CHAnging Rare disorders of LysInE metabolism

• Applicants: Professor Dr. Martin Hrabe de Angelis; Professor Dr. Stefan Kölker, since 11/2022
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461214393

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: (1) inhibition of the enzyme in lysine metabolism upstream of the defect enzymes in GA1 and PDE, with the potential to prevent build-up of highly reactive metabolites; (2) 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 the 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. To sum up, the overall aim of this project is to evaluate novel treatment strategies for PDE and GA1 that target a new causative pathway in lysine metabolism. At the end of the project, we will have successfully tested the efficacy of nucleic acid-based therapies and small molecule inhibitors strategies in novel translational models for PDE and GA1, and evaluated novel translational biomarkers for treatment monitoring and prognostication. By this, the CHARLIE consortium focuses on the right target, the right tissue, and the right safety profile for the right patient.

• DFG Programme: Research Grants
• International Connection: Canada, Italy, Luxembourg, Netherlands, Spain
• Cooperation Partners: Dr. Karlien Coene, Ph.D.; Dr. Cristina Fillat, Ph.D.; Professorin Dr. Clara van Karnebeek; Professor Dr. Blair Leavitt, Ph.D.; Professorin Dr. Carole Linster, Ph.D.; Dr. Giancarlo la Marca, Ph.D.
• Ehemalige Antragstellerin: Dr. Bianca Dimitrov, until 11/2022