How drugs could repair damage from multiple sclerosis | National Institutes of Health (NIH)

How drugs could repair damage from multiple sclerosis | National Institutes of Health (NIH)

How drugs could repair damage from multiple sclerosis

At a Glance

• Drugs that help repair the nerve cell lining that’s damaged in multiple sclerosis were found to target certain enzymes.
• The finding could help researchers develop new treatments for multiple sclerosis.
  
  

Illustration of an oligodendrocyte, right, creating a myelin coating around a nerve cell extension. Damage to myelin can affect communication between nerve cells.Ralwel/iStock/Thinkstock

Multiple sclerosis is an autoimmune disease in which the body’s own immune system mistakenly attacks the lining of the nerves in the brain and spinal cord. When this insulating lining, called myelin, is damaged, communication between nerve cells can be interrupted. This leads to muscle weakness, problems with coordination and vision, and other symptoms of the disease.

Experts estimate that almost half a million people nationwide live with multiple sclerosis. Existing drugs can relieve symptoms for a while by calming the immune system. But in most people, the disease gets worse over time. If scientists can develop drugs that promote myelin repair in people, the damage caused by multiple sclerosis could potentially be reversed.

In previous research, a team led by Dr. Paul Tesar at Case Western Reserve University and Dr. Robert Miller at George Washington University found that miconazole, an antifungal drug, activated stem cells and repaired myelin damage in mice. The researchers, joined by Dr. Drew Adams from Case Western Reserve, wanted to understand exactly how this drug—and others that have been discovered—encourage myelin repair. The study was funded by NIH’s National Institute of Neurological Diseases and Stroke (NINDS) and other NIH components. Results were published on July 25, 2018, in Nature, along with a companion methods paper in Nature Methods.

The team used a series of laboratory techniques to examine how drugs interact with the molecules in the body that are involved in myelin production. They found that miconazole and eight other related drugs all blocked an enzyme called CYP51. Blocking CYP51 encouraged stem cells to form new oligodendrocytes. These are the cells that create the myelin coatings around nerve cells.

CYP51 is part of the molecular pathway that produces cholesterol. The researchers discovered that blocking two other enzymes in that pathway also promoted oligodendrocyte production.

The boost in oligodendrocyte production appeared to be due to buildup of a specific type of cholesterol precursor (called 8,9-unsaturated sterols) when any of the three enzymes was blocked. When the researchers treated stem cells with 8,9-unsaturated sterols, they saw oligodendrocyte production rise.

The team next screened over 3,000 approved drugs and other small molecules for their ability to promote oligodendrocyte production. The top ten all caused a buildup of 8,9-unsaturated sterols.

When tested on human stem cells grown in the laboratory, drugs or genetic manipulations that targeted any one of the three enzymes caused oligodendrocytes to form and start laying down myelin. In mice with damage to myelin in their spinal cords, injection of drugs that targeted one of the enzymes caused restoration of myelin in the damaged tissue.

“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,” Adams says.

The researchers have formed a company to build on these findings and develop therapeutics to promote myelin repair.

—by Sharon Reynolds

Related Links

• Drugs Lessen Multiple Sclerosis Damage in Mice
• Stem Cell Transplant Induces Multiple Sclerosis Remission
• Vitamin D Levels Predict Multiple Sclerosis Progression
• Rare Immune Cell Involved in Multiple Sclerosis
• Landmark Analysis Probes Nature vs. Nurture in Multiple Sclerosis
• Multiple Sclerosis Information Page

References: Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Hubler Z, Allimuthu D, Bederman I, Elitt MS, Madhavan M, Allan KC, Shick HE, Garrison E, T Karl M, Factor DC, Nevin ZS, Sax JL, Thompson MA, Fedorov Y, Jin J, Wilson WK, Giera M, Bracher F, Miller RH, Tesar PJ, Adams DJ. Nature. 2018 Jul 25. doi: 10.1038/s41586-018-0360-3. [Epub ahead of print]. PMID: 30046109.

Induction of myelinating oligodendrocytes in human cortical spheroids. Madhavan M, Nevin ZS, Shick HE, Garrison E, Clarkson-Paredes C, Karl M, Clayton BLL, Factor DC, Allan KC, Barbar L, Jain T, Douvaras P, Fossati V, Miller RH, Tesar PJ. Nat Methods. 2018 Jul 25. doi: 10.1038/s41592-018-0081-4. [Epub ahead of print]. PMID: 30046099.

Funding: NIH’s National Institute of Neurological Diseases and Stroke (NINDS), National Institute of General Medical Sciences (NIGMS), National Center for Advancing Translational Sciences (NCATS), National Cancer Institute (NCI), and Office of the Director (OD); Conrad N. Hilton Foundation; Mallinckrodt Foundation; Mt. Sinai Health Care Foundation; CWRU School of Medicine; Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families.