First stem cell clinical trial for treating brain's "communication highway" to begin

By Jennifer O'Brien

UCSF researchers are set to begin a Phase I clinical trial in collaboration with StemCells, Inc. to test the safety and preliminary effectiveness of using neural stem cells to treat children with a rare, fatal form of a brain disorder known as Pelizaeus-Merzbacher disease (PMD). Currently, there are no effective treatments for the fatal forms of the disease, which affects males that inherit a single defective gene.

The trial is the first neural stem cell trial in the United States designed to treat a disease resulting from a lack of “myelin,” a substance that insulates nerve cells’ communications fibers. Nerve cells communicate through axons that function much like electrical wires. Myelin is the insulating coat that surrounds the axons to prevent short circuits. Damage to the cells in the brain that make myelin, called “oligodendrocytes,” is the hallmark of multiple sclerosis and is involved in certain forms of cerebral palsy.

The study is the second neural stem cell clinical trial for neurodegenerative diseases to be conducted in the United States. A Phase I trial using the same type of neural stem cells was completed in January, with reported positive safety results and evidence that the cells engrafted into the brain. This study concerned another rare and fatal disease, called neuronal ceroid lipofuscinoses (Batten disease), and was conducted by researchers at Oregon Health & Science University (OHSU).

Both studies originated with StemCells, Inc., whose proprietary purified human neural stem cells are the focus of the trials. The long-term goal of both studies is to see if the cells – while used differently in each disease – promote function in damaged nerve tissue.

In PMD, the oligodendrocytes contain a defective gene on the X chromosome that makes them unable to produce the myelin sheath. This defective gene is a recessive genetic trait that is carried by mothers and passed on to their sons. Because the sons have only one X chromosome, without a second normal X to counteract it, a mutated gene on that chromosome causes the defect to manifest as PMD. Patients with the severe form of PMD cannot walk or talk and they undergo progressive deterioration leading to death between ages five and seven.

In the UCSF clinical trial, surgeons will transplant neural stem cells into the brains of PMD subjects to see if this approach is safe and whether the cells will develop into oligodendrocytes and form myelin.

“Severe PMD is a devastating illness that is fatal and globally affects brain function, yet we know that it is caused solely by defects in a single type of brain cell, the oligodendrocyte,” says the principal investigator, David Rowitch, MD, PhD, a pediatric specialist and chief of neonatology at UCSF Children’s Hospital.

“This FDA-authorized Phase I trial will help us to judge whether this new approach—cellular replacement of defective cells in the brain—is safe for patients with PMD. We hope to open a window on a treatment strategy for PMD and other oligodendrocyte-based diseases for which we don’t have treatments. It is terribly important to be able to offer new prospects for these children.” Rowitch also is professor of pediatrics and neurological surgery, a Howard Hughes Medical Institute investigator and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The primary purpose of the Phase I trial is to determine the safety of the transplanted cells. Results presented in June by StemCells, Inc. and OHSU researchers indicated that the six children similarly treated in the Batten disease Phase I trial had an acceptable safety outcome during the 12-month period following transplantation.  Some of these patients are now more than two years post transplant and by imaging show no sign of abnormal cell reaction or tumor formation, according to the company.  A four-year follow-up study continues to monitor these patients.  Ongoing observation, says Rowitch, is needed to be sure that problems do not arise later.

The secondary purpose of the trial is to see if the cells help correct the lack of myelin in the patients’ brains. The study will use magnetic resonance imaging (MRI) to follow myelin production, as well as careful assessment of neurological function by clinical examination, parental reporting, and other tests.

“PMD represents an important early target for regenerative therapies in the brain,” says Charles ffrench-Constant, MD, PhD, an expert in oligodendrocyte biology and regenerative neurology at the University of Edinburgh. “As the oligodendrocytes that form myelin do not have to form networks over long distances, but only wrap around local nerve fibers, getting the transplanted cells to integrate into the damaged brain and repair the disease is a much less complex challenge than would be the case in diseases such as stroke and Huntington’s disease.

Evidence from studies in animals with a condition like PMD carried out both in academic laboratories, such as that of Steven A. Goldman (University of Rochester) and separately by StemCells, Inc., suggest the potential of this approach, says Rowitch. Several teams have reported that neural progenitors divide and proliferate in the brain after transplantation and, in response to chemical cues in their environment, migrate to niches where they are needed, develop into oligodendrocytes and begin to form myelin. In StemCells, Inc.’s studies, their human neural stem cells have been shown to generate the cells that produce myelin and insulate nerve cells’ axons.

“Dr. Rowitch and his colleagues are taking a very important first step in exploring the potential of neural stem cells to treat a whole class of severely debilitating neurodegenerative diseases,” says Arnold Kriegstein, MD, PhD, a leading neural stem cell scientist and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

“I applaud the thoughtful consideration that has gone into the assessment of the risks and rationale for taking this step.”

The trial will enroll four boys, ages six months to five years of age, who have the most severe form of PMD. The children will undergo neurosurgery to receive infusions of neural stem cells, and will receive immunosuppressive drugs for nine months afterwards to prevent rejection of the transplanted stem cells. Intensive follow-up will take place for one year to see whether the children show any clinical signs of improvement. MRI brain scans will be carried out for four more years to assess for any problems associated with the cells.

Co-investigators of the clinical team are Jonathan Strober, MD, Director of Clinical Services for Child Neurology and Director of the Muscular Dystrophy Clinic at UCSF Children’s Hospital, and Nalin Gupta, MD, PhD, Chief of Pediatric Neurological Surgery at UCSF Children’s Hospital.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the hospital. Medi-Cal patients constitute more than half of the patient population.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Related links:

PMD trial –

StemCells, Inc. –

PMD Foundation -

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research

Rowitch profile: -

Rowitch selected as Howard Hughes Medical Institute Patient-Oriented Research Investigator

UCSF Children’s Hospital -