PITTSBURGH, July 1, 1998 — 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.