Four boys with a rare and often fatal brain disease were implanted with stem cells that began fixing damage that impeded their ability to walk, talk and eat, a trial found.

The findings, published today in the journal Science Translational Medicine, are from the first stage of human tests funded by StemCells Inc. (STEM), a Newark, California-based company.

The children have a genetic disorder called Pelizaeus- Merzbacher, in which the brain cant make myelin, the fatty insulation for nerve cells that helps conduct brain signals. The children all had evidence of myelin growth a year later. The increased abilities shown by three of the boys in the University of California San Francisco study may bode well for other diseases caused by a lack of myelin insulation, including multiple sclerosis and cerebral palsy, the authors wrote.

Those were severely impaired children, said Stephen Back, a professor of pediatrics and neurology at Portlands Oregon Health & Science University, in a telephone interview. The fact that they showed any neurological improvement is very encouraging.

Back did work in mice that preceded todays work in humans, which he wasnt directly involved in. His study, published simultaneously, showed that the animals with no myelin at all grew some after being implanted with human stem cells.

Pelizaeus-Merzbacher disease causes the degeneration of the nervous system, and there is no cure or standard treatment. People with the illness experience a loss of coordination, thinking and motor abilities. Its one of several disorders linked to genes that control myelin production.

The incidence of the disease is 1 in 200,000 to 500,000 people, according to todays study of the boys.

The boys were between the ages of 1 and 6. They were given purified neural stem cells from a fetal brain, which was then grown in culture. The stem cells were inserted into the frontal lobe, using brain imaging as a guide. The boys brains were scanned 24 to 48 hours after surgery to assess safety.

The children were on drugs to suppress their immune systems and prevent their bodies from rejecting the stem cells for nine months. Side effects included rashes, diarrhea and fever. One boy had fluid collect under his scalp, which later vanished on its own. A second subject had some bleeding in the brain after the surgery, which was without clinical consequence, according to the paper.

One of the boys developed the ability to take steps with assistance and began to speak single words. Another started eating solid food on his own. A third began to walk without the assistance of a walker and began eating on his own.

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Brain Stem-Cell Implants Help Children With Rare Illness

ScienceDaily (Oct. 10, 2012) Physician-scientists at Oregon Health & Science University Doernbecher Children's Hospital have demonstrated for the first time that banked human neural stem cells -- HuCNS-SCs, a proprietary product of StemCells Inc. -- can survive and make functional myelin in mice with severe symptoms of myelin loss. Myelin is the critical fatty insulation, or sheath, surrounding new nerve fibers and is essential for normal brain function.

This is a very important finding in terms of advancing stem cell therapy to patients, the investigators report, because in most cases, patients are not diagnosed with a myelin disease until they begin to show symptoms. The research is published online in the journal Science Translational Medicine.

Myelin disorders are a common, extremely disabling, often fatal type of brain disease found in children and adults. They include cerebral palsy in children born prematurely as well as multiple sclerosis, among others.

Using advanced MRI technology, researchers at OHSU Doernbecher Children's Hospital also recently recognized the importance of healthy brain white matter at all stages of life and showed that a major part of memory decline in aging occurs due to widespread changes in the white matter, which results in damaged myelin and progressive senility (Annals of Neurology, September 2011).

In this breakthrough study, Stephen A. Back, M.D., Ph.D., senior author and clinician-scientist in the Pap Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital, used a transgenic mouse model (Shiverer-immunodeficient) that develops progressive neurological deterioration because it is unable to make a key protein required to make normal myelin. Although this mouse has been widely investigated, prior to this study, true human brain-derived stem cells had not been tested for their potential to make new myelin in animals that were already deteriorating neurologically.

"Typically, newborn mice have been studied by other investigators because stem cells survive very well in the newborn brain. We, in fact, found that the stem cells preferentially matured into myelin-forming cells as opposed to other types of brain cells in both newborn mice and older mice. The brain-derived stem cells appeared to be picking up on cues in the white matter that instructed the cells to become myelin-forming cells," explained Back.

Although Back, in collaboration with investigators at StemCells Inc., had achieved success implanting stem cells in presymptomatic newborn animals, it was unclear whether the cells would survive after transplant into older animals that were already declining in health. Back and his colleagues put these cells to the test by transplanting them in animals that were declining neurologically and found that the stem cells were able to effectively survive and make functional myelin.

The study also is important because the research team was able to confirm by MRI that new myelin had been made by the stem cells within weeks after the transplant. Until now, it was unclear whether stem cell-derived myelin could be detected without major modifications to the stem cells, such as filling them with special dyes or iron particles that can be detected by the MRI.

These studies were particularly challenging, Back explained, because the mice were too sick to survive in the MRI scanner. Fortunately, OHSU is home to a leading national center for ultra-high field MRI scanners that were used to detect the myelin made by normal, unmodified stem cells.

"This is an important advance because it provides proof of principle that MRI can be used to track the transplants as myelin is being made. We actually confirmed that the MRI signal in the white matter was coming from human myelin made by the stem cells," Back said.

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Human neural stem cells study offers new hope for children with fatal brain diseases

David Rowitch, MD, PhD, professor and chief of neonatology, in the NICU.

A Phase I clinical trial led by investigators from the University of California, San Francisco (UCSF) and sponsored by Stem Cells Inc., showed that neural stem cells successfully engrafted into the brains of patients and appear to have produced myelin.

The study, published in Wednesday's issue of Science Translational Medicine, also demonstrated that the neural stem cells were safe in the patients brains one year post transplant.

The results of the investigation, designed to test safety and preliminary efficacy, are encouraging, said principal investigator David H. Rowitch, MD, PhD, a professor of pediatrics and neurological surgery at UCSF, chief of neonatology at UCSF Benioff Childrens Hospital and a Howard Hughes Medical Institute Investigator.

Nalin Gupta, MD, PhD

For the first time, we have evidence that transplanted neural stem cells are able to produce new myelin in patients with a severe myelination disease, said Nalin Gupta, MD, PhD, associate professor of neurological surgery and pediatrics and chief of pediatric neurological surgery at UCSF Benioff Children's Hospital, and co-principal investigator of the PMD clinical trial.

We also saw modestgains in neurological function, and while these cant necessarily be attributed to the intervention because this was an uncontrolled trial with a small number of patients,the findings represent an important first step that strongly supports further testing of this approach as a means to treat the fundamental pathology in the brain of these patients.

The study, one of the first neural stem cell trials ever conducted in the United States, is emblematic of UCSFs pioneering role in the stem cell field. In 1981, Gail Martin, PhD, professor of anatomy, co-discovered embryonic stem cells in mice. In 2001, Roger Pedersen, PhD, professor emeritus of obstetrics, gynecology and reproductive sciences, derived two of the first human embryonic stem cell lines. On Monday, Shinya Yamanaka, MD, PhD, of the UCSF-affiliated Gladstone Institutes and Kyoto University, received the Nobel Prize in Physiology or Medicine for his discovery that adult cells can be reprogrammed to behave like embryonic stem cells.

In the trial, human neural stem cells developed by Stem Cells, Inc., of Newark, California, were injected directly into the brains of four young children with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease (PMD).

This image illustrates direct injection of human neural stem cells into the brain's white matter, which is composed of bundles of nerve axons. There is lack of myelin, an insulating coating, in the severe pediatric condition Pelizaeus-Merzbacher disease (PMD). Over time, some stem cells become myelinating oligodendrocytes as reported in the papers from Uchida et al. and Gupta et al. Image by Kenneth Probst.

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Transplanted Neural Stem Cells Produced Myelin, UCSF Study Shows