This came from a friend in the biological field.
Michel
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PROFILE
Progress in Parkinson's
Diacrin and Fetal Pig Neurons
by Pamela Weintraub
Posted February 16, 2001 · Issue 96 of the HMS Beagle at bmn.com
Abstract
Diacrin's positive experiences with xenotransplantation into Parkinson's
patients may lead to a slew of other applications for pig fetal brain cells.
Parkinson's disease is a chronic, progressive disorder that robs patients of
their ability to move normally. On trips to the clinic, the newly diagnosed
observe other, sicker, brethren and read the writing on the wall. Unable to
initiate any voluntary muscle movement whatsoever, patients with advanced
forms of the disease are literally frozen in place. Their fate is a living
death, and then, death itself.
That is why it didn't take much convincing for Jim Finn, 51, to agree to be
a guinea pig in an extraordinary experiment. Already sick with Parkinson's
for some 20 years, he could now hardly walk. Eating was arduous, and the
fatigue continual. Time was running out for him and, he was told, little
could be done. Then, in 1996, he was given a second chance. Neurosurgeons
from the Lahey Clinic in Boston had room for 12 patients in a clinical trial
that, if successful, might halt progression of the Parkinson's or, in the
best-case scenario, even reverse damage that had already been done.
Without much to lose, Finn readily agreed to allow Lahey neurosurgeons to
inject some 12 million brain cells from a pig fetus into the right side of
his brain. Twelve weeks later, with symptoms abating, he knew his gamble had
paid off. The improvement was so marked that Finn was eventually able to
climb stairs, walk unaided, prepare food, speak fluidly to friends, and even
drive.
The source of Finn's good fortune, the engine behind the pig cells that
stabilized his brain, is a small Charleston, Massachusetts company known as
Diacrin. First funded in 1989 to pioneer cell-transplant technology in
diabetes, Diacrin soon switched its focus to diseases of the nervous system
and brain. The first disease it targeted, for a host of reasons, was
Parkinson's. Researchers understood the cause of the disease: the gradual
deterioration of the brain's dopamine-producing cells, responsible for
movement. At the time of diagnosis for patients such as Finn, 80 percent of
such cells are already destroyed. Scientists had already alleviated symptoms
for Parkinson's patients by grafting cells from the human fetus to the
brains of adults, apparently counteracting the deterioration process.
Douglas Jacoby, Diacrin's research director, says that the human fetal
strategy was problematic. There were, of course, the political problems
associated with harvesting a human fetus. But those paled beside the
technical hurdles. "The amount of tissue available from aborted fetuses is
limited," hardly sufficient for commercial quantities of a product, he
notes. "And because abortions are done in doctors' offices, tissue may be
contaminated, or partially destroyed."
One potential solution was the use of embryonic stem cells - human precursor
cells that scientists hope one day to direct along numerous developmental
pathways, ultimately growing large cultures of the range of human tissues to
treat all kinds of disease. But stem-cell technology, while promising to
revolutionize the future, was still so new it could take a decade or more to
arrive. Hoping to reach market sooner than later, Diacrin took another tack:
looking across species, Diacrin researchers decided to test cells from pigs.
As a model for treating Parkinson's, the idea of using pig cells was
elegant: Because the mammalian brain is preserved to a large degree across
species, Jacoby explains, it seemed possible to transfer dopamine-producing
cells from the pig brain to human brain, function intact. "Pig neural cells
are functionally indistinguishable from human fetal neural cells," he notes,
"and they are going through rapid growth."
Of course, there was the problem of rejection. Transferring a pig heart or
lung to a human would provoke the most powerful of immune responses, leading
to outright rejection of the organ. But the brain, Diacrin scientists
thought, might be more neutral ground. They already knew that a heart
transferred from one strain of rat to another leads to rejection, but
transferring brain cells between the same two animals would not. Indeed, by
sending cells past the blood-brain barrier, directly into the central
nervous system, it seemed possible to elude the most vigorous human
antibodies, generally carried in the blood.
With the powerful antibody response neutralized, scientists transplanting
across species had only to deal with the cellular immune response. Two
methods, Jacoby explains, were at hand. The first was the immunosuppressant
cyclosporin, the drug that had enabled organ transplants in the first place.
The second was a special "masking" method licensed from the Massachusetts
General Hospital. The system works by coating the pig cell surface,
comprised of MHC class I antigens, with human antibodies. The antigens are
generally recognized by human killer T cells, resulting in the death of
implanted cells. But the antibody coating acts as camouflage, fooling the T
cells into thinking foreign elements have been kept at bay.
