"Game Changer" Potential for People with Multiple Sclerosis – ScienceDaily

The discovery, involving mice genetically modified to mimic multiple sclerosis, published in the journal JCI Insight.

MS is a chronic disease that affects approximately 2.3 million people worldwide. In MS, the sheath covering the nerve fibers of the brain and spinal cord is damaged, slowing or preventing electrical signals from reaching the eyes, muscles, and other parts of the body. This sheath is called myelin. Although myelin can regrow through exposure to thyroid hormones, researchers have not continued treatment with thyroid hormones because of unacceptable side effects.

Although many treatments and medications alleviate the symptoms of MS, there is no cure.

"There is no medication available today that remyelinates demyelinated axons and demyelinated nerve fibers, and ours does," said lead author Tom Scanlan, Ph.D., a professor of physiology and pharmacology at the OHSU School of Medicine.

Co-author Dennis Bourdette, MD, chair of neurology at the OHSU School of Medicine and director of the OHSU Multiple Sclerosis Center, said he expects that it will only be a few years before that the compound only goes to the stage of a clinical trial involving people. Still, the study offers new hope to patients in Oregon and beyond.

"This could have a significant impact on patients debilitated by MS," said Bourdette.

The discovery, if ultimately proven in clinical trials involving people, seems to achieve two important goals:

• Myelin repair with minimal side effects: The study has demonstrated that the compound – known as sobetirome – promotes remethylenation without the serious side effects of thyroid hormone therapy. Thyroid hormone therapy has not been tried in humans because a chronic high exposure called hyperthyroidism harms the heart, bones and skeletal muscles.
• Effective Delivery: Researchers have developed a new derivative of the sobetirome (Sob-AM2) that enters the blood-brain barrier, allowing a ten-fold increase in infiltration into the central nervous system.

"We are leveraging the endogenous capacity of the thyroid hormone to repair myelin without side effects," said lead author Meredith Hartley, Ph.D., a postdoctoral researcher in physiology and pharmacology at OHSU.

The authors attributed this breakthrough to a collaboration involving scientists and physicians with expertise in the fields of neurology, genetics, advanced imaging, physiology and pharmacology.

One patient said the research could be a "total game changer" for people with MS.

Laura Wieden, 48, has had multiple sclerosis since her diagnosis in 1995. Daughter of Portland Advertising Manager Dan Wieden, she is the namesake and Laura Fund Board member. for innovation in multiple sclerosis, which funded much of the research study published today.

"I'm really optimistic," said Wieden. "I hope it will literally be a missing link that could simply change the lives of people with MS."

Originally, Scanlan had developed the synthetic molecule sobetirome more than two decades ago, with the aim of using it to lower cholesterol. In recent years, Scanlan's laboratory has adapted it as a promising treatment for a rare metabolic disease called adrenoleukodystrophy, or ALD.

Six years ago, Bourdette suggested trying the compound to repair myelin in MS.

Backed by funding provided by the Laura Fund and the National Multiple Sclerosis Society, the team turned to Ben Emery, Ph.D., an badociate professor of neurology at the OHSU School of Medicine. Emery, an expert who previously established his own laboratory in Australia, has focused on the molecular basis of myelination. He genetically designed a mouse model to test the treatment.

With promising preliminary results, the researchers wanted to see if they could increase the amount of sobetiroma entering the central nervous system.

They did it through a chemistry trick known as the drug precursor strategy.

The scientists added a chemical label to the original sobetirome molecule, creating an inert compound called Sob-AM2. The main purpose of the label is to eliminate a negative charge preventing the sobetirome from effectively penetrating the blood-brain barrier. Once Sob-AM2 crosses the barrier and reaches the brain, it encounters a particular type of brain enzyme that cleaves the tag and converts Sob-AM2 into a sobetirome.

"It's a type of Trojan," Scanlan said.

The researchers found that treatment in mice not only caused myelin repair, but also measured substantial motor improvements in the mice treated with the compound.

"The mouse has shown almost complete recovery," Scanlan said.

Scientists are confident that the compound will translate from mice to people. To this end, OHSU has licensed this technology to Llama Therapeutics Inc., a biotechnology company based in San Carlos, California. Lama strives to advance these molecules to human clinical trials related to MS and other diseases.

Bourdette said that although it could not help his patients today, he is optimistic that this discovery will eventually move from the laboratory to the clinic.

"At the moment, it means hope," he said.

The research was funded by the National Institutes of Health, grant DK52798; National Multiple Sclerosis Society, grants 5199A4 and RG-1607-25053; the race to eradicate MS; and the Laura OHSU Fund for Innovation in Multiple Sclerosis.