Genetic Research in Lupus Offers New Lines of Attack

Researchers have identified multiple gene variants tied to lupus.

PETER SCHAFER, EXECUTIVE DIRECTOR OF TRANSLATIONAL MEDICINE AT CELGENE, BELIEVES WE ARE AT A TIPPING POINT WHERE THE COLLECTION OF LUPUS GENETIC RESEARCH IS ABOUT TO GIVE WAY TO NEW THERAPEUTIC APPROACHES.

PETER SCHAFER, EXECUTIVE DIRECTOR OF TRANSLATIONAL MEDICINE AT CELGENE, BELIEVES WE ARE AT A TIPPING POINT WHERE THE COLLECTION OF LUPUS GENETIC RESEARCH IS ABOUT TO GIVE WAY TO NEW THERAPEUTIC APPROACHES.

In the past 50 years, only one new therapy has been developed exclusively for lupus. Meanwhile, patients with this inflammatory disease — in which the body’s immune system attacks its own tissue — continue to combat symptoms like fatigue, joint pain and rashes.

But Peter Schafer, executive director of Translational Medicine at Celgene, believes new genetic research in lupus is finally giving way to new investigational approaches that target mutations driving the disease.

As this year’s Annual European Congress for Rheumatology (EULAR) 2017 gets underway in Madrid, Schafer explains how genetic research is opening up new avenues of research for this difficult-to-treat disease.

How is our growing understanding of the genetic changes underlying lupus influencing the development of new treatments options?

We’re living in an era that’s beyond the sequencing of the human genome. Over the past decade, researchers have identified a multitude of genetic variants linked with particular diseases. Companies are beginning to realize the value of targeting the proteins that are encoded by those genes.

Managing Lupus Remains a Challenge

How has our understanding of genetics evolved over the past decade?

Three years ago, if I told someone that there was a change in a part of a gene that did not include the “recipe” for a protein, they would dismiss that mutation. Now we know that you shouldn’t necessarily ignore it. We’re realizing that other parts of the gene may be doing something else—for instance, controlling the quantity of protein being produced. Sometimes, the most obvious experiments go undone. One example is comparing the amount of a protein being produced in people with a given disease and those without. You may never bother to look if you dismiss that genetic change.

Have researchers found such variants that are believed to contribute to lupus?

Yes. For instance, there are variants in the genes for two proteins, called Ikaros and Aiolos, that help with the development of the immune cells that can cause inflammation. Lupus patients have twice the normal Ikaros levels and four times the normal Aiolos levels.

“Until this year, there had not been a program to evaluate a treatment that is designed specifically to target the genetic drivers of lupus.”

Have therapies that target such mutations linked with lupus been developed?

A few medications exist that target some of the proteins of the identified genes, but they are not approved for treating lupus. Their use in lupus will have to be investigated. Until this year, there had not been a program to evaluate a treatment that is designed specifically to target these potential genetic drivers of lupus.

What makes developing targeted therapies for lupus more challenging than for diseases such as cancer?

Lupus can be a debilitating disease, but the mortality rate isn’t as high as in cancer. As a result, a patient is less likely to be willing to deal with side effects, and their expectation is much higher.

Also, you’re not trying to kill a tumor. Instead, you’re trying to maintain some degree of suppression of the immune system over the long term. Lupus patients don’t use a high dose of treatment for a short period and then stop; they have to keep using their therapy. You want to know how low the dose can be and still be effective, so you don’t put the patient at risk unnecessarily.

High Levels of Ikaros & Aiolos in Lupus

How challenging is it to test the efficacy of treatments for lupus?

Lupus affects so many different tissues, joints and organs. Clinical efficacy measures of a new lupus treatment should evaluate the effectiveness of that treatment across the various organ systems involved in lupus. You’re looking for an improvement in at least some of those symptoms without worsening others.

At this time, lupus patients are being classified by which tissues are affected. But now that we’re looking at the disease from a genetic perspective, we have seen genetic variants in lupus patients regardless of the tissue affected. This finding is shifting our thinking about how to approach a disease like lupus, because if all lupus cases have similar root causes, genetic evaluation is important. Classifying patients solely by their affected organs might not be as useful for treatment purposes.

To learn about how targeted therapies are being explored for other inflammatory diseases, read “Accelerating MS Research Through Teamwork, New Approaches.”