BioWorld International Correspondent
EDINBURGH, UK - The devil is in the detail, and never more so than in the complex thickets of biological, clinical, regulatory and manufacturing issues that must be resolved if the promise of stem cells is to be fulfilled.
That complexity was highlighted at the Stem Cell 2005: Progress To Therapy conference here by speakers ranging from Ph.D. students studying a single signaling pathway implicated in proliferation of stem cells, to directors of stem cell laboratories concerned with how embryonic stem cells make the basic choice between self renewal and differentiation, to CEOs of stem cell companies with shareholders to satisfy.
Many of the difficulties were summarized by the keynote speaker Jane Lebkowski, senior vice president of Geron Corp., of Menlo Park, Calif., who described the company's progress in developing embryonic stem cells (ESCs) for the treatment of degenerative diseases. While ESCs have many properties that make them suitable candidates for cell therapy, "many difficult things are needed to make them safe and efficacious," Lebkowski said.
Those include the need to simplify, standardize and scale human ESC growth, developing reproducible methods to selectively differentiate cells, finding methods to deliver them to the target tissue and get them to survive, and developing scalable, low-cost production methods.
Some problems have been overcome. Geron worked initially with the University of Wisconsin's cell lines that were raised on mouse feeder cells, and thus classified as xenografts. The company since has developed ESC lines without the use of any animal product. Those remain pluripotent after 70 passages, and work is proceeding to generate the first master cell bank.
The next challenge is understanding how to control differentiation of ESCs into specific cell types. "We need to nudge them along one path or another, using growth factors, hormones, extracellular matrices, specific media, genetic modification; there are many different factors and timing influencing outcome," Lebkowski said.
To date Geron has devised methods to differentiate three cell types. The first, an oligodendroglial progenitor improved the outcome in mice with spinal cord injuries, with histological studies showing evidence of survival of human cells, sprouting of axons and remyelination.
"In other words, this is a proof-of-concept study showing that if you transplant ECS-derived cells into animal models of spinal cord injury you could see an improvement," Lebkowski said. "But a lot of work is needed before it goes to the clinic."
That includes the need for animal studies of biodistribution of cells after they are injected into a lesion, understanding the appropriate dosing and delivery, and toxicology studies of the long-term effects.
"And these same studies will have to be repeated for every sort of therapy," Lebkowski said.
In addition, Geron has isolated a human neural cell line that is ready to be tested in an animal model of Parkinson's disease, and a cardiomyocyte line for treating heart disease also is ready for animal studies.
All animals in Geron's studies to date were immune-suppressed, but Lebkowski said the company has intriguing data indicating human embryonic stem cells are immuno-privileged.
"We fully expected when we go into the clinic we would need some low-dose immunosuppression. But we found out [human ESCs] seem to actively inhibit an immune response." It is not yet clear if that is a property of differentiated populations.
Another speaker, Alan Colman, CEO of ES Cell International, of Singapore, said that in his view the fear of litigation was "the biggest problem and why big pharma has not embraced [stem cell therapy]."
After a thorough market survey and risk-assessment exercise, ES Cell chose diabetes as its target disease. The decision was based on the existing point of principle for cell transplants from cadavers, the accessibility of the transplant site, and the fact that a successful outcome can be assessed simply by measuring blood glucose.
But the company has found it difficult to culture beta cells and Colman exposed the gulf that exists between the basic research being carried out and getting products to market, by claiming a lot of the published work is not reproducible.
"Beta cells and Rolex watches share a common heritage," Colman said. "Poor copies of both abound."
While there is general agreement that expression of the pdx1 gene - needed for the formation of the pancreas - can be induced, no one is close to producing islet cells, Colman claimed. ES Cell's approach has been to selectively enrich insulin-producing cells. "In terms of getting from ESCs to islets cells, we are on our way," he said.
ES Cell also is developing cardiomyocytes and has progressed to transplanting them into mice.
"There is connectivity, but is there functional integration? There is no direct evidence that transplanted cells participate directly," Colman said. The company now is scaling up production to test the cells in pigs later this year.