Glial ErbB2-receptor inhibition as a novel therapeutic rational for Charcot-Marie-Tooth disease 1A (CMT1A).

• Applicant: Professorin Dr. Ruth Martha Stassart
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450539354

Charcot-Marie Tooth Disease 1A is the most common inherited neuropathy, caused by a duplication of the gene encoding for the peripheral myelin protein of 22kDA (PMP22). Affected patients suffer from a slowly progressive distally pronounced muscle atrophy and sensory symptoms. No causative treatment is available for CMT1A disease, as the pathological mechanisms are still poorly understood. We could previously demonstrate that Schwann cells in rodent models for CMT1A disease induce the persistent expression of the soluble growth factor Neuregulin-1, which is associated with a chronic hyperactivation of the ErbB-receptor and the MEK/ERK signaling pathway. Importantly, we found this maintained glial Neuregulin-1 autostimulation to negatively influence the disease course in CMT1A by driving specific disease hallmarks on the long term. Indeed, the genetic disruption of the Neuregulin-1 gene in CMT1A mice exclusively in Schwann cells suppressed the formation of ‘onion bulb’ Schwann cells around myelinated fibers, normalized molecular Schwann cell differentiation and ErbB/MEK/ERK activity, improved the electrophysiological properties of peripheral nerves and strongly gained the motor performance of CMT1A miceWe hence propose that a suppression of the hyperactivated Neuregulin-1/ErbB/MEK/ERK signaling constitutes a promising therapeutic strategy for CMT1A disease. Importantly, aberrant ErbB2 or MEK/ERK signaling are well-known driving factors for some types of cancer, which led to the development of antagonizing drugs, such as the ErbB2 antibody Herceptin® /Trastuzumab and small molecule MEK inhibitors, such as Selumetinib, which are considered safe and are clinically available. Within this proposal we plan to (1) conditionally ablate ErbB receptors from Schwann cells of young adult CMT1A mice in order to investigate the dynamics of ErbB-receptor functioning on the molecular and histological features of Schwann cells as well as on the clinical phenotype in CMT1A. This genetic approach will provide mechanistic insight on the role of ErbB-receptor signaling in CMT1A and constitutes the basic scientific equivalent of a clinically oriented pharmacological approach that will be performed in parallel. Indeed, next to the genetic approach, we will (2) perform preclinical proof of concept therapy trials with drugs that are clinically available and either target the ErbB receptor or downstream MEK/ERK signaling in the CMT1A rat model. Together, the complementary genetic and pharmacological approaches will provide a holistic view on ErbB/MEK/ERK function in CMT1A and its eligibility as a clinical therapeutic target for this life-burdening disease.

• DFG Programme: Research Grants