Shiverer mice provide a model for pediatric leukodystrophy. The animals shake, seize, and die prematurely but, according to a new study, they can be saved by infusions of human glial progenitor cells that can restore all affected white matter. The human donor cells provided enough myelin to insulate axons, halt symptoms, and substantially prolong life.
The collaborative work — published in the June issue of Cell Stem Cell- was led by Steven Goldman, MD, PhD, chief of the Division of Cell and Gene Therapy and the Dean Zutes Chair and Professor of Neurology and Neurosurgery at the University of Rochester Medical Center. Dr. Goldman's goal was to repopulate the developing mouse brain postnatally with enough human glial progenitor cells to restore normal myelination. And it worked.
If similar events occur in the developing human brain, scientists say that this cellular therapy may be an effective therapy for childhood disorders of myelin.
“This is an important study,” said biology and genetics professor Ian Duncan, PhD, a myelin expert at the University of Wisconsin in Madison, who was not involved with the current study. “We are working on cellular therapies and have had success but not at this level. The whole brain myelinated in the transplanted mice. Their symptoms were gone and it extended life span. It is remarkable.”
In the shiverer mouse, oligodendrocytes fail to make myelin, and the mice become impaired at a young age, invariably dying by 21 weeks of age.
Dr. Goldman and his colleague Martha S. Windrem, along with collaborators at Baylor University College of Medicine, Weill Medical College of Cornell University, and the University of California-Los Angeles, found that it was possible to transplant the cells into five different regions of the brain.
They reported on 26 day-old shiverer animals and 86 controls. Six animals lived to 14 months, roughly ten months longer than control animals who did not receive the transplanted human glial progenitors. The cells migrated within the white matter and developed largely as oligodendrocytes, which remained in the white matter. The cells then migrated throughout the entire CNS, including the entire length of the brainstem and spinal cord. Over time, the hemispheres and brainstem of the animals were completely myelinated, and the spinal cord almost completely so.
The effect was dramatic. Normally, shiverer mice die between 18 and 21 weeks of age. This cellular transplant kept about 25 percent of them alive for 56- to 60-weeks, at which point they were deemed cured, and sacrificed for histological analysis. What's more, by about week 47, surviving mice were completely free of convulsions.
According to Dr. Goldman, it took three months before the brain started to make human myelin. By nine months, the myelin was about almost completely restored. Four animals were cured. The shivering gait and wild ataxia were gone, as were the seizures. At 14 months, survivors seemed to be neurologically normal.
When the investigators examined the animals' brains, they found fully myelinated white matter. More than half of the glial cells in the brain were human, and these donor cells had taken over the brain.
“We know that donor cell populations compete to myelinate the brain, and behave the same way they do in humans,” Dr. Goldman said. “We just never thought it would be possible to remyelinate the entire nervous system.”
“There has never before been anything that has given these animals another day of life,” Dr. Goldman continued. He said that he is hopeful that the success of these transplanted oligodendrocytes might allow physicians to treat children with rare genetic conditions that result in a loss or dysregulation of myelin.
Many of these children, with conditions like Pelizaeus-Merzbacher and other leukodystrophies, fail to develop normally and suffer a range of neurological abnormalities, often dying young. The neural wiring is there, but without myelin, normal electrical conduction is disrupted. Dr. Goldman believes that by infiltrating the brains of these patients with functionally competent glial progenitor cells, the cell type that gives rise to new myelinating oligodendrocytes, could cure these children, just as it did the shiverer mouse.
“We should be able to design clinical trials to treat infants with progenitor cell grafts following an early diagnosis of either Pelizaeus-Merzbacher, or any of the demyelinating lysosomal storage diseases. Another possible target is a form of cerebral palsy called periventricular leukomalacia, in which oligodendrocytes are lost. The team is now working on manufacturing guidelines to meet FDA regulations for cell delivery to human patients.”
Experts in multiple sclerosis and other diseases where myelin is lost or damaged say that the investigators have to figure out why only some of the animals responded to the treatment. “The most impressive observation is that they increased the lifespan of the mice,” said Bruce Trapp, PhD, chair of the department of neurosciences at the Cleveland Clinic Foundation. “Dr. Goldman is asking the transplanted cells to remyelinate the brain rather than repair it.”
This model would mean that they need to get the cells into the brain early enough, he added.
Scientists will be working towards heading into the clinic to test these therapies on sick children. The question is: which patients will be first? “The inherited leukodystrophies will probably be the best condition to test first,” said Dr. Trapp. “The risk-to-benefit ratio in these babies is attractive.”
But there are many challenges on the road, he added, including how to scale up to humans. And this question would need to be answered: Are more cells and injection sites needed?
“This work is a practical demonstration,” added Dr. Duncan. “Put in enough cells at the right places to allow them to colonize the brain and spinal cord. The improvement is not immediate. But when it happens, it's dramatic.”
Dr. Duncan said inherited pediatric problems will be first on the list but cellular transplants might ultimately work in multiple sclerosis, white matter stroke, and adult disorders of myelin.
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