Synthetic Molecule May Promote Remyelination, Shows Promise for Multiple Sclerosis

Early results have demonstrated that a compound known as sobetirome may help promote remyelination with minimal adverse effects, which could lead to a potential new treatment for multiple sclerosis (MS), according to new research.

A study published in JCI Insight evaluated the compound in mice genetically engineered to mimic MS. Although therapies for MS currently exist, they are used to alleviate the symptoms associated with the disease and there are no drugs available that can repair myelin, the protective sheath the covers nerve cells in the brain and spinal cord, according to the study. In MS, damage to myelin leads to neurodegeneration and disability. The demyelination of axons in the central nervous system (CNS) is the primary feature of the disease.

Sobetirome was originally developed as a synthetic molecule intended for use in lowering cholesterol. Since then, the compound has also been adapted as a promising therapy for the rare metabolic disease adrenoleukodystrophy, according to the study authors.

Thyroid hormone (TH) therapy is known to stimulate myelination through enhancing oligodendrocyte differentiation. However, its use in promoting remyelination in a clinical setting has not be explored due to the systemic adverse effects associated with excessive exposure to TH, according to the study.

The researchers noted that sobetirome is unique among thyromimetics for its ability to cross the blood-brain barrier and distribute to the CNS from a systemic dose. By developing a selective TH agonist that penetrates the CNS, the researchers were able to use sobetirome for its myelin-repairing effects without the severe adverse effects associated with TH therapy. The novel prodrug, Sob AM2, was shown to systemically lead to increased CNS distribution and decreased peripheral exposure of the parent drug sobetirome.

In the mouse model, the authors found that chronic treatment with sobetirome led to significant improvement in both clinical signs and remyelination. However, chronic treatment with a thyroid hormone in the mice inhibited endogenous myelin repair and exacerbated the disease, according to the study.

Additionally, the study showed that the treatment in mice also demonstrated substantial motor improvement.

“These results support the clinical investigation of selecting CNS-penetrating TH agonists, but not TH, for myelin repair,” the researchers wrote in the study.

Reference

Hartley MD, Banerji T, Tagge IJ, et al. Myelin repair stimulated by CNS-selective thyroid hormone action. JCI Insight. 2019. Doi: 10.1172/jci.insight.126329