Title: Developing small molecule inhibitors for a rare childhood seizure disorder
Funder: Action Medical Research

Abstract: Background_x000D_ Pyridoxine dependent epilepsy (PDE) is a rare form of childhood epilepsy. Affected children typically develop seizures soon after birth which do not respond to conventional antiepileptic medications. PDE is caused by a faulty gene that prevents the children from making a certain protein. As a result, toxic compounds build up in the body causing recurrent seizures. Many children with PDE also have delayed development and learning disabilities. Current treatment involves lifelong supplementation with pyridoxine which usually provides effective seizure control. However, this does not address the broader neurological symptoms and new treatments are urgently needed to improve the lives of these children and their families. _x000D_ _x000D_ The research project_x000D_ These researchers aim to treat the root cause of PDE by developing a drug that prevents the build-up of the toxic compounds which result in disease. Such a drug would inactivate an early step in the metabolic pathway and therefore reduce levels of the toxic metabolite. This approach is called substrate reduction therapy and has been successfully applied to other rare diseases. The team has already identified a number of potential candidate drugs and now wants to design and further develop these compounds so that they can be studied in cell models of the disease. This project will pave the way for future development of these compounds into treatments for patients. The ultimate goal is to develop a new disease-modifying treatment for PDE that addresses the root cause of the neurological symptoms and therefore greatly increases the quality of life of children affected by this rare and debilitating disease._x000D_ _x000D_ Action Medical Research and LifeArc are jointly funding this research._x000D_ _x000D_

Lay abstract: Background_x000D_ Pyridoxine dependent epilepsy (PDE) is a rare form of childhood epilepsy. Affected children typically develop seizures soon after birth which do not respond to conventional antiepileptic medications. PDE is caused by a faulty gene that prevents the children from making a certain protein. As a result, toxic compounds build up in the body causing recurrent seizures. Many children with PDE also have delayed development and learning disabilities. Current treatment involves lifelong supplementation with pyridoxine which usually provides effective seizure control. However, this does not address the broader neurological symptoms and new treatments are urgently needed to improve the lives of these children and their families. _x000D_ _x000D_ The research project_x000D_ These researchers aim to treat the root cause of PDE by developing a drug that prevents the build-up of the toxic compounds which result in disease. Such a drug would inactivate an early step in the metabolic pathway and therefore reduce levels of the toxic metabolite. This approach is called substrate reduction therapy and has been successfully applied to other rare diseases. The team has already identified a number of potential candidate drugs and now wants to design and further develop these compounds so that they can be studied in cell models of the disease. This project will pave the way for future development of these compounds into treatments for patients. The ultimate goal is to develop a new disease-modifying treatment for PDE that addresses the root cause of the neurological symptoms and therefore greatly increases the quality of life of children affected by this rare and debilitating disease._x000D_ _x000D_ Action Medical Research and LifeArc are jointly funding this research._x000D_ _x000D_

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL