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One step closer to brain repair

The first transplant of human neurons "opens up the door."

Thursday, July 02, 1998

Unlike the stroke patients they hope to treat, doctors at UPMC Health System took nimble first steps toward repairing stroke-induced brain damage by performing the world's first human neuron transplant.

On June 23, surgeons injected lab-produced human nerve cells deep into the brain of Alma Cerasini, 62, a former health care worker from Pittsburgh. She went home the day after the three-hour procedure and is doing well, although it is too soon to tell if the new cells are going to restore her ability to speak or move her right side, doctors said.

"We have achieved the first use of manufactured human neurons, or nerve cells to put into the brain for the treatment of a degenerative disease of the brain," said neurosurgeon Dr. Douglas Kondziolka at a news conference yesterday, acknowledging that the cells' treatment potential went far beyond strokes.

Cerasini, who had a stroke in September 1997, is the first of 12 patients taking part in an initial trial of the cells, called LBS-neurons. The university is the only site for the study, which is meant to demonstrate the technique is safe. Future studies will look specifically for improvements in function.

But even now, "it's obvious everybody is looking for a glimmer of efficacy," said Kondziolka, one of the study's principal investigators. For the moment, only people who have had severe strokes in an area deep within the brain called the basal ganglia are included in the guidelines.

Participants must be between 40 and 75, have had a stroke six months to six years ago, and have a severe neurological deficit that has remained stable for at least two months. The next two patients, one each for transplants to be performed in July and August, have already been chosen, Kondziolka said.

Strokes were chosen as the subject of study because they cause localized damage to brain tissue, and thus a target for a transplant.

Before the procedure, a stereotactic frame is placed on the patient's head and CT or magnetic resonance imaging scans are taken. This enables the surgeon to see the dead tissue inside the brain and use the frame to guide a long needle inserted in a small hole drilled through the skull.

A total of 2 million cells are injected through the needle in and around the dead tissue. The needle is removed and the opening closed with a stitch.

Participants will be examined regularly with scans and other studies to look for neural activity at the transplant site. It may be months before patients show any improvement.

For now, patients will take an anti-rejection drug so the immune system doesn't fight off the transplant. Early data from other researchers suggests the medications might not be necessary for human-to-human neuron transplants, but that has not been established as fact, Kondziolka said.

Rehabilitation therapy may help the transplanted nerve cells learn their new role in the brain, but the uncertainty about its usefulness has led the researchers to omit it as an official part of their study protocol.

Success in animal models encourages belief that the transplants will work in other areas of the brain. Researchers from the University of South Florida College of Medicine and the University of Pennsylvania Medical Center published a study in the February issue of Experimental Neurology showing that rats that received human neuron transplants as stroke treatment got better in terms of movement and behavior.

The transplanted cells looked like their neighboring neurons, produced the same proteins and formed communication points called synapses that allow nerve cells to relay messages to each other.

Repairing stroke damage may be just the beginning.

"It opens up the door for studies in all neurological diseases that are (localized)," like Parkinson's disease, Kondziolka said. "This is what we've been waiting for forever."

Source of the cells

Experiments with fetal animal nerve cell transplants for Parkinson's are under way at other centers, but the human cells, produced in mass quantities from a single source, provide an option that avoids the ethical dilemmas of using fetal tissue.

The source of the lab-made neurons, a 22-year-old man who saw doctors at Memorial Sloan-Kettering Cancer Institute in New York, could not have known that his cancer cells would be touted, more than a decade later, as a potential treatment for a myriad of neurological diseases.

He had a rare cancer called a teratocarcinoma, a reproductive organ tumor that contains cells similar to that of an embryo. Samples of the cancer tissue would be the focus of many researchers, not only to learn about cancer, but also about how immature cells grow to take on particular functions, becoming a nerve cell, or a muscle cell, or a liver cell.

Virginia M.-Y. Lee, a professor of pathology and laboratory medicine at the University of Pennsylvania, isolated some of the immature cells and treated them with a naturally produced agent called retinoic acid. To her delight, a mature neuron appeared at the other end of such biochemical manipulations.

More cells are grown from the purified line, which in theory can no longer overgrow and cause cancer. The neurons produced for experimentation are examined to exclude viruses, bacteria or other contaminants that could endanger those that receive them. The cells are frozen in liquid nitrogen and delivered to the research center to thaw and use.

"This is the phenomenal luck in science," said Lee's research collaborator and husband, Dr. John Trojanowski, also from Penn's pathology department. "It is a Holy Grail in neuroscience to have a cell line you can do experiments on."

They are now examining the integration of the LBS neurons -- named after Atherton, Calif.-based Layton BioScience, Inc. -- in spinal cords of lab animals that have no injury. Their colleagues have suggested investigating the cells' potential in the treatment of epilepsy.

The cells could also act as a carrier of genes into the brain, for example, to produce chemicals that fight off nearby cancers, Trojanowski said. If it turns out that some psychiatric illnesses are the result of a lack of some agent, the cells could deliver the needed gene to the brain.

"We're both tremulous and scared because this is an experiment in a person and you always worry," he added. "No matter how many experiments you do in animals, when you go into humans, there's unexpected things."

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