Funding outcome

The research we propose in this application will investigate a group of rare childhood diseases that result from an imbalance in the body's energy production within the central nervous system (CNS). Normally, cells in the CNS generate energy through two main processes: mitochondrial respiration and glycolysis, the consumption of sugar. Mitochondrial respiration is used primarily by neurons, while astrocytes and microglia tend to use glycolysis. Neurons often rely on lactate (the end product of glycolysis) provided by glycolytic astrocytes to support their respiratory processes. This interdependent energy system keeps the brain functioning smoothly. However, when something disrupts this balance, cells in the CNS cannot produce or share the metabolites they need. This can lead to various childhood diseases and health problems in the context of rare gene mutations. Symptoms can range from developmental delays and intellectual disabilities to facial irregularities and eye problems, and are often accompanied by seizures, and epilepsy. Currently, there is limited information on how to treat these rare diseases. To find potential treatments, this proposal focuses on a specific disease called PACS-2 syndrome, also known as developmental and epileptic encephalopathy-66 (DEE66). This disease falls under the category of early infantile developmental and epileptic encephalopathies (EIDEE). With our research, we aim to understand the metabolic changes in cells from patients with PACS-2 syndrome by examining the cells' energy production. We will characterize these changes in detail and manipulate them with known and novel drugs, using control and patient-derived induced pluripotent stem cells (iPSCs). We also plan to create brain organoids, which are small, lab-grown brain models, from control and patient cells, where we can further test our drugs. Our approach will lead to new treatments for these rare childhood diseases and improve the lives of those affected.