A scientific breakthrough provides new hope for millions of people living with multiple sclerosis. Researchers at Oregon Health & Science University have developed a compound that stimulates repair of the protective sheath that covers nerve cells in the brain and spinal cord.

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

MS is a chronic condition that affects an estimated 2.3 million people worldwide. In MS, the sheath covering nerve fibers in the brain and spinal cord becomes damaged, slowing or blocking 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 pursued thyroid hormone therapies due to unacceptable side effects.

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

“There are no drugs available today that will re-myelinate the de-myelinated axons and nerve fibers, and ours does that,” said senior author Tom Scanlan, Ph.D., professor of physiology and pharmacology in the OHSU School of Medicine.

Co-author Dennis Bourdette, M.D., chair of neurology in the OHSU School of Medicine and director of the OHSU Multiple Sclerosis Center, said he expects it will be a few years before the compound advances to the stage of a clinical trial involving people. Yet the study provides fresh hope for patients in Oregon and beyond.

“It could have a significant impact on patients debilitated by MS,” Bourdette said.

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

• Myelin repair with minimal side effects: The study demonstrated that the compound – known as sobetirome – promotes remylenation without the severe side effects of thyroid hormone therapy. Thyroid hormone therapy has not been tried in people because chronic elevated exposure known as hyperthyroidism harms the heart, bone, and skeletal muscle.
• Efficient delivery: Researchers developed a new derivative of sobetirome (Sob-AM2) that penetrates the blood brain barrier, enabling a tenfold increase in infiltration to the central nervous system.

“We’re taking advantage of the endogenous ability of thyroid hormone to repair myelin without the side effects,” said lead author Meredith Hartley, Ph.D., an OHSU postdoctoral researcher in physiology and pharmacology.

Co-authors credited the breakthrough to a collaboration that involved scientists and physicians with expertise ranging across 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 lived with multiple sclerosis since being diagnosed in 1995. The daughter of Portland advertising executive Dan Wieden, she is the namesake and board member of the Laura Fund for Innovation in Multiple Sclerosis, which funded much of the research involved in the study published today.

“I am really optimistic,” Wieden said. “I hope that this will be literally a missing link that could just change the lives of people with MS.”

Scanlan originally developed sobetirome as a synthetic molecule more than two decades ago, initially with an eye toward using it to lower cholesterol. In recent years, Scanlan’s lab 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.

Supported by funding provided through the Laura Fund and the National Multiple Sclerosis Society, the team turned to Ben Emery, Ph.D., an associate professor of neurology in the OHSU School of Medicine. Emery, an expert who previously established his own lab in Australia focused on the molecular basis of myelination, genetically engineered a mouse model to test the treatment.

With promising early results, researchers wanted to see if they could increase the amount of sobetirome that penetrated into the central nervous system.

They did so through a clever trick of chemistry known as a prodrug strategy.

Scientists added a chemical tag to the original sobetirome molecule, creating an inert compound called Sob-AM2. The tag’s main purpose is to eliminate a negative charge that prevents sobetirome from efficiently penetrating the blood-brain barrier. Once Sob-AM2 slips past the barrier and reaches the brain, it encounters a particular type of brain enzyme that cleaves the tag and converts Sob-AM2 back into sobetirome.

“It’s a Trojan horse type of thing,” Scanlan said.

Researchers found that the treatment in mice not only triggered myelin repair, but they also measured substantial motor improvements in mice treated with the compound.

“The mouse showed close to a full recovery,” Scanlan said.

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

Bourdette said even though it may not help his patients today, he’s optimistic the discovery eventually will move from the lab into the clinic.

“Right now, what it means is hope,” he said.

 

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which the body’s own immune cells attack the fatty, insulating myelin sheath surrounding nerve fibers. The regeneration of intact myelin sheaths is a necessary prerequisite for patients to recover from MS relapses. Nevertheless, the body’s ability to regenerate myelin decreases with age.

A team led by Prof. Mikael Simons from the Technical University of Munich (TUM) has now published a possible explanation in the journal Science: Fat derived from myelin, which is not carried away rapidly enough by phagocytes can trigger chronic inflammation that in turn impedes regeneration. Furthermore, in a second publication Simons’ team describes the discovery of novel cell type, which appears only when a myelin sheath is being created.

The myelin sheath plays a decisive role in the function of the central nervous system: it is a specialized membrane enriched in lipids, which insulates nerve fibers so that electrical signals can be passed on quickly and efficiently. In MS, there is a multifocal autoimmune attack against the myelin sheath in the central nervous system, which causes neurological deficits such as loss of motor function. Regeneration of myelin is possible, but in MS it is inadequate.

One of the reasons is presumably chronic inflammation occurring in the lesions. A team led by TUM Molecular Neurobiology professor Mikael Simons has now discovered that after the destruction of myelin crystalline cholesterol can trigger persistent inflammation which prevents regeneration, similar as in arteriosclerosis.

Dangerous crystals

“Myelin contains a very high amount of cholesterol,” explains Prof. Simons. “When myelin is destroyed, the cholesterol released has to be removed from the tissue.” This is performed by microglia and macrophages, also referred to as phagocytes. They take up the damaged myelin, digest it and transport the non-digestible remainder, such as cholesterol, out of the cell by transport molecules. However, if too much cholesterol accumulates in the cell, cholesterol can forms needle-shaped crystals, which cause damage the cell. Using a mouse model, Simons and his team showed the devastating impact of the crystalline cholesterol: It activates the so-called inflammasome in phagocytes, which results in the release of inflammatory mediators, attracting even more immune cells. “Very similar problems occur in arteriosclerosis, however not in the brain tissue, but in blood vessels,” says Simons.

How well the microglia and macrophages did their job was ultimately also dependent on the age of the animal: the older the animal, the less effective was the clearance of cholesterol and the stronger the chronic inflammations. “When we treated the animals with a medication that facilitates the transport of cholesterol out of the cells, inflammation decreased and myelin was regenerated,” says Mikael Simons. Next he and his team want to investigate whether this mechanism can be used therapeutically to promote regeneration in MS.

Newly discovered cells indicate regeneration

A crucial prerequisite for the development of therapies that promote repair is a better understanding of myelin formation. In another study, recently published in the journal Science Translational Medicine and led by Prof. Simons and Prof. Christine Stadelmann of the University of Göttingen’s Institute of Neuropathology, provides important new insights into this process. The scientists discovered a novel oligodendroglial cell type. Oligodendrocytes are specialized glial cells that are responsible for myelination in the central nervous system.

“We believe that the BCAS1-positive oligodendrocytes that we discovered represent an intermediate stage in the development of myelin-forming cells. In humans they can only be identified for a relatively short period of time, exactly then when myelin is actually being formed,” says Mikael Simons. In the human brain, for example, they are found in newborns, which generate myelin at high rate. In adults, these cells disappear, but they can be re-formed when myelin has been damaged and needs to be regenerated.

“We hope that the BCAS1 positive cells will help us to identify new regenerative medicines,” says Mikael Simons. We can now rapidly screen for drugs that promote the formation of these cells, he adds. Furthermore they could be used to get a better understanding of exactly when and how myelin is created during the course of a human life, he says.