Grant: CIHR Fellowship

Rare diseases (RDs) are often life threatening conditions caused by mutations in our genetic material. Although individually rare (<1 in 2,000 individuals), collectively RDs affect an estimated 1 in 12 Canadians, impacting families, society and the health care system. One such RD is pyridoxine dependent epilepsy (PDE), caused by a genetic defect in the breakdown of lysine, one of the building blocks of proteins; the condition is characterized by seizures and progressive intellectual disability. This defect in lysine breakdown leads to the accumulation of a toxic biochemical; this compound is believed to cause PDE and thus its reduction may have therapeutic benefit lessening seizures and neurodevelopmental problems. My work has led to the identification of drug candidates that, by two different pathways, may lower the levels of the toxic metabolites in cells isolated from PDE patients. We believe that one or both compounds may have a beneficial impact on PDE patients; importantly one of these is a safe widely used medication. An important step to translate what I have shown in patient cells into actual clinical trials is testing the drugs in an animal genetically engineered to have PDE. I propose here the generation of such an animal, specifically a zebrafish that will have the same mutations as our PDE patients. Zebrafish have emerged as an important epilepsy model, as they often display seizures that resemble the ones observed in humans. Engineering these fish to have the same lysine degradation defect as PDE patients may also result in them also displaying spontaneous seizures, we also believe they will accumulate the toxic metabolites. The animals will therefore not only help yield answers on how the seizures occur, but also be used to test the drugs candidates and perform drug screens. If successful, the zebrafish research shall lead directly clinical trials in PDE patients providing them a better quality of life.