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/


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