Researchers find promising new treatment approach for multiple sclerosis

In an animal model of multiple sclerosis (MS), reducing the amount of a protein made in the liver significantly protects against development of the characteristic symptoms of the disease and promotes recovery in symptomatic animals, UTSW scientists report.

The findings, published online today by Science Translational Medicine, could lead to a new treatment strategy for this neurological disease and other conditions marked by chronic inflammation.

In 1997, researchers discovered a protein secreted in the brain called Reelin. Subsequent work showed that Reelin seems to help the brain to organize itself during development and to help form connections between brain cells during adulthood. However, as researchers learned more about Reelin, they discovered that large amounts are produced in the liver and that cells that contain blood fats have receptors for this protein.

A 2016 study by Joachim Herz, MD, director of the Center for Translational Neurodegeneration Research and professor in the departments of molecular genetics, neurology and neurotherapeutics, and neurosciences at UTSW, and his colleagues showed that the levels of circulating Reelin-protected mice protect from atherosclerosis. Trying deeper into the mechanism behind this phenomenon, they found that Reelin appears to regulate the production of adhesion molecules on blood vessel walls that trap circulating monocytes, a type of inflammation-inducing immune cell. As scientists reduced Reelin in animal models, the levels of these adhesion molecules dropped, preventing them from taking up monocytes and causing inflammation.

Wondering if Reelin plays a similar role in other inflammatory diseases, Herz, together with Laurent Calvier, Ph.D., an instructor in the Department of Molecular Genetics at UTSW, and her colleagues investigated the role of this protein in MS, a neurodegenerative disease affecting an estimated 2.3 million people worldwide. She began by examining Reelin’s blood levels in patients with relapsing-remitting MS, the most common form of the disease. They found that although Reelin concentrations were approximately the same in patients in remission as those without the disease, concentrations were elevated in patients during relapse. These findings suggest that circulating Reelin levels may correlate with MS severity and stages, and that reducing Reelin levels may be a new way to treat MS.

Further researching, Herz, Calvier, and her colleagues worked with mice affected by a disease called experimental autoimmune encephalomyelitis (EAE), a condition that mimics human MS. When these animals were genetically modified so that the researchers could control the production of Reelin, they found that eliminating this protein substantially reduced the typical paralysis of the disease or even completely eliminated it, unlike mice with normal Reelin. levels. These effects appear to stem from the lack of monocytadhesion on the walls of the blood vessels of the altered animals, which prevented entry into the central nervous system.

The researchers had further success in preventing paralysis when unaltered animals with EAE received antibodies that inactivated Reelin. This strategy was even effective in animals that already closely mimic symptoms of the disease – a situation that human patients diagnosed with MS – more closely mimic – thereby reducing the severity of paralysis and promoting healing.

Herz and Calvier suggest that reducing the ability of immune cells to accumulate inflammation and cause it by altering Reelin levels may represent a new strategy for treating patients with MS, a disease that includes several effective drugs that are important side-effects. can have effects. In addition, they say, reducing Reelin can alter the course of several other conditions, marked by chronic inflammation, including psoriasis, Crohn’s disease, and rheumatoid arthritis.

“We think we can use this intervention for a wide range of inflammatory diseases that have been difficult to address therapeutically,” says Herz. “We are currently in the process of testing this in animal models for these human diseases. In preparation for future human clinical trials, we are also working on humanizing a monoclonal antibody that can remove Reelin from human blood.”

Herz holds the Distinguished Chair Presbyterian Village North Foundation in Alzheimer’s Disease Therapeutic Research and the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer’s Disease Research.