• Posted June 29, 2023

Discovery of MS 'Severity Gene' Could Lead to Better Treatments

For the first time, scientists have identified a genetic variant that may make some people with multiple sclerosis (MS) vulnerable to faster progression.

In a study of more than 22,000 people with MS, researchers found that those who carried a particular genetic variant faced a faster decline: They needed to use a walking aid about four years earlier, on average, than people who did not carry the variant.

Experts said the finding -- reported June 28 in the journal Nature -- is a key first step to developing new treatments to slow the course of MS.

There's nothing to be done about the genes people inherit, but understanding the genetics of MS progression could allow researchers to develop new medications that target the underlying mechanisms.

"The road from basic research to a new drug is a long one, but this is an important first step," said Sergio Baranzini, a professor of neurology at the University of California, San Francisco and a senior researcher on the study.

MS is a neurological disorder caused by a misguided immune system attack on the body's own myelin -- the protective sheath around nerve fibers in the spine and brain. Because the central nervous system is affected, MS symptoms can be wide-ranging. But among the most common are fatigue, vision problems, muscle weakness, numbness and difficulty with balance and coordination.

Most people with MS are initially diagnosed with the relapsing-remitting form -- where symptoms flare for a period, then get better. Over time, many develop secondary progressive MS, where their functioning steadily worsens. About 15% of people with MS go straight into a progressive course after their first symptoms arise.

It's not clear, Baranzini said, why some people with MS end up using a wheelchair within 10 years, while others can still run marathons. But researchers have suspected that genetic susceptibility is involved.

So far, research has uncovered many genetic variants -- more than 200 -- that are linked to the risk of developing MS. All are related in some way to immune function.

But none of those genetic traits, Baranzini said, has been tied to MS progression. And the suspicion has been that MS severity is not a matter of immune function, but is related to the central nervous system and its ability to withstand the abnormal immune system attack.

Baranzini and his colleagues found the first genetic evidence that may be true.

The researchers started with data on more than 12,000 MS patients from Europe, North America and Australia. They dug through more than 7 million genetic variants before hitting on something: a chromosome region that sits between two genes with no previously known link to MS -- called DYSF and ZNF638.

Past studies have shown that DYSF helps repair cell damage, while ZNF638 has a role in controlling viral infections. Both are active in the brain and spinal cord.

It turned out that MS patients who carried a particular variant in this genetic region typically had a faster disease progression. Those who had inherited the variant from both parents needed the help of a walking aid nearly four years sooner, on average, than people without the variant.

The researchers confirmed the findings in a second group of nearly 10,000 MS patients.

Bruce Bebo, executive vice president of research at the nonprofit National MS Society, agreed that the study is an important first step.

In the future, he said, it might be possible to use genetic tests to identify MS patients at risk of a faster progression and treat them more aggressively. (Some existing MS drugs can delay disability to some degree, he noted, but also tend to have more side effects.)

Even more importantly, Bebo said, this kind of research lays the groundwork for new treatments to slow MS down.

"This gives us clues that MS severity and progression may be related to neurological function, rather than immune-related," he said.

Right now, there are many MS medications that can prevent symptom relapses, generally by targeting the immune system.

"They're great drugs, and can really improve quality of life," Baranzini said.

But, he added, any effects on progression are modest at best.

More research is needed to understand exactly what this genetic variant may be doing, or not doing, to speed MS progression. Baranzini said his team suspects that it somehow makes cells in the central nervous system less equipped to repair damage to myelin.

But no one thinks this is the only genetic variant linked to MS progression. As genetic studies go, Baranzini said, this was a small one. Larger studies may be able to turn up more variants.

Bebo agreed and also pointed to the bigger picture: For years, research has advanced the treatment of relapsing MS -- which is great, but also frustrating for people with progressive MS.

"Now we're finally making progress in understanding the basis of progressive MS," Bebo said.

More information

The National Multiple Sclerosis Society has more on progressive MS.

SOURCES: Sergio Baranzini, PhD, professor, neurology, University of California, San Francisco; Bruce Bebo, PhD, executive vice president, research, National Multiple Sclerosis Society, New York City; Nature, June 28, 2023