By David N. Leff

Science Editor

A Connecticut-based biotechnology company won a double-header Monday on opposite sides of the world.

One event was played in Nagoya, Japan, at the Fifth International Congress for Xenotransplantation. There, William Fodor, director of xenotransplantation at Alexion Pharmaceuticals Inc. in New Haven, described successful implantation of myelin-forming pig cells into primates with surgically severed spinal cords. His co-author, neurologist Jeffrey Kocsis at Yale University, conducted the actual experiments on African green monkeys.

Meanwhile, in Miami, at the 1999 meeting of the Society for Neuroscience, an Alexion poster reported on porcine fetal dopamine-secreting neurons grafted into a rhesus monkey model of human Parkinson's disease (PD). Neuroscientist Ole Isacson, at the Neuroregeneration Lab of Harvard University, administered the Alexion-modified pig cells to the PD-mimicking primates.

Those non-human animal models had acquired the irreversible symptoms of human PD, Isacson told BioWorld Today, "by treatment with the classic MPTP compound, which reflects the motor disabilities of the disease. Six of these monkeys received pig fetal brain neurons via injection through the skull into dopamine-secreting areas of their brains."

To avoid immune rejection of the alien tissues, Alexion scientists modified those porcine cells by genetically engineering them to express a protein that inhibits the recipient's complement system. The fifth protein (C5) of the complement cascade acts as the lethal graft terminator by immune rejection. In addition, the monkeys received systemic injections of antibodies specifically programmed to counterattack complement killer cells, along with conventional immune suppressor agents.

"We found that with complement inhibitors present," Isacson said, "we could markedly enhance the transplant survival in this monkey model. So far," he added, "we are looking only at the cell transplant survival issue." He went on to make the point that, "To my knowledge, this study represents the first successful engraftment of pig neurons into primates. It further demonstrates that the combination of these immunoprotected neural cells with Alexion's pharmaceutical C5 inhibitor may provide an optimal means to overcome the critical immune barrier that has historically limited successful engraftment."

From Parkinson's To Damaged Spines

To block the C5 complement factor in spinal injury, Alexion's Fodor told the meeting in Japan, "two different types of myelin-producing cell types, olfactory ensheathing cells and Schwann cells, both derived from transgenic pigs expressing a human complement inhibitor protein, were transplanted [by Yale's Kocsis and his collaborators] into the transected dorsal columns of the immunosuppressed primates to induce axonal regeneration. In four monkeys with damaged spinal cords," Fodor reported, "transgenic pig cells engrafted, produced myelin, and ensheathed native primate nerve axons.

"These results," he pointed out, "indicate that transplantation of genetically engineered, immunoprotected pig myelin-forming cells is able to induce elongative regeneration of functionally intact axons across the transected spinal cord. The pronounced survival and myelination observed in the lesioned primate spinal cord," he said, "offers hope for the potential application of this approach in spinal cord injury patients."

Yale's Kocsis added, "Following transplantation, these engineered cells survived, restored nerve cell function, produced myelin and ensheathed the surgically damaged nerve fibers in four of five primates studied. Furthermore," he continued, "we are encouraged that our results reflect those we have seen earlier in rodent models of spinal injury."

Fodor also recalled to his audience in Japan that similar experiments last year in spine-damaged rats achieved "significant engraftment at the lesion site. Also, impulse conduction was observed for over a centimeter beyond the lesion. Cell labeling indicated that the donor cells migrated into the denervated host tract, while conduction velocity measurements and morphology showed that the regenerated axons were myelinated." The co-authors have yet to look at restored electrical conductance in these monkeys. (See BioWorld Today, Nov. 16, 1998, p. 1.)

Alexion's senior vice president and chief technical officer, Stephen Squinto, told BioWorld Today that "the genetically modified pig cells express an altered carbohydrate structure, so it looks more like the human type-O blood sugar."

Forward-Looking Views On Pig-Cell Future

"The promising data reported in Nagoya and Miami," Squinto observed, "demonstrates that immunoprotected transgenic pig cells can survive and regenerate myelin sheaths around damaged neurons within the spinal cords of non-human primates too." He added that "this approach may lead to the development of a new therapy for spinal-cord injury patients."

Others have suggested that its myelin-replacing effect might well aid the treatment of multiple sclerosis sufferers as well.

At least 200,000 people in the U.S. have suffered a spinal cord injury, according to the National Spinal Cord Injury Association, and their number increases by some 8,000 new cases a year. Most of them are young adults, slightly over half of whom suffer quadriplegia - the loss of use in all four limbs.

"The achievement of survival and functioning of our patented transgenic cells after transplantation into the damaged spinal cord of a primate," pointed out Alexion's president and CEO, Leonard Bell, "represents a particularly important milestone in view of the high degree of similarity between the primate and human immune systems." Therefore," he continued, "we are now focusing our efforts on optimization of product manufacturing and definition of a potential clinical program for the treatment of patients with spinal cord injuries."

Harvard's Isacson told BioWorld Today, "I think it's very exciting that transgenic pigs were used. It may be a realistic way of improving on cells so they can be transplanted for neurodegenerative diseases." He concluded: "We hope to continue to develop a better understanding of xenotransplant immunology, and these results are helping us toward, potentially, planning clinical trials."