To test the concept, Diacrin collaborated with McLean Hospital in Belmont,
Massachusetts to experiment on rats. Although rats do not contract
Parkinson's, researchers were able to simulate the condition by killing
dopamine-producing cells on one side of the brain. "When we did that," says
Jacoby, "the rats spun in a circle." But grafts of dopamine-producing cells
taken from fetal pigs and masked with antibodies corrected the imbalance.
Treated rats soon stopped spinning - or, in some instances, started spinning
in the other direction because the scientists had overcompensated, providing
more dopamine on the grafted side of the brain than the rats tended to need.
"From rats we went to monkeys," Jacoby explains, "and from there we went to
the FDA."
The Food and Drug Administration approved the company's phase I trial for
Parkinson's disease in 1995. The 12 participants chosen were facing "a death
sentence," Jacoby states. "They knew where they were going," and decided to
enter the Diacrin study instead. Each trial participant received a graft of
12 million dopamine-producing cells from the brain of a fetal pig. To
protect against disaster, researchers inserted the cells into a single brain
hemisphere, instead of both. To prevent rejection, half the participants
received cyclosporin, and half, the masked porcine cells; both techniques,
reports Jacoby, fought rejection equally well. The big news was the impact
of the treatment, with quality of life for the 12 subjects significantly
improved. "It was dramatic," Jacoby says. "Before the grafts some were
wheelchair-bound or bedridden. Afterward, some of these patients were able
to walk, feed themselves, and more."
In collaboration with Genzyme Corporation, which provided money, technical
expertise, and vast experience in clinical trials, Diacrin embarked upon
phase II trials for its product, called NeuroCell-PD, in 1998. Unlike the
phase I trial, phase II was double-blinded and placebo-controlled. Graft
recipients, treated on both sides of the brain, were each injected with 48
million dopamine-producing porcine fetal brain cells. Controls were placed
under anesthesia, but received just a surface cut to the scalp instead of
cell transplants deep inside. According to Jacoby, results of the trial
won't be known until the blinds are broken this spring.
But Diacrin isn't just sitting around waiting. Instead, it has launched a
series of other studies aimed at treating Huntington's disease, stroke,
epilepsy, chronic pain, and even spinal-cord injury by transplanting cells
from fetal pigs into the central nervous system and brain. The wide-ranging
applications for Diacrin technology is based on the discovery that, when
transplanted into humans, porcine neural cells - in particular, porcine
embryonic neural cells isolated during certain stages of gestational
development - promote the development of efferent connections between graft
cells and distant brain targets in the host subject and receive afferent
input from the host. Moreover, the porcine neural cells provide a source of
neurotransmitters that are regulated by feedback control systems. Amazingly,
cells moved from a pig brain to the analogous region of a human brain often
keep functioning, sending connectors or releasing neurotransmitters without
so much as missing a beat.
Huntington's disease patients in a phase I clinical trial, for instance,
received striated brain cells from fetal pigs. The cells not only grafted
right onto the region in the human brain analogous to the pig brain region,
they also appeared to assume analogous functions, to some degree picking up
the slack. "It is notable that treatment has halted progression of the
disease," says Jacoby. But unlike the Parkinson's patients, their conditions
did not improve.
More recently, Diacrin has begun phase I clinical trials with five patients
suffering ischemic stroke, caused when blood to the brain is blocked and
cell death results. Researchers have found that inserting some 30 million
striated cells into the "dead zone" deep within the striatal region of the
brain can restore damaged tissue. Says Jacoby, "We have seen measurable
improvement for these patients in motor function for the affected limbs."
Similar transplants have been a boon to patients with temporal lobe epilepsy
as well. There, researchers using Diacrin porcine striatal cells hope to
prevent seizures by supplying the inhibitory neurotransmitter GAMA amino
buteric acid. Though it is still too early to assess the efficacy of this
treatment, Jacoby notes that one of three patients in the phase I trial
experienced enough improvement to delay surgical intervention, at least for
the time being.
The future for Diacrin is especially clear from a search of its patent
holdings, which are ambitious, to say the least. The company has recently
filed for patents covering the use of fetal pig cells to treat spinal
injuries and other neurodegenerative diseases, including multiple sclerosis
and amyotrophic lateral sclerosis or Lou Gehrig's disease. Projects aimed at
treating chronic pain are set to launch as well. "Our goal," says Jacoby,
"is improving the quality of life. How far we can take these techniques is
still wide open. We have a long way to go."
Pamela Weintraub is a science journalist based in Chappaqua, New York.
