Grant: Team Grant: E-Rare Joint Transnational Call

Rare inborn errors of lysine metabolism such as pyridoxine-dependent epilepsy (PDE) and glutaric aciduria type 1 (GA1) cause debilitating, often progressive neurologic symptoms with chronic care dependency. Medical needs are unmet as current dietary therapy is burdensome and often ineffective, with negative impact on quality of life and socio economics. Our international CHARLIE project synergizes the expertise of patient representatives, basic and clinical scientists, to collaboratively develop and validate new therapies and biomarkers. We pursue different strategies to avoid brain damage: inhibition of the enzyme upstream to GA1 and PDE with the potential to prevent build up of highly reactive metabolites as well as gene therapy to replace the missing GA1 enzyme. We will first apply these in PDE and GA1 model systems, such as neuronal stem cells, mouse and zebrafish models. To evaluate and compare the efficacy of these different treatment approaches, we will perform biochemical, morphological, neurobehavioural analyses. We will develop tools for monitoring therapeutic effect, enabling personalized medicine. With our patient advocacy organizations, we will prioritize the most promising treatment strategy/-ies and enhance trial readiness. To inform families, professionals, and stakeholders, we will organize regular meetings and create digital platforms. For successful exploitation we engage industry and policymakers. Together our CHARLIE consortium will translate knowledge from bench to bedside, with drug access for improved outcomes for PDE and GA1 patients and families.