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University of Pittsburgh Medical Center Background Information: LBS-Neurons for Treating Stroke July 2, 1998 PITTSBURGH, July 1 /PRNewswire/ via NewsEdge Corporation -- 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 Pitt 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 perfected 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 2 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 Douglas Kondziolka, M.D., and Lawrence Wechsler, M.D., will assess 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 4 and 24 weeks after the transplant also will allow investigators to study the grafted brain site. In addition, the researchers will monitor blood levels of chemicals to assess for any adverse effects. 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. Many investigators contributed important pre-clinical research findings that made possible this historic clinical neuron transplant for stroke. For additional information about the history of the development and testing of LBS-Neurons, the pre-clinical application of LBS-Neurons to other disease processes and a corporate profile of Layton BioScience, Inc., please visit http://www.laytonbio.com For additional information about the role of these neurons in the clinical trial, please look in the News Bureau section of UPMC Health System's web page, http://www.upmc.edu. SOURCE University of Pittsburgh Medical Center World`s First Procedure to Repair Brain Damage from Stroke Performed at the University of Pittsburgh Medical Center July 2, 1998 PITTSBURGH, July 1 /PRNewswire/ via NewsEdge Corporation -- On June 23, 1998, doctors at the University of Pittsburgh Medical Center (UPMC) performed the world's first cell transplant to reverse brain damage from stroke on a 62-year old woman with paralysis of the right leg and arm and loss of most speech. This trial marks a transition in stroke medicine from prevention and damage-limiting efforts to restoration of lost brain function. While fetal human and fetal animal cell transplants have been tried for neurodegenerative disorders, such as Parkinson's disease, with promising results, this is the first study to address neurological deficits from stroke. It is also the first brain cell transplant to use tissue grown in the lab, avoiding the ethical issues arising from the use of fetal tissue. "This trial opens the door to fuller recovery from stroke. While physical and occupational therapy helps many patients adapt to the damage their brain has suffered from stroke, neuron cell transplantation may allow patients to recover lost abilities," said Douglas Kondziolka, M.D., co-principal investigator for this study and professor of neurological surgery and radiation oncology, University of Pittsburgh School of Medicine. Dr. Kondziolka developed the study and is the surgeon performing the operations that are part of this cell transplant protocol. "This is an exciting day in the treatment of stroke. Vigorous research to date has concentrated on prevention and ways to limit damage that has already occurred in the stroke patient's brain. If the phase I trial proves successful, the next step would be a multi-center trial," said Lawrence Wechsler, M.D., director of the UPMC Stroke Institute, professor of neurology at the University of Pittsburgh School of Medicine and a co-investigator on this trial. "Use of manufactured cells to reverse brain damage removes the ethical concerns many people have about the use of fetal tissue," said Peter Jannetta, M.D., chairman emeritus of the UPMC Department of Neurological Surgery and Walter Dandy Professor of Neurological Surgery, University of Pittsburgh Medical Center. He added, "The potential of neuron transplants as a therapy includes not only neurodegenerative diseases, but also spinal cord damage." Stroke is the third leading cause of death and the most common cause of adult disability in the United States, according to the National Institutes of Health. Each year, 700,000 Americans suffer a stroke. Thirty percent die and 20-30 percent become severely and permanently disabled. The total cost for caring for all aspects of stroke is $41.9 billion annually in the United States. Currently, rehabilitation through physical and occupational therapy is the only treatment available for patients with established stroke. No direct treatment is recognized as safe and effective for reversing the neurologic damage months after the event. The neuron-transplant study is a single-site FDA approved phase I trial. The primary goals of a phase I trial are to ensure the safety and tolerance of the therapy in patients. The researchers also will collect and analyze data to detect neuronal and functional responses to this treatment, as well as any other clinical response. Twelve patients will participate. The first four cases will take place at one-month intervals. The study is open to male and female patients between the ages of 40 and 75, whose stroke occurred six months to six years previously and have a fixed functional motor deficit that has been stable for at least two months. The initial patient, Alma Cerasini, is a 62-year-old former healthcare worker who suffered a major stroke last fall, resulting in paralysis of her right arm and leg. The patient also lost nearly all her ability to speak. The implanted neurons are provided by Layton Bioscience, Inc., located in Atherton, Cal. 