Pharmacological and bioelectric enhancement of remyelination and recovery

Nearly 1 million people in the United States alone are affected by Multiple Sclerosis (MS). MS is an inflammatory, demyelinating disease of the central nervous system (CNS) in which the loss of myelin can lead to physical disability or cognitive impairment. Recent evidence indicates that gray matter areas have significant myelin loss and increased cortical lesion load is associated with increased cortical atrophy and cognitive decline. Interestingly, the capacity for repair of demyelinated axons persists in the adult brain, as oligodendrocyte precursor cells can generate new oligodendrocytes, which restore neuronal function through the remyelination of denuded axons. Current disease-modifying therapies modulate the immune system to decrease the frequency of MS attacks, but do not prevent the accumulation of disability or cognitive impairments. Therapeutic approaches that that increase remyelination reduce clinical severity in animal models of MS and can enhance neuronal function in MS patients. This supports the continued development of remyelinating therapies to enhance myelin repair. The overarching goal of this work is to determine if paired-VNS may drive remyelination and motor functional recovery in an animal model of demyelination. Our preliminary data indicate that paired-VNS promotes remyelination following a demyelinating episode, restore the myelin pattern and improves short- and long-term functional recovery. Our studies will provide, for the first time to our knowledge, evidence for the pro- myelinating role of paired-VNS, laying the groundwork for future clinical investigations in the use of VNS for patients with MS. Results from the proposed experiments will explore how paired-VNS influences differing aspects of myelin biology during remyelination, including oligodendrogenesis and specificity of sheath replacement. In addition, we will determine if paired-VNS can rescue the hyperexcitability that accompanies demyelination. We expect that changes in neural activity will drive sheath replacement, which will correlate to motor functional recovery. Additionally, we will explore possible synergistic effects between paired-VNS and the remyelinative agent, by boosting oligodendrogenesis with the drug, but shaping myelin sheath placement with paired VNS. This study will provide key insights into the use of VNS during demyelination and facilitate the development of restorative therapies in MS and other demyelinating disorders. Project Number: 1R01NS143960-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Cristin Welle (+1 co-PI) | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $575,655 | Activity Code: R01 | Study Section: Bioengineering and Tissue Engineering for Neuroscience Study Section[BTEN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368203