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.
|Before time ran out, Jim Finn became a guinea pig.|
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.
|Diacrin pioneered brain cell transplant technology.|
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."
|Stem cells were promising, but Diacrin decided on pig cells.|
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."
|The blood-brain barrier keeps antibodies at bay.|
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.
|Diacrin went from rats to monkeys to the FDA.|
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."
|Results from phase II trials are expected this spring.|
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.
|Pig cells are also being tested in Huntington's disease.|
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."
|Fetal pig cell transplants may reduce the frequency of seizures.|
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.
Cary Barnhard grew up in New Jersey, where his senior class voted him "most unique." He maintains that honor is a polite way of being voted "most likely to need therapy." After a few misadventures in the music industry, he started pretending to be a graphic artist. Eventually it became the truth.
Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease - after HMS Beagle's publication of "Progress in Parkinson's: Diacrin and Fetal Pig Neurons," a new study published in the March 8, 2001 issue of the New England Journal of Medicine has cast doubt on the therapy. In the New York Times, Gina Kolata reports (free registration required for access) further.
Porcine Possibilities - examines whether transgenic technology can reduce the risk of xenotransplantation. From the October 16, 2000 issue of The Scientist.
The Transplantation Xeno-Derby - a look at the companies involved in xenotransplantation technologies. From the July 20, 2000 issue of Signals.
Transplanted Fetal Striatum in Huntington's Disease: Phenotypic Development and Lack of Pathology - results from recent experiments with human fetal striatal cells. From the December 5, 2000 issue of PNAS.
Basal Ganglia, Parkinson's Disease and Levodopa Therapy: A Supplement to Trends in Neurosciences - a collection of articles from 2000, with full text available from BioMedNet.
Xenotransplantation, Endogenous Pig Retroviruses and the Precautionary Principle - considers public health issues related to xenotransplantation. From Molecular Medicine Today, 2001, 7:2:62-63. Full text available from BioMedNet.
Xenotransplantation for CNS Repair: Immunological Barriers and Strategies to Overcome Them - a review of known mechanisms that underlie neural xenograft rejection and attempts to bypass them. From Trends in Neurosciences, 2000, 23:8:337-344. Full text available from BioMedNet.
Xenotransplantation: Is the Risk of Viral Infection as Great as We Thought? - considers the likelihood of animal virus transfer. From Molecular Medicine Today, 2000, 6:5:199-208. Full text available from BioMedNet.
Xenotransplanted Neurons Show Potential to Treat Spinal Injuries and Parkinson's Disease - a news article about technologies developed by Alexion Pharmaceuticals. From Molecular Medicine Today, 2000, 6:2:46-47. Full text available from BioMedNet.
Recent Advances in Xenotransplantation - a review focusing on strategies used to eliminate hyperacute rejection. From Current Opinion in Immunology, 1999, 11:527-531. Full text available from BioMedNet.
Efficacy of Adhesive Interactions in Pig-to-Human Xenotransplantation - considers the roles that adhesion molecules and their ligands play during transplantation. From Immunology Today, 1999, 20:7:323-330. Full text available from BioMedNet.
Human Neural Stem Cells on Trial for Parkinson's Disease - a news article from Molecular Medicine Today, 1999, 5:4:144. Full text available from BioMedNet.
Xenotransplantation: How to Overcome the Complement Obstacle - reviews methods available for overcoming rejection in pig to human transplants. From Molecular Immunology, 1999, 36:4-5:269-276. Full text available from BioMedNet.
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