Development of a vector-based therapeutic for CMT2E using a novel mouse model

Charcot-Marie-Tooth (CMT) is one of the most common inherited neurological disorders affecting 1 in 2,500 people in the U.S. and nearly 3 million people worldwide. There are five main types of CMT with each type having numerous subtypes, such as CMT type 2E (CMT2E), and more than 100 different disease-causing genes have been identified. While most types of CMT are not lethal, these diseases significantly impact the quality of life of individuals with CMT and their families. To address CMT disease, several animal models associated with distinct genetic mutations have been developed that faithfully mimic CMT pathology providing tremendous value to our understanding of CMT disease initiation and progression. Despite these advances, no cures for any CMT subtype have been approved. We are proposing to develop a precision medicine-based approach to treating CMT2E, using a specific patient-derived mutation as the pre-clinical model developed in the Lorson laboratory. CMT2E is caused by mutations in the neurofilament light gene (NEFL). NEFL codes for the neurofilament light protein (NF-L), which, along with other intermediate filaments, including neurofilament middle and heavy, are involved in maintaining structural stability of neurons among other roles. Neurofilament aggregation is also a pathology of several neurodegenerative diseases. CMT2E-causing missense mutations have been identified throughout the various functional domains within the NF-L protein. To address the extent of NEFL mutations, we developed a mutation agnostic therapeutic approach; therefore, our therapeutic vector should address disease associated with most NEFL mutations. We developed a novel CMT2E animal model that represents a specific human patient mutation (NEFL- E396K) within the mouse Nefl gene (E397K). The Nefl-E397K mouse model faithfully recapitulates CMT2E disease. Using this disease context, we will leverage the AAV9 gene therapy system to deliver a dual cargo therapeutic vector developed in the Lorson laboratory. This vector delivers two complementary therapeutic “payloads” designed to reduce mutant NEFL, restore healthy/functional NF-L protein and prevent disease development. This project is a collaboration between several labs that bring together ideally suited areas of expertise: 1) the Lorson lab which has a long-standing interest in developing therapeutics and viral vectors for SMA, SMARD1 and other neurodegenerative diseases; 2) the Arnold lab which brings CMT experience in pre- clinical models as well as within the clinic; and 3) Dr. Hong An, an expert in bioinformatic analysis. This is a project focused upon furthering our understanding of CMT2E disease progression as well as further optimizing and validating a therapeutic for this important disease. This cross-disciplinary team is well positioned to successfully complete this project. Project Number: 1R01NS142297-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Christian Lorson (+1 co-PI) | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $574,083 | Activity Code: R01 | Study Section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293077