Neural Stem Cells Produce Myelin in Human Clinical Trial


Neurons are the cells in the brain that conduct nerve impulses. Nerve impulse conduction is the result of ion movements across the membrane of neurons, and these ion movements are mediated by ion channels embedded in the cell membranes of the neurons. Neurons consist of a main cell body that houses the nucleus, and two sets of extensions: axons that conduct nerve impulses away from the cell body and dendrites that conduct the nerve impulse toward the cell body. The axons of some neurons are coated with a layer of insulation that increases the speed at which neural impulses are conducted. This insulating layer is called the “myelin sheath,” and damage to the myelin sheath can decrease conductivity through these neurons and decrease nervous system function.

Spinal cord injury damages the myelin sheath that insulated spinal nerves. Also diseases such as multiple sclerosis can damage the myelin sheath of nerves and cause neural degeneration. Drug treatments can only delay the inevitable, but replacing the lost myelin sheaths is one of the holy grail goals of regenerative medicine.

We might be closer to such a goal than previously thought. A Phase 1 clinical trial at the University of California, San Francisco that was sponsored by Stem Cells Inc. has shown that a neural stem cell line can be safely transplanted into the brain of patients who suffer from demyelination diseases. Furthermore, these patients were devoid of side effects from the transplant one year after the procedure. However even more exciting is that these transplanted cells seem to have successfully engrafted into the brains of these patients and have produced new myelin sheaths.

This investigation was designed to determine the safety and preliminary efficacy of implanted neural stem cells and the results are extremely encouraging, according to the principal investigator for this trial, David H. Rowitch, MD, PhD, who is also professor of pediatrics and neurological surgery at UCSF, and chief of neonatology at UCSF Benioff Children’s Hospital and a Howard Hughes Medical Institute Investigator.

The co-principal investigator for this trial, Nalin Gupta, MD, PhD, associate professor of neurological surgery and pediatrics and chief of pediatric neurological surgery at UCSF Benioff Children’s Hospital, said: “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.” Gupta continued: “We also saw modest gains in neurological function, and while these can’t 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.”

In this trial, human neural stem cells that had been developed by Stem Cells, Inc., a Newark, California biotechnology company, were directly injected into the brains of four children who had been diagnosed with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease (PMD). PMD is a genetic disease that typically occurs in males and affects brain-specific stem cells known as oligodendrocytes that construct the myelin sheath that insulate the neurons of the central nervous system. Defective oligodendrocytes prevent deposition of a functional myelin sheath and without a myelin sheath the white matter neural tracts are unable to correctly propagate nerve signals. This results in neurological dysfunction and neurodegeneration. Patients with early-onset PMD can neither walk nor talk and also have trouble breathing and undergo progressive neurological deterioration leading to death between ages 10 and 15.

All the PMD children who participated in this clinical trial were given standard neurological examinations and developmental assessments before and after the transplant procedures, which were conducted from 2010-2011. All patients also underwent magnetic resonance imaging (MRI) in order to assess myelin formation.

After the neural stem cells had been transplanted, Rowitch and his collaborators found evidence that the stem cells had successfully engrafted into the brains of the children. There was also indication that they were receiving blood and nutrients from the surrounding tissue and integrating into the brain. Rowitch likens stem cells engraftment to a “plant taking root.” This is a very significant finding because the engrafted cells were not the patients’ own stem cells. The implanted cells were not rejected by the patients.

The MRIs provided another very exciting piece of evidence, albeit and indirect piece of evidence, that the transplanted stem cells had become oligodendrocytes and were producing myelin. According to Rowitch: “There is no non-invasive way to test this definitively, but our MRI findings suggest myelination in the regions that have been transplanted.”

These neural stem cells have the capacity to differentiate into a wide variety of neural cell types. The differentiation of the neural stem cells appears to be greatly influenced by the environment into which the cells find themselves. The sites chosen for the Phase I study were determined by pre-clinical experiments done with animals. Investigators, at Oregon Health & Science University’s Papé Family Pediatric Research Institute published their animal work in the same issue of Science Translational Medicine. Stem Cells Inc’s neural stem cells were injected into mice and differentiated into oligodendrocytes and formed myelin. “The animal study is consistent with the MRI findings from the clinical trial and further supports the possibility of donor-derived myelination in human patients,” said Rowitch.

Dr. Arnold Kriegstein, who is the director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF said: “This is a landmark study for the field. Without such studies in human patients, we won’t really know how transplanted cells behave –whether they disperse or migrate, whether they engraft or degenerate and die, whether immune-suppressing regimens really work or not. It’s only through these investigations that we will be able to refine the necessary procedures and technologies and make progress toward cell-based therapies for this disease and related disorders.”