Researchers have developed a compound based on the thyroid hormone T3 that is able to repair damaged myelin in the brain of mice, a discovery that holds promise for healing myelin loss in patients with multiple sclerosis (MS), results of an early study reveal.
The compound combines a brain-penetrating agent and a chemical mimic of T3, and may be a future remyelination therapy delivered specifically to the central nervous system (CNS) — brain and spinal cord — with few side effects.
The study “Myelin repair stimulated by CNS-selective thyroid hormone action” was published in the journal JCI Insight.
During development, the active form of the thyroid hormone T3 promotes the formation of myelin-producing cells at the CNS; these cells are called oligodendrocytes. As a result, the myelin sheath around nerve fibers grows in the presence of this hormone.
However, using thyroid hormone has not been eyed as a potential remyelination therapy given its unwanted side-effects when delivered systemically (into the bloodstream) and affecting the entire body.
That’s why scientists at Oregon Health & Science University (OHSU), in collaboration with researchers from other institutions, devised a novel approach to address this limitation.
The team used sobetirome, a thyromimetic — a molecule that mimics T3, binding to and activating its natural receptor in the body.
Sobetirome is devoid of the adverse side effects associated with excess thyroid hormone, “and unique among thyromimetics for its ability to cross the blood-brain barrier and distribute to the CNS from a systemic dose” researchers wrote. The blood-brain barrier is a protective barrier between the brain’s blood vessels and the brain tissue.
To further improve the compound’s availability in the brain and reduce off-targets, the team also created a sobetirome prodrug called Sob-AM2, that is selectively activated at the CNS.
Sob-AM2 basically consists of the original sobetirome attached to a chemical tag that takes out the negative charge of the molecule, facilitating its crossing through the blood-brain barrier. Once this happens, the compound enters the brain and finds a specific enzyme that cleaves the tag and converts Sob-AM2 back into sobetirome.
The prodrug is known to significantly increase delivery of sobetirome to the brain, while at the same time decreasing the amounts of the compound in the blood and peripheral organs.
In different mouse models of demyelination (myelin loss) and remyelination (myelin regrowth), continued treatment with either sobetirome or Sob-AM2 restored myelin around nerve fibers in the brain, leading to substantial motor improvements.
In addition, sobetirome also increased the number of myelinated nerve fibers at the spinal cord.
“The mouse showed close to a full recovery,” Tom Scanlan, PhD, professor of physiology and pharmacology in OHSU School of Medicine and the study’s senior author, said in a press release.
In contrast, treatment with T3 inhibited myelin repair and worsened disease, confirming this is not a viable treatment option.
“Sobetirome, Sob-AM2, and other recently developed sobetirome derivatives, are the only thyromimetics reported to date that distribute to the CNS from systemic administration, making this subset of selective TH [thyroid hormone] agonists suitable for clinical evaluation in demyelinating diseases such as MS,” researchers wrote.
“There are no drugs available today that will re-myelinate the de-myelinated axons and nerve fibers, and ours does that,” Scanlan said.
Laura Wieden, MS patient and namesake board member of the Laura Fund for Innovation in Multiple Sclerosis, which helped fund the project, added: “I am really optimistic. I hope that this will be literally a missing link that could just change the lives of people with MS.”
Even though the discovery is a sign of hope, researchers expect it will be years before the compound can move into clinical trials in humans.
With that in mind, OHSU already has licensed the technology to Llama Therapeutics, a biotech company based in California, which is pursuing this and other therapy candidates for MS and other disorders.