Ischemic brain injury - another promising avenue for stem cell therapy

Adult stem cell therapy quickly and significantly improves recovery of motor function in an animal model for the ischemic brain injury that occurs in about 10 percent of babies with cerebral palsy, researchers report.

Within two weeks, treated animals were about 20 percent less likely to favor the unaffected side of their bodies and experienced about a 25 percent improvement in balance, compared to untreated controls, Medical College of Georgia researchers say.

"We found that when these cells, provided by Athersys, Inc., were injected directly into the brain, it significantly improves the outcome in the animals," says Dr. James E. Carroll, chief of the MCG Section of Pediatric Neurology and the study's principal investigator.

Athersys, Inc., a Cleveland-based biopharmaceutical company pursuing cell therapy programs in cardiovascular disease, stroke, cancer and other diseases, funded the research in which about 200,000 cells were injected directly into the brain injury site.

The adult stem cells, called multipotent progenitor cells because of their ability to make different types of tissue, were taken from the bone marrow of rats and expanded by Athersys for dosing in the injury model, Dr. Carroll says.

Seven days after injury, stem cells were injected directly into the brains of 22 animal models through a tiny hole in the skull. As with human transplant recipients, the animals were placed on immunosuppressive therapy to avoid rejection, although Athersys' experience in multiple animal models for human disease has shown donor-recipient matches and immunosuppression are not required.

Behavioral tests seven days after transplant showed a trend toward recovery and significant recovery by day 14. About 1 percent to 2 percent of the transplanted cells actually survived, apparently replacing some cells destroyed by the original injury, while others helped injured cells recover.

"Recovery might be even more important in baby brains than forming new cells," Dr. Cesario V. Borlongan, neuroscientist at MCG and the Veterans Affairs Medical Center in Augusta, says of newborn brains that recover more readily than adult brains. Dr. Borlongan, a co-author on the abstract, is exploring stem cell therapy's potential for aiding stroke recovery, including the use of clinical-grade human adult cells provided by Athersys in a stroke animal model. About 80 percent of strokes are caused by clots that cause ischemic brain injury similar to that of cerebral palsy.

The MCG researchers have evidence that the healing benefit of stem cells comes from nourishing factors they secrete. The cells seem attracted by chemokines, growth factors that rally to an injury site, Dr. Carroll says. Next steps include looking at longer-term recovery and at whether surviving stem cells actually function as brain cells, networking with other cells by forming points of communication called synapses.

Perhaps most importantly, they also will look at whether stem cells produce similar results when they are given intravenously rather than injected directly into the injury site, Dr. Carroll says. "If the ideal way of doing it scientifically doesn't work, why move on from here?" he says. "Now that we know it does work, we are going to look at different methods of injection to try and find the one that is the easiest. We think the chemokines, at least in part, attract the cells, so we hope it will work even when given through the bloodstream."

He notes that the therapy likely will need to be done soon after injury. Whether this therapy could help the some 500,000 people in the United States living with cerebral palsy still must be explored, he says.

He and Dr. Borlongan note much work needs doing before their findings might move to clinical trials. But they are optimistic that the availability of clinical-grade cells would expedite such a move.

"We hope this will eventually be something that can be used in the neonatal intensive care unit in babies with severe asphyxial brain injuries," Dr. Carroll says of cerebral palsy patients. He and other pediatric neurologists and neonatologists already have begun to discuss such possibilities.

"These results suggest another promising avenue for stem cell therapy, this time to help newborn babies recover from a potentially devastating injury of birth for which there currently is no treatment," says Dr. Gil Van Bokkelen, chairman and chief executive officer of Athersys.

Ischemic brain injury accounts for about 10 percent of cerebral palsy, broadly defined as brain injury that occurs before or during birth, and about 80 percent of strokes. For every 1,000 babies born, one or two have cerebral palsy, with consequences ranging from undetectable to major physical and mental impairment. Currently there is no treatment to repair or reduce the damage of cerebral palsy; tPA was approved in 1996 by the U.S. Food and Drug Administration as the first stroke treatment to reduce the damage of ischemic injuries.

Co-authors on the study include Dr. David Hess, chair of the MCG Department of Neurology; Dr. Lin Xu, research scientist; Drs. Noriyuki Matsaukawa, Guolong Yu, Takao Yasuhara and Koichi Hara, postdoctoral fellows; and Athersys scientists Robert Mays, Jim Kovach and Robert Deans.