Progress in finding new treatments for neurologic disorders is often slow and incremental, and it rarely yields therapies that inhibit progression of these diseases. Treatment usually focuses on relieving symptoms. An exception to this pattern is treatment for multiple sclerosis (MS). In the late 1980s, researchers began trials on interferon beta-1b, a drug that was shown to modify MS activity. It was approved by the US Food and Drug Administration (FDA) in 1993.
Since then, almost two dozen disease-modifying therapies have been approved by the FDA to treat MS. These medications inhibit the immune system's ability to attack the nervous system, which can decrease the number and severity of symptom flare-ups; inhibit the development of new lesions in the brain and spinal cord; and, in some cases, delay progression of disability.
Before these therapies were available, up to 65 percent of patients diagnosed with relapsing-remitting MS—marked by periods of flare-ups followed by recovery (remission)—would progress to secondary progressive MS (in which disability steadily worsens with no periods of remission) within 10 years. Almost 90 percent would progress to the more severe form of the disease within 25 years, and about half of patients would be unable to walk unaided after 15 years. Now the percentage of people with relapsing-remitting MS who develop secondary progressive MS may be as low as 15 to 30 percent, according to data from a consensus paper by the Multiple Sclerosis Coalition updated in 2019.
“Many drugs substantially decrease progression of MS, but don't reverse the course of the disease,” says Seema K. Tiwari-Woodruff, PhD, professor of biomedical sciences in the School of Medicine at the University of California, Riverside. For that, she says, drugs that protect or regrow myelin are needed.
Myelin Basics
Nerves are like electric cables. The wire, or axon, that conducts electrical and chemical signals between nerves is covered by myelin, an insulating material that protects the axons and ensures the swift and efficient conduction of electrical impulses.
In MS, inflammation damages myelin and oligodendrocytes (cells that form myelin). As the myelin is removed—a process called demyelination—the axon can become damaged. The demyelinated nerves become vulnerable and signal for help, which comes from cells called oligodendrocyte progenitor cells. They move to the damaged area and morph into more mature oligodendrocytes, which can generate new myelin, a process known as remyelination. If too many oligodendrocytes are damaged, there is limited remyelination.
Blocking factors such as proteins also can interfere with the ability of oligodendrocyte progenitor cells to become mature myelin-forming cells and move to the area that needs repair. All of this results in thinner, less protective myelin sheaths.
Therapies focused on remyelination involve two different but complementary mechanisms, says Moses Rodriguez, MD, FAAN, director of the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, MN. The first is to remove damaged myelin. The second is to stimulate oligodendrocyte progenitor cells to proliferate and migrate into the damaged area. He compares the process to gardening. “To encourage healthy growth in a plant you need to trim and remove any dead limbs and possibly live ones that may be inhibiting growth. Then you need fertilizer to stimulate beautiful growth.”
In people with MS, remyelination can occur spontaneously and is more effective if the axon has not been irreversibly damaged.
Researching Remyelination
In 2020, in a phase 2 clinical trial researchers at the University of Cambridge showed, through brain scans and vision tests, that bexarotene (Targretin)—a drug used to treat cancer—could trigger remyelination in humans. The results were tempered by the medication's serious side effects, including thyroid disease and potentially damaging levels of blood fats. The scientists are now looking at whether the diabetes drug metformin (Glucophage) can produce the same result with fewer side effects. In a phase 2a trial, participants on disease-modifying therapies will take metformin with the antihistamine clemastine (Tavegyl), which has been shown to enhance remyelination in humans in a small pilot trial. Evidence from animal studies shows that metformin enhances the effect of clemastine on myelin repair, but the two drugs have never been tested in combination in human trials.
In a phase 1 clinical trial of 72 patients with MS, Dr. Rodriguez tested a monoclonal antibody—one of three his lab identified that bind to the surface of oligodendrocytes and trigger remyelination in experimental models of MS—for safety and to see if it could cross the blood-brain barrier, a boundary between circulating blood and the extracellular space of the brain that helps protect the brain from damage. None of the patients experienced major side effects, and the antibody was seen in the cerebrospinal fluid of all patients tested, indicating that it was able to cross the blood-brain barrier. Entering the central nervous system means the antibody would be present to help promote remyelination. A phase 2 clinical trial is in the works to test whether the drug can promote remyelination in humans; it has promoted it in animal studies.
Animal Studies
At the Oregon Health & Science University School of Medicine in Portland, Dennis Bourdette, MD, FAAN, chair emeritus of neurology, is looking at sobetirome, a synthetic compound that has promoted remyelination in mice. In a study published in the Journal of Neuroimmunology in 2021, Dr. Bourdette found that the compound prevented damage to myelin and nerve fibers in mice with an MS-like disease by stimulating a protective response in myelin-producing cells; it also reduced inflammatory activity in cells in the brain and spinal cord. Sobetirome, he says, not only encourages remyelination, it also can prevent demyelination.
Some studies have shown that estrogens and estrogen-like compounds reduce MS-like inflammation and disability in mice. As part of her research, Dr. Tiwari-Woodruff is looking at whether chloroindazole (IndCl), a compound that acts on a subset of estrogen receptors, can promote remyelination and reduce inflammation. “In mice, IndCl has also been shown to lessen damage to the spinal cord, corpus callosum, and parts of the visual system,” she says. In an animal study published in Brain Pathology in 2021, Dr. Tiwari-Woodruff reported that IndCl was about 50 percent effective in repairing myelin, protecting nerve fibers, and increasing visual function. Another estrogen receptor modulator, bazedoxifene, which has been shown to promote remyelination in animals is now being tested in humans.
