'Reelin' in a new treatment for multiple sclerosis
Depleting key protein could protect against conditions marked by chronic inflammation

Date:
August 12, 2020
Source:
UT Southwestern Medical Center
Summary:
In an animal model of multiple sclerosis (MS), decreasing the
amount of a protein made in the liver significantly protected
against development of the disease's characteristic symptoms and
promoted recovery in symptomatic animals, scientists report.



FULL STORY ==========================================================================
In an animal model of multiple sclerosis (MS), decreasing the amount of a protein made in the liver significantly protected against development of
the disease's characteristic symptoms and promoted 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 appears to help the brain organize
itself during development and assist in forming connections between brain
cells during adulthood. However, as researchers learned more about Reelin,
they discovered that large amounts of it are produced in the liver and
that cells lining blood vessels have receptors for this protein.

A 2016 study by Joachim Herz, M.D., director of the Center for
Translational Neurodegeneration Research and professor in the departments
of molecular genetics, neurology and neurotherapeutics, and neuroscience
at UTSW, and his colleagues showed that depleting levels of circulating
Reelin protected mice from atherosclerosis. Probing deeper into the
mechanism behind this phenomenon, they found that Reelin appears to
regulate the production of adhesion molecules on blood vessel walls that capture circulating monocytes, a type of inflammation-inducing immune
cell. When the scientists decreased Reelin in animal models, levels of
these adhesion molecules also declined, preventing them from capturing monocytes and causing inflammation.

Wondering if Reelin plays a similar role in other inflammatory diseases,
Herz, along with Laurent Calvier, Ph.D., an instructor in the department
of molecular genetics at UTSW, and their colleagues investigated
this protein's role in MS, a neurodegenerative disease that affects
an estimated 2.3 million people worldwide. They started by examining
blood concentrations of Reelin in patients with relapsing-remitting
MS, the most common form of the disease. They found that while Reelin concentrations were about 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 might
correlate with MS severity and stages, and that lowering Reelin levels
might be a novel way to treat MS.

Investigating further, Herz, Calvier, and their 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 Reelin production, they found that eliminating this protein substantially mitigated the disease's typical paralysis or even eliminated
it altogether, in contrast to mice with normal Reelin levels. These
effects appeared to stem from the lack of monocyte adhesion on the
altered animals' blood vessel walls, which prevented entry into the
central nervous system.

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

Herz and Calvier suggest that reducing immune cells' ability to accumulate
and cause inflammation by altering Reelin levels could represent a new
strategy for treating patients with MS, a disease for which several
effective drugs exist that nevertheless can have significant side
effects. Additionally, they say, reducing Reelin could 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 therapeutically address," Herz
says. "We are now in the process of testing this in animal models for
these human diseases. In preparation for future human clinical trials,
we are also working at humanizing a monoclonal antibody that can clear
Reelin from human blood." Herz holds the Presbyterian Village North
Foundation Distinguished Chair in Alzheimer's Disease Therapeutic
Research and the Thomas O. and Cinda Hicks Family Distinguished Chair
in Alzheimer's Disease Research.


========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Laurent Calvier, Guillaume Demuth, Navid Manouchehri, Connie Wong,
Anastasia Sacharidou, Chieko Mineo, Philip W. Shaul, Nancy
L. Monson, Maria Z. Kounnas, Olaf Stu"ve, Joachim Herz. Reelin
depletion protects against autoimmune encephalomyelitis by
decreasing vascular adhesion of leukocytes. Science Translational
Medicine, 2020; 12 (556): eaay7675 DOI: 10.1126/scitranslmed.aay7675 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200812161329.htm

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