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. Layton Bioscience, Inc., has perfected and patented a process that uses several chemicals to cleverly transform this rapidly dividing cell line into fully differentiated, non- dividing neurons (LBS-Neurons) that can safely be used clinical use. In extensive preclinical testing, transplants of LBS-Neurons reversed cognitive and motor deficits in animals in which stroke had been induced. The procedure begins with the placement of a stereotactic frame on the head of the patient. The frame is a standard tool in neurosurgery to provide a fixed way to find specific locations within the brain. The patient then receives a CT or MRI scan of the brain. The surgical team then makes its final plans for implantation of the neurons. Concurrently, the Pitt lab team thaws the neurons that were frozen by and transported from the Layton BioScience, Inc. Researchers then check the LBS- neurons to ensure there are 2 million or more viable cells to transplant. After the manufactured neurons are transferred to a long-needled syringe, a surgeon uses CT to guide their injection at three sites. The surgeon injects these cells through an opening of the skull smaller than a pea. After injection, the opening is closed with one stitch. The patient goes home the next morning. Follow-up assessments for safety and efficacy will be done at 1, 2, 4, 8, 12, 16, 24, and 36 weeks. Beginning with the 12-month visit, a yearly neurological examination will evaluate the status of functional deficit and screening for side effects. Different Magnetic Resonance Imaging (MRI) sequences will be used to evaluate the brain tissue response to treatment and appearance. Positron Emission Tomography (PET) scanning will be used for assessment of regional brain metabolism. Neurological status will be assessed before surgery and at the follow-up visits with both the NIH Stroke Scale and the European Stroke Scale. Functional disability and quality of life assessments will also be conducted. The patient will received cyclosporine, an anti-rejection drug, for one week prior to surgery, and will continue to receive it for two months after surgery. Other co-investigators on the study are Howard Yonas, M.D., Peter Jannetta professor of neurological surgery and co-director, UPMC Stroke Institute; Carolyn Meltzer, M.D., assistant professor of neurology and medical director, PET Scanner; Jorge Rakela, M.D., chief, Division of Transplantation Medicine; Laurie Knepper, M.D., assistant professor of neurology; and Elaine M. Elder, Sc.D., program coordinator, Immunologic Monitoring and Diagnostic Laboratory. This trial is one of many research initiatives of the University of Pittsburgh Stroke Institute and is supported by Layton Bioscience, Inc. For additional information about this historic procedure, please access the News Bureau section of the UPMC Health System web page at http://www.upmc.edu. NOTE TO BROADCAST: This is the first cell transplant study for people who have suffered brain damage from stroke. In this University of Pittsburgh Medical Center research, neuronal cells grown in a lab will be injected into an impaired portion of the brain. It is expected that the implanted neurons will link up with cells in the same area to restore lost functions, such as movement of paralyzed arms and legs. The early phase of this research in humans is not designed to actually treat patients, but to ensure the safety of the procedure. However, the researchers also will look for evidence that would suggest, at a preliminary level, whether or not this cell transplant is working. SOURCE University of Pittsburgh Medical Center /CONTACT: Mark Kanny or Lauren Ward of UPMC, 412-624-2607, or fax, 412-624-3184, or e-mail, [log in to unmask] or [log in to unmask] /Web site: http://www.upmc.edu/ University of South Florida Science Behind Nation`s First Neuron Transplant For Stroke July 2, 1998 TAMPA, Fla., July 1 /PRNewswire/ via NewsEdge Corporation -- The University of Pittsburgh is making national news today for the first neuron transplant into the human brain aimed at repairing stroke damage. The transplant, done June 23, is based on Florida science. Researchers at the University of South Florida in Tampa devised the idea of using the transplanted neurons for stroke. USF published laboratory results in the February issue of the journal "Experimental Neurology." The neurons are derived from tissue of a specific tumor that includes embryonic cells. "If the cells prove to be safe in this first group of patients, it can open up a new way of treating the brain," said Paul Sanberg, Ph.D., director neurosurgical research at USF. "We're now doing early research that will lead to transplants not only for stroke but also for Parkinson's, spinal cord injury and Huntington's." In the laboratory, the cells restored movement in rats subjected to experimental stroke. The process of developing the cells was patented by the University of Pennsylvania and licensed to Layton BioScience, Inc. of Atherton, Calif. SOURCE University of South Florida /CONTACT: Anne DeLotto Baier, University of South Florida, 813-974-3300/ John Stafford -- http://pw2.netcom.com/~johnws/index.html -- [log in to unmask] ................... Si fallatis officium, quaestor infinitius eat se quicquam scire de factis vestris.