Therapeutic strategies for preclinical treatment of L1 syndrome

• Applicants: Professorin Dr. Melitta Schachner; Professor Dr. Michael K. E. Schäfer
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2011 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 200158289

Mutations in the L1CAM gene cause neurodevelopmental disorders collectively termed L1 syndrome which is characterized by hydrocephalus, mental retardation, corpus callosum agenesis, and corticospinal tract malformations. The etiology and pathological mechanisms of the L1 syndrome are incompletely elucidated and no therapy is available to treat the L1 syndrome. We have established different L1 syndrome mouse models either constitutively deleted in the L1CAM gene, or engineered to carry a missense mutation in the murine L1 gene which is pathogenic at a homologous site in L1 syndrome patients. In this project, we aim to develop and test first therapeutic approaches to treat L1 syndrome in mouse models. To this end we will apply (a) genetic L1 restoration by in utero electroporation and (b) pharmacological stimulation of mutant L1 by L1 mimetic compounds at critical neurodevelopmental stages. To examine effects of these approaches on CNS malformations, animals will be subjected to neuroanatomical monitoring using various (immuno-) histological analyses and magnetic resonance imaging of the CNS as well as behavioral testing. Moreover, combining genetic rescue and L1 mimetic compounds in human embryonic stem cell-derived neurons will provide first clues for the feasibility of translational approaches in L1 syndrome.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Gabriele Loers