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Modulating the Hippo pathway in Charcot-Marie-Tooth disease

Award Number: R01NS146225
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/06/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $562,051 )
2026	2026	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/5/2026	NEW	$562,051
														Subtotal = $562,051

Grand Total All Awards = $562,051

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Modulating the Hippo pathway in Charcot-Marie-Tooth disease

Award Number: R01NS146225

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/06/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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