is a major problem for athletes, and recent reports have revealed that many of them develop a neurodegenerative disorder called chronic traumatic encephalopathy. Military personnel also experience repeated concussions, and we will evaluate the beneficial effect of our new therapeutic drug following repeated concussions. A recent report also indicates that a single episode of concussion increases the risk for developing Parkinson’s disease, and our work might provide a new way to limit the risk of developing this disease after concussion. Clinical Application: The ideal treatment will be with an initial intravenous bolus injection of the drug, followed by a daily injection for a short period (1-2 weeks). The availability of a blood biomarker directly related to the targeted mechanism will provide rapid indication regarding the effectiveness of the treatment and the possibility of adjusting the dosage required for each patient. Projected Timeline: The goal of the proposal is to bring a molecule to the clinic at the end of the funding period (5 years). Service Members: As mentioned above, we think that Service personnel experiencing any form of TBI could be eligible for the treatment, once it is approved by the FDA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910329
Entities
People
- Michel Baudry
Organizations
- United States Army
- Western University of Health Sciences