Compound That Mimics Thyroid Hormone Prevents MS Nerve Damage in Mice
A thyroid hormone-mimicking compound not only prevented nerve cell damage but promoted the cells’ survival in a mouse model of multiple sclerosis (MS).
This discovery advances previous research showing that the compound, called sobetirome, can induce the repair of myelin, the protective sheath around nerves. The data suggest that thyromimetics — molecules that mimic the thyroid hormone — could form the basis of a therapeutic strategy to prevent the progression of MS and other neurodegenerative disorders.
“Sobetirome and related drugs are effective at stimulating myelin repair after damage has occurred,” Dennis Bourdette, MD, the study’s senior author and a retired professor from Oregon Health and Science University (OHSU) School of Medicine, said in a university press release.
“Our new findings now suggest that these drugs could also prove to be beneficial for preventing damage from occurring,” Bourdette said. “It means that these drugs have a dual effect that we didn’t know about before.”
The study reporting the findings, “Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE,” was published in the Journal of Neuroimmunology.
Myelin coats nerve fibers, insulating the electrical charges that they conduct, much like the plastic that insulates electrical wires. The loss of myelin, as occurs during MS progression, underlies many of the disorder’s symptoms.
Thyroid hormone, via T3, its active form, regulates the development of myelin-producing nerve cells called oligodendrocytes and stimulates myelin production and repair. It is not used therapeutically in MS, however, due to a toxic effect called thyrotoxicosis.
In contrast, sobetirome binds to the same thyroid receptor but avoids triggering a toxic response.
Researchers at OHSU have now developed a way to increase the levels of sobetirome in the brain, with the goal of preventing and repairing the damage done over the course of MS and other neurodegenerative disorders.
Here, the team investigated whether their compound, called Sob-AM2 — a product that specifically targets the central nervous system — could prevent myelin and nerve fiber degeneration in experimental autoimmune encephalomyelitis mice. These are a common animal model of MS.
Mice treated with either T3, sobetirome, or Sob-AM2 showed significantly less disease severity than untreated mice. The difference was greatest among mice treated with Sob-AM2.
Importantly, this effect only occurred when the mice were treated prior to symptom onset. Treatment did not alter the disease course after symptoms had begun.
Inflammation is known to accompany — and is thought to accelerate — nerve damage and myelin loss in MS.
Although T3, sobetirome, and Sob-AM2 showed inconsistent effects on inflammatory cells, they did reduce the overall activity of microglia — inflammatory cells of the central nervous system (CNS), comprised of the brain and spinal cord. Microglia are implicated in MS and other diseases.
All three compounds also limited damage to the axons (nerve fibers) and myelin of mice. Sob-AM2 again showed the strongest effect.
Alongside reduced damage, mice treated with Sob-AM2 and T3 retained significantly more oligodendrocytes than untreated mice. Mice treated with sobetirome alone also lost fewer oligodendrocytes but the difference was not statistically significant.
Consistent with the results observed in mice, T3 and sobetirome promoted the survival of mature oligodendrocytes in cell cultures in the laboratory.
Although it remains unclear exactly how Sob-AM2 accomplishes its neuroprotective effects, the OHSU researchers say that its therapeutic potential warrants further investigation.
“Given its ability to produce high concentrations of Sob [sobetirome] within the CNS, its low potential to cause systemic thyrotoxicosis and its neuroprotective effects and ability to stimulate remyelination, Sob-AM2 and related compounds warrant consideration as a treatment for MS,” the researchers wrote, noting that the compound’s “effects are impressive.”
The team believes that Sob-AM2 could potentially be particularly useful for those diagnosed with MS early in the disease’s progression.
“The drug could protect the nervous system from damage and reduce the severity of the disease,” Bourdette said.
Of note, OHSU has licensed this technology to a spin-off called Autobahn Therapeutics, which was founded by Bourdette and two study co-authors.