April, 2019

Making new and efficacious lupus therapies available to patients has long been a major focus of the Lupus Research Alliance, and today we’ve taken an important step toward that aim.

Based on a breakthrough discovery made by Betty Diamond, MD of Feinstein Institutes for Medical Research, Meggan Mackay, MD, MS, also at Feinstein, will conduct a clinical trial to test whether a drug can prevent brain cell damage in people with lupus that leads to problems with concentration and memory.

A significant piece of this story that we are excited to share is that the very drugs that will be tested in our Lupus Therapeutics’ trial — known as ACE inhibitors —are already being used to treat high blood pressure. This means these drugs have the U.S. Food and Drug Administration (FDA) stamp of approval and have worked safely for people over several decades, so testing them as a treatment for lupus could result in enormous savings in time and financial resources.

Considering that it takes between 10 to 15 years —and a staggering average price tag of $1.5 billion — to test and bring a new drug to market, the clinical trial Dr. Mackay is about to undertake is truly significant.

THE GENESIS OF THIS IMPORTANT TRIAL

In 2004, Lupus Research Alliance grantee Dr. Diamond made an important discovery — a subset of anti-DNA antibodies can cause cognitive and emotional alterations in lupus patients if they cross the blood-brain barrier, a protective barrier surrounding the brain. Specifically, Dr. Diamond and her team used a murine model to show that some lupus autoantibodies attach to neurons in the brain, causing them to die. The dead neurons are then cleared by other cells in the brain, called microglial cells. This “clean up squad” of microglial cells becomes activated, leading them to attack and destroy healthy neurons and synapses (places where neurons communicate with each other) that are necessary for several functions, including generating and retaining memories.

The team then discovered that a common and safe class of medications for blood pressure, ACE inhibitors, also control the activation of the microglial cells. Several kinds of ACE inhibitors have been approved by the FDA for treatment of hypertension; some of these can cross the blood brain barrier and some cannot.

ACE inhibitors were then used in the murine model and the ACE inhibitor that was able to cross the blood brain barrier stopped the microglial cell over-activation and preserved neuron function in the mice.

One of the important reasons why clinical trials for cognitive function in lupus have not been possible so far is that there have been no objective methods established to measure cognitive function other than neuropsychological testing, which is often unreliable because cognition can be influenced by depression, medications, infections, other illnesses, and more.

Using highly sophisticated brain imaging in people with lupus, Drs. Diamond and Mackay found that high levels of the damaging autoantibodies correlated with increased metabolism in specific brain regions and with poor performance on cognitive testing. These studies suggested that the increased brain metabolism was a marker for cognitive impairment related to the damaged neurons and activated microglial cells. Dr. Diamond received the 2018 Lupus Insight Prize from the LRA to continue this work.

THE TRIAL: Potential for Vast Numbers of Patients

“Dr. Diamond discovered one of the autoantibodies that causes nerve cell dysfunction and results in over-activated microglial cells that cause further neuron damage — and our aim is to block the microglial cell activation and ultimately prevent this damage,” said Dr. Mackay.

Because of the limitations of studying the human brain, Dr. Mackay uses sophisticated scanning technology to image the brains of lupus patients. In the process, she discovered a reproducible pattern of increased metabolism in certain areas of the brain, including the hippocampus — one of the big centers of memory formation. Increased metabolism in some brain regions correlated with high levels of the autoantibody and poor performance on neuropsychological testing, suggesting that the increased metabolism may be a marker for damaged neurons and activated microglial cells.

The clinical trial Dr. Mackay has designed aims to stop microglia cell activation using ACE inhibitors, a class of drugs used to treat hypertension. For more evidence that she was on the right track, Dr. Mackay looked to their cohort of lupus patients who were imaged once a year for two years to see if metabolism changed over time. It just so happened that a small number of these patients were already taking ACE inhibitors.

 “When we looked at the patients who were on the protective ACE inhibitor that crossed the blood brain barrier, compared to the others in our group, we saw that the regional metabolism in the brain actually decreased,” stated Dr. Mackay.

 All this critical data contributes to the formation of Dr. Mackay’s hypothesis: lupus patients treated with an ACE inhibitor that crosses that blood brain barrier will show significant decreases in brain metabolism after 12 months of treatment compared to lupus patients treated with an ACE inhibitor that does not cross the blood brain barrier. The team will also measure microglial cell activation directly with a different imaging technique and assess improvement in neuropsychological testing.

The Lupus Research Alliance is proud to help fund this pioneering work through its clinical trial affiliate, Lupus Therapeutics, and Dr. Mackay is grateful for the opportunity to bring her ideas to fruition.

 “Help from the Lupus Research Alliance, in all of its iterations, has been huge — for all of my colleagues and  me. We wouldn’t be at this stage — of actually conducting a clinical trial — without the support of this incredible organization,” beamed Dr. Mackay.

Improving the day-to-day lives of people with lupus takes an organization like the Lupus Research Alliance … its many generous donors … and the most brilliant minds in lupus research working together.

 “Together” — as we have witnessed with Drs. Diamond and Mackay — is the operative word!