Endocrine Abstracts

Thyroid hormone plays a critical role in the production and maintenance of myelin, the lipid-rich sheath that surrounds the outer surface of axons. Myelin is made from processes that extend from oligodendrocytes (OL), a glia cell that comprises about 20% of the cells in the adult central nervous system (CNS). Mature, myelinating OL are produced from a differentiation pathway that begins with neural stem cells and involves the differentiation of oligodendrocyte progenitor cells (OPC), and this final step in the process is regulated by thyroid hormone. Demyelinating lesions in the CNS of multiple sclerosis (MS) patients often contain large numbers of OPC that are unable to differentiate into OL because of an unknown disease associated inhibition of the process. Because there are currently no therapies that stimulate myelin repair for demyelinating diseases like MS, we are pursuing a line of research that asks whether an appropriate thyroid hormone analog can stimulate myelin repair in a mouse model of demyelination. For the thyroid hormone analog, we used the TRß-selective and cardiac and bone sparing thyromimetic sobetirome to avoid the well-known adverse effects associated with chronic hyperthyroidism. We also employed a new prodrug version of sobetirome that increases the blood-brain barrier (BBB) penetration of sobetirome, substantially increasing the amount of drug in the brain while reducing the amount of drug in plasma from a systemic dose. For the demyelinating model we used a novel genetic mouse model (iCKO-Myrf) based on inducible and conditional ablation of myelin regulatory factor (Myrf), a gene critical for mature OL survival. Induction of Myrf knock-out results in essentially complete and CNS-wide disappearance of myelin with a concomitant motor defect phenotype. Results will be presented showing that thyromimetic treatment improves neurological clinical signs and repairs damaged myelin in iCKO-Myrf mice.