In another mouse study, researchers at the University of California, Irvine discovered that a simple sugar found in human breast milk promotes myelin repair. The results, which were published in the Journal of Biological Chemistry in 2020, showed that delivering the sugar orally to lactating mice activated stem cells which triggered myelination in their nursing infant mice.
Swiss researchers were able to regenerate damaged myelin sheaths and restore nerve-cell function in mice by injecting them with theophylline, an asthma drug. Theophylline speeds up remyelination and helps repair or reduce MS lesions by activating an enzyme called HDAC2, they reported in their July 2020 study in Nature Communications.
Nondrug Therapies
Scientists are also looking at how diet and exercise affect the central nervous system and remyelination. A 2016 study published in Molecular Basis of Disease found that mice on high-fat diets, especially those that were more sedentary, were likely to have fewer myelin-forming cells. When the mice exercised, they produced more oligodendrocyte progenitor cells and oligodendrocytes, which mitigated some of the harmful effects of an unhealthy diet and enhanced central nervous system function.
A 2019 study funded by MS Research Australia and published in Nature Communications looked at repetitive transcranial magnetic stimulation (rTMS), which stimulates electrical activity in certain areas of the brain, in monkeys. After administering rTMS for two weeks, the researchers saw an increase in the number of new myelin-producing cells in the monkeys' cortex, the outer layer of the brain.
Other studies in animals also suggest that stimulating neuronal activity is important for remyelination.
MS researchers like Dr. Bourdette are optimistic about the future. “Now that we're focusing on developing reparative therapies,” he says, “I believe we'll have treatments that promote remyelination and repair in MS within the next 10 to 15 years.”
The Basics of Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disorder that affects the brain, spinal cord, and optic nerve. It's caused by immune cells and antibodies attacking and destroying the myelin sheath, a coating made of fat and proteins that protects nerves and helps transmit electrical signals.
People with MS experience neurologic symptoms related to the part of the nervous system damaged. For example, if the optic nerves are affected, patients may experience vision problems. The breadth of symptoms is wide and may include sensory loss, difficulty with coordination and movement, muscle weakness, fatigue, numbness, and bowel and bladder problems. Cognitive symptoms are seen in more than half of people with MS. During an exacerbation—also known as an attack, relapse, or flare-up—new symptoms may appear or preexisting ones worsen.
Medication Options
MS is treated with disease-modifying therapies (DMTs), which help control inflammation, reduce the number and severity of relapses, lessen the development of new lesions in the brain and spinal cord, and delay progression of disability. While DMTs cannot repair existing damage or reduce the number of lesions already present, they can slow damage to the nervous system. To some degree, most DMTs slow the progression of brain shrinkage and brain volume loss.
DMTs can be taken orally, by injection, or by intravenous infusion; administration varies widely from once or twice daily to once or twice a year.
Patients and neurologists may approach treatment in different ways. In the escalation approach, doctors begin treatment with a lower-risk drug, usually from the first generation of injectables, which don't need to be monitored as closely and generally have fewer long-term side effects. Patients remain on those drugs as long as they are doing well, and may move to different medications only if they develop new MS symptoms or show evidence of new brain lesions on MRIs.
With a more aggressive approach, neurologists prescribe stronger medications as early as possible. These highly effective treatments, generally using the more recently developed drugs, have a better chance of suppressing the inflammatory process and stopping disease progression, but they also have a higher risk of adverse side effects, including serious infections. Some doctors prescribe these drugs only to patients who cannot tolerate or have an inadequate response to other drugs or to those who appear to have a highly active form of the disease.
Two large-scale randomized clinical trials are underway to study these approaches.
Healthy Habits
Self-care is an important factor in managing MS. No diet has been shown to have disease-modifying effects, but some diets do improve symptoms such as fatigue. In addition, eating healthfully can improve or prevent other coexisting conditions such as diabetes, hypertension, or hardening of the arteries, which lead to poorer outcomes in people with MS.
Getting adequate vitamin D is also key. A roundup of studies in the June 2018 issue of Neurology and Therapy found that low vitamin D levels may affect the onset of MS and its progression.
Exercise is also beneficial. In addition to maintaining cardiovascular and bone health, decreasing symptoms and improving function, physical activity may have immunomodulating properties. Guidelines published in the Multiple Sclerosis Journal in April 2020 suggest a minimum of 150 minutes of physical activity per week, ideally a mix of aerobic, resistance, and skill-based neuromotor activities like dance or tai chi that involve a combination of gait, balance, agility, and hand-eye coordination.
Be wary of overheating, which can trigger symptoms, says John Corboy, MD, FAAN, professor of neurology at the University of Colorado School of Medicine in Aurora. He suggests keeping ice water handy or wearing a cooling vest or collar—a flexible ice pack that attaches with Velcro—if the weather is especially warm.
To counter fatigue, Dr. Corboy recommends exercise, adequate sleep, maintaining a healthy weight, energy-conserving strategies, and even pharmaceutical options. He encourages patients to work with their doctors to rule out thyroid problems, other medical conditions that could cause fatigue, and sleep disorders. In fact, sleep disorders are more common in people with MS than in the general population.
And quit smoking. Evidence strongly suggests that it's a risk factor for both getting MS and promoting disease progression.
Don't dismiss mood changes, says Dr. Corboy. As many as 50 percent of people with MS experience depression and 30 percent report anxiety. If you are feeling depressed or anxious, be sure to share that with your doctor or consider psychotherapy and, if necessary, medication.
