For Children With a Rare Neurological Disease, a First-Ever Treatment May be on the Horizon

The Context: Pelizaeus-Merzbacher disease (PMD) is a rare genetic disorder that affects myelin, the ‘cable insulation’ that helps neurons send signals, leading to severe muscle stiffness or weakness and cognitive dysfunction. It primarily affects young boys and there are currently no effective treatments or cures.

The Study: PMD is caused by a mutation in a gene called PLP1, and new study in Nature by NYSCF – Robertson Stem Cell Investigator Alumnus Paul Tesar, DPhil, of Case Western Reserve University finds that interfering with expression of mutant PLP1 using a category of drugs called antisense oligonucleotides (ASOs) can restore the health of PMD mice. 

The Importance: This study identifies a new target for PMD treatments as well as a possible class of drugs that could be effective in patients, with implications for other myelin disorders like multiple sclerosis. 


Pelizaeus-Merzbacher disease (PMD) is a rare genetic disorder primarily affecting young boys and leading to severe muscle stiffness or weakness and cognitive dysfunction. PMD can rob a child of their ability to walk or speak, and many patients do not survive past adolescence. There are no effective treatments or cures.

However, a study in Nature by NYSCF – Robertson Stem Cell Investigator Alumnus Paul Tesar, DPhil, of Case Western Reserve University is offering new hope for a possible PMD treatment. Dr. Tesar’s team discovered that using a drug to suppress the expression of the mutant gene PLP1 that causes PMD can block the toxic effects of the mutation on cells in mouse models, reducing hallmark symptoms and extending lifespans.

“The preclinical results were profound,” said Dr. Tesar, a professor in the Department of Genetics and Genome Sciences at the School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics, in a press release. “PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan. Our results open the door for the development of the first treatment for PMD.”

The Mechanics of PMD

PMD is a disease that affects myelin, the fatty coating that surrounds neurons and helps them send signals. Patients with PMD carry mutations in a gene called PLP1, causing production of toxic proteins that attack myelin rather than support it, leading to cognitive and motor deficits.

Myelin is Dr. Tesar’s specialty: he has spent years studying myelin-related disorders such as PMD, dementia, autism, and multiple sclerosis, even establishing a company that brings myelin-regenerating drugs to the clinic. His innovative work on myelin earned him the 2017 NYSCF – Robertson Stem Cell Prize, and he used the flexible funding from this award to pursue research into PMD. For this work, he aimed to see whether targeting PLP1 could restore myelination.

His team knew that PLP1 was creating faulty RNA: the ‘instructions’ for making the PLP1 protein. Interfering with RNA could, they reasoned, block the production of the toxic proteins.

The scientists teamed up with Ionis Pharmaceuticals to test the efficacy of a certain class of drug called antisense oligonucleotides (ASOs) that do just this — bind to a specific RNA and stop it from creating a protein. 

“ASOs provided an opportunity to cut the disease-causing protein off at its source,” explained Matthew Ellitt, PhD, the study’s first author.

Promising Results in Mice

Excitingly, PMD-affected mice given ASOs responded extremely well to the treatment: they regenerated myelin, reduced their symptoms, and lived normal lifespans. 

“We’ve opened the door to move this forward rapidly into the clinic for this particular disease, but more broadly, we’ve opened the door for a new therapeutic approach to treat this large class of neurological disorders impacted by faulty myelin,” Dr. Tesar told ideastream.

Lili Barbar, who worked on the study as a former undergraduate researcher in Dr. Tesar’s lab, before joining NYSCF as an intern and then full-time researcher, is enthusiastic about the implications of the research for patients.

“This is a very promising study with the potential to impact patients and families who are in desperate need of treatment options,” she remarked. “It’s innovative thinking like this that drives scientists throughout the NYSCF community, and I’m proud to have been a part of this group, both during my time in college and afterward.”

Before the treatment hits the clinic for patients with PMD, there is still further research to be done. Dr. Tesar’s team plans to next examine how long the therapy lasts, when it should be administered, and whether it will be effective for all forms of the disease. The drugs must also be tested in humans before reaching a wider patient population.

“While important research questions remain, I’m cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients,” Dr. Tesar said. “I truly hope our work can make a difference for PMD patients and families.”

Journal Article:

Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.
Matthew S. Elitt, Lilianne Barbar, H. Elizabeth Shick, Berit E. Powers, Yuka Maeno-Hikichi, Mayur Madhavan, Kevin C. Allan, Baraa S. Nawash, Artur S. Gevorgyan, Stevephen Hung, Zachary S. Nevin, Hannah E. Olsen, Midori Hitomi, Daniela M. Schlatzer, Hien T. Zhao, Adam Swayze, David F. LePage, Weihong Jiang, Ronald A. Conlon, Frank Rigo & Paul J. Tesar.  Nature (2020). https://doi.org/10.1038/s41586-020-2494-3

Diseases & Conditions:

Neurobiology

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