Older Meds May Offer New Hope for Rare Demyelinating Disease

New insight into the underlying mechanisms of a rare and fatal pediatric dymyelinating disease suggests older medications approved by the US Food and Drug Administration (FDA) may help these patients.

Pelizaeus-Merzbacher disease (PMD) has no approved treatment and is often fatal by the time children reach adolescence. It is caused by mutations in the proteolipid protein 1 (PLP1) gene that triggers the death of oligodendrocytes that produce protective myelin around nerve axons.

An international team of investigators found that abnormal iron metabolism and hypersensitivity to free extracellular iron play an important role in oligodendrocyte death.

Uncovering this mechanism led them to investigate whether commercially available agents that chelate iron could reduce the amount of extracellular-free iron and found that this was indeed the case.

"The finding that iron chelation might be able to help patients with PMD has implications for physicians," lead author Hiroko Nobuta, PhD, a postdoctoral scholar at Stanford University and at the University of California, San Francisco, told Medscape Medical News.

The results were published online October 3 in Cell Stem Cell.

Multiple Disease Pathways

PMD is an X-linked leukodystrophy caused by dysfunction of PLP1 major myelin protein. The condition affects an estimated 1:200,000 to 1:500,000 children.

Although previous research has pointed to involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, the investigators note these mechanisms are unlikely to explain the entirety of PMD.

They confirmed this suspicion by comparing gene-corrected oligodendrocyte precursor cells (OPCs) with oligodendrocyte cells with the PLP1 mutation; the OPCs did not involve significant UPR or ER pathways, suggesting there is more to the story.

Another clue was a finding that the mutated cells uniquely produced oxidative stress in animal models.

"Finding multiple mechanisms of cell death or disease pathology expands our choice of drugs when we think about therapy," Nobuta said. "Because we identified multiple disease pathways — iron toxicity, lipid oxidative stress, ferroptosis — we were then able to test drugs involved in these pathways to see the beneficial effects in dying oligodendrocytes."

To create human cellular PMD models, the investigators started with a skin biopsy from a patient with an early and severe presentation. The patient had many telltale signs of the condition including nystagmus, respiratory distress, loss of developmental milestones, spasticity, and hypomyelination.

From these skin cells, investigators generated induced pluripotent stem cell lines. This allowed them to demonstrate that cells with the PLP1 mutation develop into oligodendrocytes, but subsequently die before differentiating into myelinating cells.

This led to the realization that helping oligodendrocytes survive to the point where they can myelinate axons in the brain and may be an essential step in treating PMD.

Cell Death Reversed

It is well known that oligodendrocytes in PMD cannot properly myelinate and die, but "there is not much known about how iron is involved in the cell death," Nobuta said.

"We know oligodendrocytes store large amounts of iron as they mature, and an implication is that because high iron levels are toxic cells need to accommodate by balanced import/export, chelation, etc. In PMD oligodendrocytes, this balance seems to be dysregulated," he added.

The investigators tested their hypothesis that the FDA-approved chelating agents deferiprone (Ferriprox, ApoPharma) and deferasirox (Jadenu, Novartis) would reduce death of the oligodendrocytes in mice that carried the PLP1 mutation.

Results showed that iron chelation reversed the death of oligodendrocytes.

This discovery suggests that, "the rescue is caused by the effective decrease of the extracellular iron concentration rather than making more iron available to cells," the researchers note.

The findings were surprising because "dysregulation of iron homeostasis was never implicated in the PMD pathology," Nobuta said. "It suggests that the myelinating oligodendrocyte can face significant problems handling iron in certain diseases."

The study results may also apply to other conditions, the researchers add.

"Evidence in the literature suggests the involvement of iron pathobiology in multiple sclerosis and neurodegeneration with brain iron accumulation, which suggests our findings might have wider significance beyond PMD," they write.

Further studies are needed and the investigators "are looking further at the ways that iron gets into oligodendrocytes," Nobuta said. "We will examine whether iron handling is also pathological in other diseases like multiple sclerosis [and] a clinical trial of deferiprone for boys with severe PMD is in the planning stages."

A New Understanding?

Commenting on the findings for Medscape Medical News, Ken Inoue, MD, PhD, Department of Mental Retardation & Birth Defect Research, National Institute of Neuroscience and National Center of Neurology & Psychiatry, Kodaira, Japan, noted that cellular pathology of PMD has not been fully understood before.

"In addition to the ER stress and unfolded protein response-mediated apoptosis, which does not fully explain the cellular pathology on PMD, now [the investigators] identified an iron toxicity and subsequent ferroptosis as novel key players that potentially explain the mechanism as to how myelination failure occurs in PMD," Inoue said.

"Of note," he added, the researchers report how it can be rescued as well.

Inoue, who was not involved with the research, has published studies on the role of PLP1 in PMD, including a 2019 study on drug screening based on levels and localization of PLP1.

After the current research, the question still remains as to "how mutations in PLP1, both point mutations and duplications, which have been thought to cause completely different molecular pathology in the oligodendrocytes, result in the same cascade of iron toxicity," Inoue said.

The study was funded by the National Multiple Sclerosis Society, the European Leukodystrophy Association, the New York Stem Cell Foundation, Action Medical Research, the Adelson Medical Research Foundation, the National Institute for Health Research Cambridge Biomedical Research Centre, and the European Research Council. Nobuta and Inoue have reported no relevant financial relationships.

Cell Stem Cell. Published online October 3, 2019. Abstract

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