Therapeutic strategies for preclinical treatment of L1 syndrome

L1CAM基因突变导致神经发育障碍，统称为L1综合征，其特征是脑积水、智力低下、胼胝体发育不全和皮质脊髓束畸形。L1综合征的病因和病理机制尚未完全阐明，目前尚无有效的治疗方法。我们已经建立了不同的L1综合征小鼠模型，要么是结构性缺失的L1CAM基因，要么是在L1综合征患者的同源位置携带错义突变的小鼠L1基因。在这个项目中，我们的目标是开发和测试第一种治疗L1综合征的方法在小鼠模型上。为此，我们将应用(A)通过宫内电穿孔的遗传L1恢复和(B)在关键的神经发育阶段用L1模拟化合物对突变的L1进行药理刺激。为了检验这些方法对中枢神经系统畸形的影响，动物将接受神经解剖学监测，使用各种(免疫)组织学分析和中枢神经系统磁共振成像以及行为测试。此外，在人类胚胎干细胞来源的神经元中结合遗传拯救和L1模拟化合物将为翻译方法治疗L1综合征的可行性提供初步线索。

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.