Why Some Drugs Cause A Deadly Brain Disease

Jonathan Wosen

Medicines that reshape or tamp down immune responses may be life-changing for patients with cancer and autoimmune disorders, but in some cases they can awaken a dormant virus and unleash a deadly brain disease. A new study suggests that the root of the problem is buried in our genetic code.

Researchers uncovered four gene variants connected with the immune system that significantly increase a person’s risk of developing the disease, known as progressive multifocal leukoencephalopathy or PML. These variants were far more common among those suffering from PML than in the general population. And they were conspicuously absent in multiple sclerosis patients who’d been receiving treatment for years without developing PML.

These variants could be used to screen patients and ensure that those with a higher risk of PML aren’t given drugs linked to the disease — similar to how doctors already use genetic testing in some patients to determine the right dose and type of medication used to treat depression, high cholesterol, and other conditions. 

The study that was published recently in the journal Frontiers in Neurology focused on how DNA shapes our risk of developing certain side effects from medication. But outside experts found the findings compelling. “This would be a major advance not only in preventing PML, but also in potentially reassuring patients that it is safe to take many of the drug therapies associated with PML risk,” said Revere Kinkel, a neurologist and director of the University of California, San Diego’s multiple sclerosis programme.

PML is a rare disease triggered by a remarkably common virus: John Cunningham virus, or JC virus, named after the man in whom doctors first discovered it in 1971. Odds are that you, like most adults, carry the virus, which resides in the tonsils and kidneys, among other places.

These infections are almost always harmless. But immunosuppressive therapies or diseases sometimes rouse the virus from its slumber. In these cases, JC virus attacks the cells that produce myelin, the blubbery layer of fat and protein that swaddles the electrical signals that zip back and forth through neurons. The first symptoms are often mild — a bit of clumsiness, or issues speaking and seeing. But things get worse, and around 30 per cent to 50 per cent of people with PML die within the first few months of their diagnosis.

Eli Hatchwell, chief scientific officer of Population Bio, suspected the answer could be found in our genetic code. So he and colleagues launched an initial study that compared the DNA sequences of 184 PML cases with those of the general population, focusing their search on genes linked to the immune system.

Researchers developed a simple genetic test using the four variants. A positive result gives a person a roughly 20 per cent chance of developing PML while on treatment — far higher than the rate among the general population. And that’s information Hatchwell says could one day guide physicians to prescribe different drugs to such patients.

“This is an example of how precision medicine can give patients very specific advice in very specific situations,” he said. “We believe that tests such as ours will become more important when it comes to studying people on drugs.”

- Statnews.com