Promotion of remyelination by a thyromimetic drug leading to functional recovery

• Published in: Experimental neurology Vol. 389; p. 115227
• Main Authors: Duncan, Ian D., Vivian, Jeffrey A., August, Benjamin K., Keuler, Nicholas S., Komro, Abigail, Radecki, Daniel, Kiland, Julie A., Gandhi, Rohan, Reilly, Madelyn, Cameron, Starr, Rylander, Helena, Pritchard, Jessica, Ver Hoeve, James N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2025
• Subjects: Animals; Cats; Demyelinating Diseases - drug therapy; Demyelinating Diseases - etiology; Demyelinating Diseases - pathology; Demyelination; Disease Models, Animal; Female; Male; Recovery of Function - drug effects; Recovery of Function - physiology; Remyelination; Remyelination - drug effects; Remyelination - physiology; Thyromimetic drug; Demyelination; Remyelination; Thyromimetic drug
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2025.115227

Promotion of remyelination has become a critical therapeutic approach in the treatment of demyelinating disorders including multiple sclerosis (MS), both to restore function and protect intact axons against future degeneration. Thyroid hormone receptor agonist mediated signaling is critical for the maturation of oligodendrocytes (Ols) from oligodendrocyte precursor cells (OPCs) and may be a rational target for drug development in the treatment of MS. Therefore, we tested the potential of a thyromimetic drug pro-drug, LL-341070, to promote remyelination and neurologic recovery in a unique large animal model in which there is extensive demyelination throughout the CNS that results from the prolonged feeding of irradiated food. In four out of eight cats fed the irradiated diet that had developed significant neurologic dysfunction, daily treatment with LL-341070 led to clinical improvement or complete recovery of baseline function. Extensive evidence of remyelination was observed throughout the brain, spinal cord and in the optic nerve in these four animals when compared with non- treated animals. These results provide support for thyroid hormone receptor agonism as a potential novel target to promote remyelination and clinical outcomes in patients with MS. •Drugs that promote remyelination in multiple sclerosis and other myelin disorders are a major therapeutic target.•A thyromimetic drug which targeted the central nervous system was tested in a large animal model of demyelination.•Treatment with the drug resulted in marked neurologic improvement in test subjects.•Clinical improvement was related to robust remyelination in the brain, optic nerve and spinal cord.