It is embryonic stem cells, however, that are at the heart of ethical debates throughout the world. Typically, they are extracted from blastocysts. "Embryonic stem cells are developmental cells that come from a place where their role was to make an organisma heart here, two lungs there, and so on," notes Cytori's Dr. Fraser.
Because of this, when you inject an embryonic stem cell into an animal, it forms a teratoma. Extensive differentiation is needed to prevent that malignancy from forming.
To put the challenge in perspective, to inject stem cells into an individual for cardiac therapy, "first, you must make an embryonic stem cell that's not rejected by the recipient, which involves therapeutic cloning, growing up those cells, differentiating them into heart cells (for example), injecting them, and relying on the differentiation to prevent them from forming a teratoma," Dr. Fraser says.
Embryonic stem cells do offer some advantages, however. They appear to be the only cells that can differentiate into all cells and tissues in the body, and can renew themselves indefinitely in the undifferentiated state.
Dr. Okarma notes that "human embryonic cells express huge quantities of telomerase (key to cellular immortality), are scalable, and are a renewable source," making embryonic stem cells amenable to scale-up and manufacturing.
Geron has shown proof of concept injecting oligodendrocytes and dopaminergic neurons derived from human embryonic stem cells directly into the injury site, in this case, into the spinal cord, and "we're seeing dramatic motor improvement," notes Dr. Okarma.
An early study to repopulate heart tissue was also successful. Currently, Geron is conducting IND-enabling studies to demonstrate safety in animals and to determine the tumor-causing threshold. "We're doing spiking studies now," Dr. Okarma says.
Geron currently has programs under way for cardiac disease, diabetes, osteoarthritis, osteoporosis, and hematology and is working with 8 of the 212 possible cell types. "This is a product-based model, just like [business models] for pills, he says, "made from frozen aliquot."
ReNeuron (Guildford, U.K.) takes cells from human fetal organs, "which have a reasonable proportion of undifferentiated cells," according to John Sinden, Ph.D., CSO. The company plans to enter clinical trials for stroke and Huntington's disease in 2006.
The approach uses what Dr. Sinden calls "a manufactured stem cell therapy." ReNeuron adds the c-MycER fusion protein to conditionally immortalize the cells. "Take away a chemical constituent of the growth media and the cells will mature into functional nerve cells," he says. "We have a number of different cell line products already partially attuned to their final cell fate," Dr. Sinden says.
Its most advanced program is in late preclinical development for stroke-disabled patients. "We're making a GMP master/working cell bank, following a conventional biopharma development route," Dr. Sinden says. The goal is to develop allogeneic products (cells in vials) that are safe, scalable, stable, and efficacious.
"We have a number of different cell line products, made to cGMP standards, and many already are partially attuned to their fate," Dr. Sinden says.