A new roadmap for repairing the damage of multiple sclerosis

July 25, 2018, Case Western Reserve University
Oligodendrocytes. Credit: Case Western Reserve School of Medicine

Research published today in the journal Nature provides new understanding about how drugs can repair damaged brain cells that cause disability in patients with multiple sclerosis. Led by researchers at Case Western Reserve University School of Medicine, the study suggests new drug targets and potent early-stage drug candidates could lead to regenerative medicines for multiple sclerosis and other debilitating neurological diseases.

Multiple , a chronic and progressive disease affecting millions worldwide, is characterized by damage to the protective sheath that surrounds nerve cells. Without this insulating layer, called myelin, nerve cells in the brain and spinal cord struggle to transmit electrical impulses. As a result, patients suffer progressive loss of motor skills, vision and balance.

The new study describes how drugs work to replenish myelin destroyed by multiple sclerosis. While the brain is known to have some capacity to regenerate new myelin during the early stages of multiple sclerosis, this innate repair process is overwhelmed as the disease progresses.

"Many labs, including at Case Western Reserve, had identified that kickstart the formation of new myelin, but exactly how each of these molecules affected brain cell function wasn't clear," said Drew Adams, Ph.D., the Thomas F. Peterson, Jr. Professor of Novel Therapeutics and assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine. "We were shocked to find that almost all of these previously identified molecules share the ability to inhibit specific enzymes that help to make cholesterol. This insight reorients drug discovery efforts onto these novel, druggable targets."

This study builds on prior work by co-author Paul Tesar, Ph.D., the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine. In work reported in 2015 in Nature, Tesar identified a drug typically used to treat athlete's foot, called miconazole, as a potent enhancer of new myelin.

In the current study, teams led by Adams and Tesar demonstrated that miconazole enhanced myelin formation by inhibiting an enzyme used by brain stem cells to produce cholesterol. Subsequent experiments identified more than 20 new drugs that enhance myelin formation by inhibiting closely-related cholesterol-producing enzymes. Surprisingly, drugs identified previously by labs across the world as enhancing new myelin also inhibited these same enzymes. "The idea that almost all drug candidates that promote myelin repair inhibit the same enzyme targets represents a bold new paradigm for the field and may redirect the course of ongoing drug discovery efforts," said Tesar.

Normally, cellular pathways are crisscrossed, complex diagrams. But cholesterol biosynthesis is linear, said Adams, who is also a Mount Sinai Scholar. "There is only one way in, and one way out. So when you block enzymes in the cholesterol pathway, the metabolites simply accumulate." In the Adams laboratory, lead authors Zita Hubler and Dharmaraja Allimuthu, Ph.D., could detect distinct cholesterol intermediaries as they accumulated, allowing them to pinpoint which enzymes were being blocked by which drugs.

Notably, several drugs accelerated myelin repair in mouse models of multiple sclerosis. Mouse experiments were performed in collaboration with Robert H. Miller, Ph.D., the Vivian Gill Distinguished Research Professor and professor of anatomy and cell biology at the George Washington University School of Medicine and Health Sciences.

To measure the formation of human myelin in the laboratory, the team used a new three-dimensional nerve cell culture model that closely mimics human brain tissue. Here too, the drug candidates promoted human myelin formation by blocking cholesterol pathway enzymes. A study describing this innovative model, developed in Tesar's laboratory, was also published today in Nature Methods.

"Together these studies provide new drug targets, new drug candidates, and new cholesterol pathway biomarkers to propel the development of medicines that can replenish lost myelin in patients with multiple sclerosis and related diseases," said Adams. While clinical candidates based on this work are not expected to enter clinical trials until 2019, say the authors, the new understanding of repair provides a promising new path toward novel, regenerative multiple sclerosis treatments.

Explore further: New drug target for remyelination in MS is identified

More information: Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination, Nature (2018). DOI: 10.1038/s41586-018-0360-3 , https://www.nature.com/articles/s41586-018-0360-3

Related Stories

New drug target for remyelination in MS is identified

July 17, 2018
Remyelination, the spontaneous regeneration of the fatty insulator in the brain that keeps neurons communicating, has long been seen as crucial to the next big advance in treating multiple sclerosis (MS). However, a lack ...

Multiple sclerosis—cholesterol crystals prevent regeneration in central nervous system

January 5, 2018
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which the body's own immune cells attack the fatty, insulating myelin sheath surrounding nerve fibers. The regeneration of intact ...

MS research could help repair damage affecting nerves

July 21, 2013
Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.

Researchers find potential path to repair multiple sclerosis-damaged nerves

December 26, 2017
Gene expression in specific cells and in specific regions can provide a more precise, neuroprotective approach than traditional treatments for neurological diseases. For multiple sclerosis, specifically, increasing cholesterol ...

How the formation of myelin sheaths is regulated by protein molecules

May 8, 2018
According to the Deutsche Multiple Sklerose Gesellschaft (German Multiple Sclerosis Society), around 200,000 people in Germany suffer from multiple sclerosis (MS), a serious neurological condition that has no known cure. ...

Recommended for you

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

Concussion tied to suicide risk

November 12, 2018
(HealthDay)—People who have experienced either a concussion or a mild traumatic brain injury are twice as likely to commit suicide than others, a new review suggests.

In live brain function, researchers are finally seeing red

November 12, 2018
For years, green has been the most reliable hue for live brain imaging, but after using a new high-throughput screening method, researchers at the John B. Pierce Laboratory and the Yale School of Medicine, together with collaborators ...

Researchers identify the neural basis of threatening and aggressive behaviors in Drosophila

November 9, 2018
You can always tell when two guys are about to get into a fight. It starts with angry stares, puffed-out chests, arms tossed out to the side, and little, aggressive starts forward. Neuroscientists call the combination of ...

Multiple sclerosis: Accumulation of B cells triggers nervous system damage

November 9, 2018
B cells are important in helping the immune system fight pathogens. However, in the case of the neurological autoimmune disease multiple sclerosis (MS), they can damage nerve tissue. When particular control cells are missing, ...

Monkey gaze study shows dopamine's role in response inhibition

November 9, 2018
University of Tsukuba researchers report the importance of the brain's dopaminergic system for inhibiting already-planned actions. They trained monkeys to redirect their gaze toward targets presented on a screen, apart from ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.