Oligodendrocytes, myelin-producing cells

In 2011, Paul Tesar, a professor at Case Western Reserve School of Medicine, worked with collaborators to come up with a method of producing massive numbers of mouse stem cells that are capable of turning into oligodendrocytes, the cells that produce myelin, the protective coating on nerve cells.

One thing you can do with such a technique, assuming you can do the same thing with human cells, is to use biochemical legerdemain to restore the myelin lost in multiple sclerosis, cerebral palsy and other disorders. But cell replacement therapies are still a work in progress–and may continue to be so for a long time.

A nearer term project for these cell populations is to test known drugs to see whether they might succeed in turning stem cells milling around the nervous system into myelin-producing oligodendrocytes. Tesar and team screened 727 drugs that had been safely used in patients. Among them they found seven that could do the job of making the switch from stem cell to oligodendrocyte. The team decided to focus on the top two, both already approved by the FDA for use on the skin. There was an antifungal (miconazole) and a steroid (clobetasol).

Both drugs, when administered by injection, substantially increased the production of myelin-producing cells and myelin itself in mouse models of multiple sclerosis when compared to a rodent control group that received placebos. The two compounds also reduced the severity of the MS-like disease model in the animals–and the drugs even promoted the transformation of human stem cells in culture into oligodendrocytes. Results were reported April 20 in Nature.

There has been more progress in developing drugs for multiple sclerosis than for other neurodegenerative diseases like Alzheimer’s and Parkinson’s. MS, which affects 2 million people worldwide and 450,000 in the U.S, results in aberrant nerve signaling from the myelin damage that can affect the ability to walk or even see. The MS field already has some drugs that can actually modify the progression of the disease by quelling the body’s auto-immune reaction against its own myelin. But there is also a need to repair damage to the myelin itself.

Dennis Bourdette, who chairs the department of neurology at Oregon State Health University and directs the university’s Multiple Sclerosis and Neuroimmunology Center, puts it this way:

All medications currently used to treat multiple sclerosis (MS) are anti-inflammatory. They control the abnormal immune response that attacks and destroys myelin in the brain and spinal cord. However they do not repair damage that has already occurred. The two drugs studied by Najm and colleagues [including Paul Tesar] are fundamentally different. They stimulate the cells, called oligodendrocytes, that make myelin and successfully stimulated remyelination in two animal models of MS. These drugs or derivatives of these drugs have the potential to be a new approach to treating MS and would be used in combination with current anti-inflammatory therapies. Such a combination offers the potential of both promoting repair and preventing further damage in MS.

For his part, Tesar compares the process to dealing with a house that has a burst pipe. The pipe…

… allows water (immune cells) to flood the house (brain). The immediate fix is to fix the pipe (current immunomodulatory drugs) but this does not actually restore the functionality of the house. It is critical to replace the components in the room that were damaged or lost (oligodendrocytes and myelin). The drugs we identified using our stem cell-based high throughput screening platform function to catalyze the body’s own stem cells to replace the cells lost in multiple sclerosis.

Others are on the same trail. In 2013, there was a report in Nature of a Parkinson’s drug, benztropine, also identified by a high-throughput screen, that promotes the conversion of stem cells into oligodendrocytes and which enhanced production of myelin in a mouse model.

One last message from the researchers: don’t try this at home. Putting Desenex (miconazole) powder into capsules and gulping down the pills is a really bad idea. Check the WebMD list of micanozle side effects for a topical formulation:

Burning, stinging, swelling, irritation, redness, pimple-like bumps, tenderness, or flaking of the treated skin may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

That’s just the skin. This stuff is not something you want coming into contact with the lining of the esophagus. “Systemic administration of these drugs is likely to carry significant side effects in human patients and we strongly caution against this,” Tesar warns, while adding: “There are closely related neighbors of both drugs that are available and approved for oral systemic administration. While we still need to optimize dosing and delivery and confirm efficacy of these related drugs, we are cautiously optimistic that we might bring them to clinical testing for MS in the very near term.”

The more-research-is-needed mantra prevails. As one of my co-editors at Scientific American likes to say a lot: this experiment was only in mice. It may eventually turn out to be a bust in humans. Most experimental drugs are. Even if it does not succeed, though, this is still a really compelling demonstration of a way to use a large stock of myelin-generating stem cells to look for new drugs.

Source: Case Western Reserve