New technology brings personalized lupus treatments one step closer

There’s more to treating disease than just finding a target and hitting it, said OMRF scientist Joan Merrill, M.D.

In a paper published in the most recent issue of the journal Clinical Immunology, Merrill, Chair of OMRF’s Clinical Pharmacology Research Program, said that new molecular targets in the fight against lupus are exciting. The new treatments are incredibly sophisticated, aimed at bringing tiny proteins in the immune system into balance. But how these treatments work in individual patients is not so simple.

Patients with lupus share certain features in the way that their immune systems are disrupted, but they differ in the details of how this comes about, she said.

Lupus is a chronic autoimmune disease caused when the wrong environmental factor encounters a person with a high-risk genetic profile. This causes the immune system to become relentlessly overactive, and the normal checks and balances break down. Eventually there is a great deal of collateral damage, almost as if the immune system has begun mistaking the body’s own cells for bacteria or viruses and is attacking them.

Symptoms include fatigue, fever, rashes and joint pain. Lupus affects about 1.5 million Americans, mostly women, and has no known cure. However, more than 30 treatments have entered development recently. Their goal is to finely target various nuanced protein interactions that regulate the immune system.

“The most frustrating thing in trying to get these treatments to work, but also the most fascinating thing when you think about how the body defends itself from invaders, is that the immune system goes around in circles,” said Merrill, who heads OMRF’s Clinical Pharmacology Research Program. “We have to be careful, because making one tiny change with some of these futuristic drugs might swing back around and cause a bigger problem elsewhere.”

Merrill said it’s best to think of tiny protein disease “targets” as dominos—biological molecules that connect to one or more components of the immune system. Depending on the patient’s genetic code, those dominos are balanced in unique ways and may react to medications with an unexpected boomerang effect.

“Patients have various roadblocks to treatment, and when you push that target domino over, you have to be aware of how it may influence all the dominos around it,” she said. “But we are learning how the deck is stacked in different people. The goal is to develop blood tests to predict which treatments are best for an individual and to guide their dosing for optimal rebalancing of the immune system.”

Merrill and her colleague Judith James, M.D., Ph.D., have led a team of researchers at OMRF and Pfizer to develop and study some of these “biomarkers.” Someday, they may be used to track the impact of targeted therapies throughout the immune system, leading to better outcomes for patients receiving these medications.

Because lupus is caused by different combinations of genetic factors in each patient, there isn’t going to be a “one size fits all” drug, she said.

“I hope that doesn’t sound bleak, because it really isn’t,” she said. “We have the technology now to begin breaking that code, to understand what downstream effects are caused by new lupus drugs and tailor the choice and dose of treatments more effectively to individuals.”

It’s slow and tedious work, but the result will be a kind of personalized medicine that can help patients manage lupus more effectively, she said.

OMRF President Stephen Prescott, M.D., said personalized medicine is the great hope for complex genetic diseases like lupus, diabetes and Sjögren’s syndrome.

“The discoveries we’re making now will help us better understand these diseases in the future, so we can combine therapeutics in the best way possible to treat individual patients,” he said.

“We’re going to nail the immune system eventually,” Merrill said. “In the meantime, we can work to increase the good outcomes in patients by better understanding the possible downstream effects of lupus medications.”