Cell-Permeable Succinate as a Therapeutic Intervention for Mitochondrial Disease
Abstract
The proposed therapeutic development project addresses the topic area of mitochondrial disease. In order to function, the cells of the body require energy in the form of ATP, the energy currency of the cell. The vast majority of this energy, ATP, is produced in the mitochondria. Within mitochondria, there is a respiratory chain, where electrons derived from food nutrients are passed down a series of protein complexes embedded in the inner mitochondrial membrane. Complexes I to IV use these electrons to pump protons across the membrane and thereby generating an electrochemical gradient. Complex V uses this gradient to produce ATP as it lets protons pass back through the membrane, much like a hydroelectric plant taps energy built by a dam to power a turbine generating electricity. Ultimately, this process converts oxygen and nutrients to carbon dioxide and water as waste products. Every 30 minutes, a child is born who will present with mitochondrial disease by the age of 10. Mitochondrial disease occurs due to a variety of genetic mutations that affect the ability of mitochondria to produce the body’s energy currency, ATP. Problems with complex I of the respiratory chain is most common culprit in mitochondrial disease. Clinically, mitochondrial disorders usually appear early in life, and affected children can present with failure to thrive, as well as a variety of problems with their muscles and nerves. Severe conditions, such as Leigh syndrome, is fatal during childhood. Unfortunately, there are no approved therapeutics for mitochondrial disease in the US. The proposed project aims to develop a treatment for mitochondrial disease by supplying an alternative source of energy that can bypass problems with CI. Succinate is a source of energy that can be used by the second protein complex of the respiratory chain, complex II. However, succinate does not work well as a drug because it cannot get into cells, and therefore cannot get to the mitochondria. We have developed drug candidates that are similar to succinate, except that we have designed them to penetrate the cell wall to their point of action within the mitochondria, a process previously impossible. Once inside the cell, these drugs are naturally broken down into succinate, which can then be used by the mitochondria. The proposed project will develop this novel concept of succinate prodrugs. At the end of the project, one drug candidate will have been identified as the lead candidate, based on its ability to safely rescue impaired mitochondrial function without toxicity in a series of experiments. The immediate outcome of this project will be to select a lead drug candidate that can be manufactured and formulated for clinical use. Using this formulated drug candidate, we will then obtain the necessary data on absorption, distribution, metabolism, excretion and toxicity (ADMET) that the Food and Drug Administration (FDA) requires for the first dose to be administered to humans. In subsequent clinical trials, our drug will be tested to determine if it can treat an acute mitochondrial energy crisis in a person with mitochondrial disease. This crisis can occur when a patient with mitochondrial disease experiences a stressor, such as a simple viral infection, that places heavy demands for energy on the cells. If the demand for energy exceeds the mitochondria’s ability to produce ATP, the patient’s life can be endangered. If these initial human trials show that our drug safely and effectively treats this problem, later studies will determine if our drug is beneficial for long-term maintenance of patients with primary mitochondrial disease. Mitochondrial dysfunction is also a major contributor to the secondary injury following traumatic brain injury (TBI) and the brain injury that occurs after cardiac arrest (CA). The initial insult triggers secondary reactions that perpetuate the brain injury, and complex I is the most commonly observed dysfunction
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810607
Entities
People
- Todd Kilbaugh
Organizations
- United States Army