Issue Date: January 15, 2007
Rolling Out Stem Cells
A rally in stem cell company shares after last fall's Democratic wins in the House of Representatives and Senate reflected hopes that a funding boost may be coming to stem cell research. Such research is supporting a burgeoning industry, which some predict will reap $30 million in sales in 2007, engaged in clinical trials to test treatments for everything from broken bones to rare genetic brain diseases.
Even though President George W. Bush's ethical concerns and consequent limits on embryonic stem cell research and funding don't impact adult stem cell research, which is the main focus of most stem cell companies, investors just don???t see the difference, says Ren Benjamin, a Ph.D. biochemist who is a stem cell analyst with investment banking firm Rodman & Renshaw.
For example, the share price of Advanced Cell Technology Inc., based in Alameda, Calif., went up 13% after the election. The company is looking at new ways to develop embryonic cell lines without destroying embryos with the long-term goal of regenerative therapeutics. Because working with embryonic stem cells is the crux of President Bush's censure, shares of Advanced Cell would be a logical beneficiary of a Democratic win. But Cytori Therapeutics, which is developing therapeutics based on adult fat tissue stem cells, for which there is no ethical debate, also enjoyed a 13% increase in share price, even though a political change of heart about embryonic stem cells wouldn't specifically affect the company.
"Whatever is good news for one part of the stem cell industry is good news for all," Benjamin tells C&EN. Share prices of stem companies have since fallen slightly, but they are still higher than they were before the run-up to the election.
This industry effectively consists of three types of companies: those that specialize in developing embryonic stem cells, others that focus on adult stem cells, and finally, companies that bank umbilical-cord-blood stem cells.
Cord-blood-banking companies offer parents of a newborn baby the option to freeze cord-blood stem cells for use in case their child develops leukemia or other blood diseases. Some of these firms, such as Cambridge, Mass.-based Viacell, are also trying to develop cord-blood stem cells into therapies for the general population. Cord-blood stem cells are less likely than other blood stem cells to be rejected when transplanted into a different human being. This characteristic is likely a consequence of these cells having to grow and survive on the mother-fetus boundary.
Blood stem cell transplants derived from both cords and adult donors have long been touted as a successful adult stem cell therapy. The procedure is pretty much a sophisticated transfusion. The donor's blood stem cells are extracted from bone marrow, blood, or umbilical cords; purified; and then injected into patients. Unfortunately, rejection by the patients' immune systems can occur, which is a disastrous situation. Sometimes the immune cells from the donor start attacking the patient, a complication called graft versus host disease.
"Most patients don't have a good marrow match, and most patients are too sick or too old to benefit from the existing therapy, because the therapy is very toxic on its own," says George Q. Daley, a stem cell researcher and professor of biological chemistry at Harvard University.
To make things more difficult, although blood stem cells are easily extracted and purified from a donor, they are remarkably hard to multiply in a dish without initiating their differentiation into other cell types. This means a constant supply of blood stem cells must be donated. As such, companies such as Vancouver's AnorMED, acquired last fall by Genzyme, in Cambridge, Mass., are developing ways to improve stem cell yield from donors. The acquisition was motivated by AnorMED's, now Genzyme's, Phase III small-molecule drug Mozobil, which, for example, appears to increase the number of stem cells released into the blood from a donor's bone marrow.
But for the most part, stem cell companies are investigating ways to deliver stem cells themselves, or their differentiated offspring, as cell therapies.
One such therapy currently in clinical trials comes from Stem Cells Inc., in Palo Alto, Calif. Last November, the firm began the first clinical trial of purified adult neural stem cells, which they are delivering to six young children with a rare and fatal condition called Batten's disease. The condition is caused by a mutation in one of two genes that code for a palmitoyl-protein thioesterase or a tripeptidyl peptidase. Malfunction of these enzymes leads to the buildup of their substrates in cellular compartments known as lysosomes. This buildup causes neural damage, which leads to seizures, blindness, and eventually death before the age of 10. According to Stem Cells Inc., treating animal disease models with neural stem cells produces enough missing enzyme to protect neurons from damage.
The step from preclinical to human trials required serious consideration of the balance between risk and reward, says Martin McGlynn, Stem Cells Inc.'s chief executive officer. "When you put stem cells into an organ, you cannot retrieve them," McGlynn says. "A true stem cell will replicate for life of the host." This means that reversing or removing the stem cell therapy is impossible. He points out that the balance is that these children have no other therapeutic options.
Another adult stem cell company with a therapy currently in clinical trials is Aastrom Biosciences, in Ann Arbor, Mich., which is developing a stem cell treatment for long bone nonunion fractures. Surgeons isolate a small amount of a patient's own bone marrow stem and progenitor cells. The cells are expanded up to several hundred-fold until their numbers are in the 120 million range. Finally, the cells are reinjected into the patient near the fracture area with a sticky scaffold matrix that initially keeps the cells from wandering away but is later reabsorbed by the body.
