Preclinical Evaluation of 2BAct, an eIF2B Activator, in Mouse Models of Pelizaeus-Merzbacher Disease (PMD)

Our goal of this project is to test a new drug, 2BAct, to see if it can help treat a rare and devastating childhood brain disease called Pelizaeus-Merzbacher Disease (PMD). PMD has no approved treatment and is caused by genetic problems that damage a type of brain cell called oligodendrocytes. These cells generate myelin, which is a protective coating around nerves and essential for proper brain function. When oligodendrocytes do not work properly, the brain’s communication system slows down or even stops, leading to developmental delay, movement problem, and often early death.

Our research focuses on a process inside these cells called the integrated stress response (ISR). This process can become overactive in PMD and cause harm to oligodendrocytes. We believe that calming down this stress response could help these cells survive and function better, allowing the brain to repair the myelin and improve nerve communication.

To test this idea, we will use 2BAct, which helps reduce cell stress response effectively, in three different mouse models of PMD. Each of them represents different forms of the disease. We will measure how well the drug extends lifespan of mice and improves brain health by looking at myelin repair under the microscope, testing motor function, and studying changes in gene activity. If successful, this study will lead to a new treatment strategy for PMD that probably work across different genetic subtypes of this disease as well as help other never-damaging diseases where brain cells are also under stress, such as other rare leukodystrophies.