University of Cambridge stem cell work offers hope for boys with rare genetic condition PMD

Progress in using stem cells to treat a rare genetic condition affecting boys has been reported in two studies.

Scientists at the University of Cambridge, UC San Francisco and Stanford University have spent a decade working on methods to develop novel therapies to help patients with Pelizaeus-Merzbacher disease (PMD).

A rare disorder of the central nervous system, PMD affects co-ordination and motor function, which can leave patients with difficulty walking or talking. Some have a shortened lifespan and the condition can be fatal by the age of 10.

The progressive neurological problems seen in PMD patients are caused by disruptions in the formation of myelin - the fatty layer of insulation that covers nerve fibres and enables rapid, long-distance communication in the nervous system. Myelin makes up the brain’s white matter.

It is not clear why myelination fails in patients with PMD and efforts to restore it in the brain have eluded scientists so far.

But a study published in Cell Stem Cell last Thursday (October 3) offers hope that patient-derived stem cells could help identify new drugs, while research published recently in Stem Cell Reports indicates that it is feasible to transplant neural stem cells directly into patients’ brains.

Prof David Rowitch, head of the Department of Paediatrics at Cambridge, who also holds a post at UCSF, said: “Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.

“We extend our utmost gratitude to the patients and families that participated in these studies, which we hope will one day lead to treatments for PMD.”

In the Cell Stem Cell study, skin cells from boys with PMD were collected and induced pluripotent stem cell (iPSC) technology was used to turn them into brain cells for study in the lab.

The work, led by post-doc Dr Hiroko Nobuta at UCSF, found myelin-producing cells called oligodendrocytes were dying as a result of iron toxicity.

This suggested a potential explanation for why myelination fails in the developing brain of children with PMD.

The scientists were able to protect the PMD oligodendrocytes by removing the excess iron, using an FDA-approved iron chelating agent called deferiprone.

This agent boosted myelin formation both in cells grown in a laboratory dish, and in a mouse model of PMD. Clinical trials are now planned.

Meanwhile, the Stem Cell Reports paper followed up ground-breaking work launched in 2010 by Prof Rowitch, who works at the Wellcome Trust-MRC Stem Cell Institute in Cambridge, and Dr Nalin Gupta, from the Departments of Pediatrics and of Neurological Surgery at UCSF.

They tested whether missing myelin could be restored by surgically implanting neural stem cells produced by the company Stem Cells Inc, which financially supported the trial, into the white matter of PMD patients’ brains.

In the first in-human trials, the phase I trial was conducted with four boys under the age of five with a severe form of PMD. The aim was to assess its safety and evaluate through brain imaging whether the transplants led to changes in myelination.

A year after the procedure, there had been no adverse effects and detailed MRI brain scans suggested myelination had occurred in the areas of transplantation.

Now the five-year follow-up has reported minimal adverse effects and MRI changes consistent with myelination had persisted in two of the four patients.

Two, however, had immunological reactions to the neural stem cells, indicating immunosuppressive therapies may be required for future studies to prevent rejection.

Dr Gupta said: “This study primarily demonstrates that cell transplantation can be performed safely in PMD patients. There were also tantalizing clues that the transplanted cells survived and may be able to replace the myelin that these boys lacked, and important lessons for refining our approach in future studies.”

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