Modulating the Hippo pathway in Charcot-Marie-Tooth disease

Modulating the Hippo pathway in Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy, affecting millions worldwide and profoundly impairing quality of life. Characterized by a toxic overexpression of PMP22, CMT1A leads to progressive demyelination and nerve degeneration. While advancements in gene therapy have sought to mitigate the disease, clinical outcomes remain modest, highlighting the need for innovative therapeutic strategies. This proposal investigates the modulation of the Hippo pathway as a novel approach to treating CMT1A. Specifically, we focus on targeting the YAP/TAZ-TEAD1 transcriptional complex, which regulates PMP22 expression in Schwann cells. Using advanced genetic models and repurposed TEAD inhibitors, we aim to evaluate the potential of reducing PMP22 levels and alleviating disease pathology. First, we will examine the molecular and cellular effects of YAP/TAZ/TEAD1 inhibition in Schwann cells, leveraging TEAD inhibitors to reduce PMP22 expression and mitigate CMT1A-associated impairments. Second, we will explore the therapeutic potential of TAZ ablation and TEAD inhibitors in vivo, assessing their ability to prevent or reverse myelin defects and restore nerve function in a preclinical mouse model. Finally, comprehensive analyses, including spatial transcriptomics and long-term safety evaluations, will deepen our understanding of the mechanisms underpinning these interventions. By integrating pharmacological and genetic approaches, this tool compound study aims to provide a transformative strategy for CMT1A, repurposing existing drugs to accelerate therapeutic development. The findings could have broad implications, offering a foundation for addressing other peripheral neuropathies and expanding the therapeutic applications of Hippo pathway modulation. Project Number: 1R01NS146225-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Yannick Poitelon (+2 co-PIs) | Institution: ALBANY MEDICAL COLLEGE, ALBANY, NY | Award Amount: $562,051 | Activity Code: R01 | Study Section: Cellular and Molecular Biology of Glia Study Section[CMBG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11273748