LBS Neurons for Treating Stroke

Physicians at the University of Pittsburgh Medical Center (UPMC) are evaluating the use of LBS-Neurons in the world's first clinical human neuron transplant into a patient's brain. This is the first effort to treat stroke patients with an intracerebral graft of cells. These neurons are provided by Layton BioScience, Inc., located in Atherton, Cal. Specifically, the University of Pittsburgh research team expects the LBS-neurons to improve the function of neurons damaged after a stroke. Based on previous studies with an animal model of stroke, researchers think that grafted LBS-Neurons will either enhance the function of host neurons that survive a stroke but are impaired, or replace host neurons that have been destroyed by a stroke.

The LBS-Neurons are derived from a cell line initially developed in the mid-1980s and manipulated further in tissue culture and in animal models by several research teams from the late 1980s onward.

LBS-Neurons originate from a human teratocarcinoma found in a 22-year-old cancer patient. Teratocarcinomas are tumors of the reproductive organs that are composed of embryonic-like cells. Researchers at the University of Pennsylvania developed and patented a process that uses several chemicals to cleverly transform this rapidly dividing cell line into fully differentiated, non-dividing neurons. They have accomplished this by treating the parent cells with retinoic acid, a biological agent known to induce the maturation of cancer cells into their normal-looking, noncancerous equivalents. This procedure has been used in other circumstances. For example, cancer investigators have used retinoic acid to transform cancer cells in tumors of the head and neck cancer into benign or non-tumor cells as a therapy. Because teratocarcinomas contain cells that are embryonic in nature, they have the capacity to respond to treatment with specific chemicals by progressively developing into different cell types. Remarkably, the Layton BioScience line of teratocarcinoma cells obtained from the young patient differentiated into non-dividing neurons in response to the treatment discovered by the Penn researchers.

At the University of Pennsylvania, initial experiments using cultured LBS-Neurons revealed that they could thrive as transplants within normal rodent brains, as well as within stroke-damaged brain regions of rats. Researchers at Penn found that the LBS-neuron transplants within normal rodent brains integrated with existing neurons, produced other neuronal proteins and formed synapses. Moreover, researchers investigating LBS-Neuron transplants in rodents found that these transferred cells started to look and function like the type of neurons near the insertion site. Thus, LBS-Neurons transplanted in the brain cortex became cortical neurons, whereas LBS-Neurons transplanted into deep brain regions resembled their neighbors. In some experiments, rats with LBS-Neuron grafts also received the immune-suppressing drug cyclosporin to block transplant rejection and promote the survival of the LBS-Neuron transplants for more than a year. However, grafts into the brains of mice with a limited functioning immune system also survived over one year without drugs to suppress the immune system.

Later experiments performed by other researchers at the University of South Florida showed that LBS-Neurons could correct cognitive deficits and motor skill problems associated with stroke-induced brain injury in rats. Significantly, all of these studies showed that the LBS-Neurons did not revert to cancer cells or cause tumors in any experimental animals.

In the current clinical trial at UPMC, investigators performed a single surgical procedure to deliver two million cells divided among three sites within and around the stroke-damaged tissue of the patient's brain.

Once implanted into and around the stroke, the LBS-Neurons are expected to integrate with existing tissue. There, they may restore brain function by interacting with the remaining neurons by mechanisms that are unknown, but which are under intense study.

The Pitt clinical investigators led by Lawrence Wechsler, MD, have assessed the activity of the implanted neurons 24 weeks after transplant using positron emission tomography, or PET, which will measure the metabolic activity, if any, in the area of the implanted nerve cells. Magnetic resonance imaging (MRI) sequences performed at four and 24 weeks after the transplant allowed investigators to study the grafted brain site. In addition, the researchers monitored blood levels of chemicals to assess for any adverse effects. At present (October 2002), two clinical trials have been completed. The second study was performed at the University of Pittsburgh and at Stanford University.

The use of LBS-Neurons in this clinical study obviates the need to use fetal cells, the other primary cell type being studied for transplant into the brain for a variety of other neurological disorders, such as Parkinson's disease and Huntington's disease. The harvesting of fetal human cells for treating disease has raised ethical concerns, especially regarding elective abortions. On the other hand, spontaneous abortions are rare and unpredictable events, so harvesting tissues from these fetuses would prove impractical. Further, cells from spontaneously aborted fetuses would be more likely to contain serious genetic defects. The use of fetal animal cells has also been questioned, because cross-species transplantation involves animal tissue cells that carry very different immune markers from human tissue cells. Thus, cross-species immune rejection of the transplanted cells is likely. Moreover, fetal animal cells may contain as-yet unknown infectious diseases that could crossover into the recipient's tissue.

Another important feature of LBS-Neurons is that they can be frozen and transported to clinical centers for transplantation, whereas fresh (non-frozen) fetal cell cultures are used for transplantation. That LBS-neurons can be frozen, thawed and inserted into living brains at all is impressive. To date, researchers worldwide have been unable to achieve this level of progress with any other neuron cell line.

A multicenter Phase 2 cell volume escalation trial is currently underway at Pitt and other centers such as Stanford University. This trial is sponsored by San Bio.