The study is "a Phase I-II trial," explains Aastrom CEO George W. Dunbar, because by definition, the therapy is already being tested in patients because it uses their own cells. The benefit of using a patient's own cells is that there is no chance of immune rejection. The trial, involving over 200 patients, will report in mid-2007, and the company plans to begin clinical trials for other bone maladies this year.
Thus far, final reports of adult stem cell clinical results have been a mixed bag. Consider results published in September from three German and Norwegian human trials that placed adult human cardiac stem cells in a patient's heart after injury (N. Engl. J. Med. 2006, 355, 1199, 1219, and 1222). A combination of disappointing and promising results provides "a realistic perspective" for cardiac stem cell therapy, wrote Associate Editor Anthony Rosenzweig in that issue's editorial, "leaving room for cautious optimism and underscoring the need for further study."
The Food & Drug Administration has yet to give the green light to a clinical trial for embryonic-stem-cell-derived therapeutics. Geron Inc., in Menlo Park, Calif., is the closest to getting the go-ahead and is planning to be in clinical trials in late 2007, a start date that has been pushed back for at least a year.
Initiating an embryonic-stem-cell-based clinical trial "has been made a little bit more difficult because we're the first, and obviously there is a spotlight on us and on this platform generally," says Thomas B. Okarma, Geron's CEO. "It raises the bar of anxiety and conservatism for everybody—not just FDA, but for us, for patients, for investigators, for the clinical trial sites."
What Geron aims to put in clinical trials are oligodendrocyte progenitor cells (OPC1) for the treatment of spinal cord injuries. The trials would be based on the research of Hans Keirstead, a neurobiologist at the University of California, Irvine, who is funded by Geron and who figured out a way to get embryonic stem cells to differentiate into oligodendrocyte progenitor cells. These cells give rise to cells that make myelin, the protective sheaths that help a neuron's axon to fire and are often damaged in spinal cord injuries. The therapy gained popularity when Keirstead showed a video of a paralyzed rat walking again following treatment.
Okarma says FDA's major toxicological concern has been whether these cells cause teratomas, tumor masses created when embryonic stem cells are injected directly into an animal and differentiate uncontrolled. Although Geron's product contains cells that have been differentiated from embryonic stem cells, there's a worry that some minute fraction of undifferentiated cells could form a tumor.
"FDA is equally concerned that we can demonstrate tight product-release specs, appropriate good manufacturing process controls, purity of the cells, and reliability and consistency of manufacturing," Okarma tells C&EN. "We need to prove that the cells are pure and that they are made the same way each time with no teratomas, that they are not toxic, and that they don't go crazy places and they don't do crazy things."
"Despite the high bar, we are going to traverse it," Okarma says. "We have agreement with FDA on exactly what the investigational new drug package will look like. We haven't seen a single teratoma for hundreds of animals. We will give them all the animals they want followed for 12 months."
Geron has also given thought to the manufacturing process, creating a facility that can produce 2,500 therapeutic doses of OPC1 cells in 42 days.
With hundreds of millions of dollars of government funding pouring into research in the U.K., China, and Singapore, it is no surprise that embryonic stem cell companies continue to crop up around the world. ES Cells International, a Singapore-based company led by CEO Alan Colman, who was involved in cloning Dolly the sheep, is focused on differentiating embryonic stem cells into insulin-producing cells as a treatment for type 1 diabetes. The firm also is using embryonic stem cells to produce cardiomyocytes that might be a therapy for congestive heart failure.
The question on many people's minds, however, is when big pharma will make the plunge into stem cell research, whether embryonic or adult.
Novartis has been working with both human and mouse adult and embryonic stem cells, says Jeffrey Lockwood, a company spokesman. He says the company established in 2002 an ethics committee that oversees human embryonic stem cell research. By all accounts, other big pharma companies have been testing the waters, some more than others. Academic researchers who consult for big pharma are reporting increasing numbers of queries about stem cell science.
Several big names in pharma and biotech have collaborative programs with stem cell companies. AstraZeneca has a collaboration with Göteborg, Sweden-based Cellartis to develop human embryonic stem cells for preclinical toxicological testing. Amgen and GlaxoSmithKline are providing Viacell with reagents for growth of stem cells.
A complete stem cell buy-in by big pharma won't happen until the industry passes a few important milestones, Geron's Okarma says. These milestones include treatment efficacy and safety in patients as well as scalable, low-cost-of-goods manufacturing.
Okarma points out that it took monoclonal antibodies 25 years to advance from patents to commercial therapeutics. "It takes a long time before there's a critical mass of information such that pharma gets confident about beginning to take a therapy into development mode."
"Whenever someone shows really good clinical data, pharma will pay attention," Aastrom's Dunbar says. "Any new stem cell product approved by FDA is going to be good for everybody."
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