New Hope for a Rare and Deadly Neurological Disease

The Context: Pelizaeus – Merzbacher disease (PMD) is a rare neurological condition typically diagnosed in infancy which often becomes fatal by a patient’s teenage years. While scientists have known that the disease results from a mutation in a gene called PLP1, which disrupts the brain’s ability to make myelin (a substance that coats neurons and helps them send signals), how exactly this mutation leads to myelination dysfunction was not well understood. Myelination defects are also a hallmark of multiple sclerosis.

The Study: A new study led by NYSCF – Robertson Stem Cell Investigator Alumnus Dr. Marius Wernig of Stanford University finds that PMD-associated PLP1 mutations can lead to iron toxicity in the brain cells that make myelin. The researchers also identified an FDA-approved drug which combated iron toxicity and reduced cell death in stem cell models and mouse models of the disease. The findings appear in Cell Stem Cell.

The Importance: Understanding exactly how PLP1 mutations lead to PMD is helping researchers identify new treatments, including an already-approved drug which scientists plan to advance to clinical trials.

Patients with Pelizaeus – Merzbacher disease (PMD) are typically diagnosed in their infancy, often showing symptoms such as lack of muscle tone and abnormal movements. While the disease is rare, it is often fatal once a patient reaches his or her teenage years.

A new study in Cell Stem Cell led by NYSCF – Robertson Stem Cell Investigator Alumnus Marius Wernig, MD, PhD of Stanford University pinpoints a mechanism behind PMD and identifies an already-approved drug that may help reverse its effects.

PMD results from a mutation in a gene called PLP1, but exactly how this mutation leads to the disease was previously unknown. PLP1 assists in the formation of myelin (the fatty coating that helps cells send signals and which is also depleted in multiple sclerosis), and the researchers were interested in examining how PMD-related PLP1 mutations affected the function of myelin-forming cells called oligodendrocytes.

The researchers used stem cells from a PMD patient with a PLP1 mutation to make oligodendrocytes and found that these cells died when transplanted into the brains of mice with myelination disorders. Oligodendrocytes made from stem cells which had their PLP1 mutation corrected, however, developed normally and contributed to myelination upon transplant.

Further study of the dysfunctional oligodendrocytes by Hiroko Nobuta, PhD, the study’s lead author, identified a possible culprit for their inefficiency: iron toxicity.

“When Hiroko studied the cells more closely, she found that they exhibited many hallmarks of iron toxicity,” said the study’s co-lead author David Rowitch, MD, PhD (an adjunct professor of pediatrics and of neurological surgery at the UCSF and a Wellcome Trust Senior Investigator at the University of Cambridge) in an article from Stanford. “Adding a molecule that can chelate, or bind, iron outside the cell restored the cells’ ability to become mature, functional oligodendrocytes.”

This drug, an already FDA-approved compound called deferiprone which removes excess iron, was able to boost myelin formation both in stem cell models and mouse models of the disease.

“The rescue of diseased cells grown in the laboratory was dramatic,” remarked Dr. Wernig. “It’s unbelievably satisfying to identify a potential treatment for such a devastating disorder.”

The findings may also have implications for multiple sclerosis, another myelination disorder. The team next plans to embark on a clinical trial to test the drug in children with PMD.

“As a researcher you hope that something you discover will eventually contribute in some way — perhaps decades later — to patient care, but this happened so much sooner than we anticipated,” said Dr. Wernig.  “It’s exciting to think that we could soon be testing this approach in patients.”

Journal Article:

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation
Hiroko Nobuta, Nan Yang, Yi Han Ng, Samuele G. Marro, Khalida Sabeur, Manideep Chavali, John H. Stockley, David W. Killilea, Patrick B. Walter, Chao Zhao, Philip Huie Jr., Steven A. Goldman, Arnold R. Kriegstein, Robin J.M. Franklin, David H. Rowitch, Marius Wernig. Cell Stem Cell. 2019. https://doi.org/10.1016/j.stem.2019.09.003