stem cell therapiesby Amber Dance

A biotech start-up sees stem cells as targets, not transplants

When Captain Kirk and the crew of the starship Enterprise travel back in time to the 1980s in Star Trek IV: The Voyage Home, Dr. McCoy runs across an elderly woman with kidney failure languishing in the hospital. He offers her a pill to swallow. Minutes later, the cured patient rejoices before her baffled physicians: "The doctor gave me a pill and I grew a new kidney!"

To physician Leonard Zon of Harvard Medical School in Boston, the scene parallels his goals for the company he helped found, Fate Therapeutics. Fate, located in La Jolla, California, launched in 2007 with a US$12 million budget. Fate aims to develop small molecules and biologics that stimulate a patient's own stem cells, marrying the tried-and-true methodology of drug development to the relatively new science of stem cells.

Rather than delivering new or improved cells, Fate will target cells in patients' bodies: the tissue-specific stem cells that maintain homeostasis in many organs. These cells are apparently too few, or too unresponsive, to regenerate tissue after many kinds of disease or injury. Fate's approach, Zon says, "is a way of transiently tickling the cells that are already there." A handful of drugs like this already exist: for example, erythropoietin, or EPO, stimulates blood stem cells to divide, and Mozobil, a drug from Cambridge, Massachusetts–based Genzyme that boosts circulating stem cell numbers so doctors can harvest more of them for transplantation, received FDA approval in December.

Fate's approach "is a way of transiently tickling the cells that are already there." —

Leonard Zon
Harvard Medical School

Because investors and regulatory agencies are more comfortable with pills and proteins than with cells, Fate hopes its treatments will reach patients faster than therapies that require growing cells and transplanting them into patients. "We're talking about developing standard drugs by standard means," says Randall Moon of the University of Washington in Seattle, another scientific founder of the company.

Companies developing stem cell–based therapies can't be sure what obstacles will appear in their path, Moon says. Person-to-person transplants will likely require donor-recipient immunocompatibility or harsh immunosuppressive regimes. Whereas cell implants will persist in a patient's body indefinitely, drug treatments can be finely tuned or stopped altogether. And it's possible that small-molecule therapies could come in a simple pill, avoiding the needles and catheters that cell therapies would require, not to mention the manufacturing costs of vats of clinical-grade cells.

"In the long run, the small-molecule approach is definitely the cheaper route," says Chris Mason, a professor of regenerative medicine at University College London and scientific advisor to several regenerative medicine companies. However, that doesn't mean it's the fastest avenue. "The cell therapy ones are probably further ahead in terms of discovery," Mason says. Additionally, there are certainly things that small molecules can't do — no simple drug is likely to mimic the effects of a bone marrow transplant, for example — so both methods will have their place.

But stem cell therapeutics is a young and unpredictable science, making pharmaceutical companies and venture capitalists commitment-shy. There are still unanswered questions about whether implanted cells will proliferate and how long they will survive. "Fundamentally, the biology of growing cells outside the body is really complicated," says Alex Rives, cofounder of Fate and an associate with ARCH Venture Partners in Seattle, Washington. "Fate was about convincing people that this was a different approach that was more likely to be successful," he says.

Scientific capital

Recent scientific advances have made stem cells, and the small molecules that stimulate them, a more appealing prospect for venture capitalists. In 2006, scientists showed that differentiated cells could be reprogrammed to pluripotency using just four genes1. Scientists are now searching for chemicals that could do the same thing, thus circumventing the need for an unpredictable viral vector that delivers potential oncogenes. Also in 2006, the lab of yet another Fate scientific founder, Sheng Ding, at The Scripps Research Institute in La Jolla, identified a small molecule that allowed mouse embryonic stem cells to stay pluripotent in culture without the usual feeder cells or serum2.

Even big pharma is joining the party. In November, Pfizer announced the formation of a new regenerative medicine unit that will eventually employ a total of 70 people in Cambridge, UK and Cambridge, Massachusetts. "Pfizer has decided that the time is right to really put some effort into this area," says Ruth McKernan, chief scientific officer for the unit. Small molecules are definitely on the menu. "Who has millions of compounds that might be useful for maintaining stem cells?" she asks. "We do."

In developing treatments, Fate seeks to tweak the body's developmental signaling pathways such as Wnt, Hedgehog and Notch. For example, Ding's group has identified a small molecule that modulates Wnt signaling3.

Moon compares Wnt signaling to music. During development, it's a full-sized orchestra playing a symphony. In adulthood, the music slows, but isn't silenced. It might crescendo during injury or disease, or drop to a whisper in a degenerative condition. Small molecules, Moon hopes, could act as an additional flute or bassoon to keep the song in the audible, harmonic range.

Alternatively, it's possible that other small molecules could turn down the volume. Such drugs could halt the rampaging division of cancer cells, where developmental pathways gone awry allow too much cell proliferation.

The small molecule approach, of course, is not without its own set of risks. "The biggest problem for Fate's approach is the delivery to a targeted site," says Luc Leyns, a developmental biologist who studies stem cells at the Free University of Brussels in Belgium. There are only a few biochemical pathways that trigger adult stem cell proliferation. "These 'usual suspects' are active in numerous tissues and acting on them in a body-wide way will probably have negative side effects," Leyns says.

"The biggest problem for Fate's approach is the delivery to a targeted site." —

Luc Leyns
Free University of Brussels

One option, Ding says, is to aim the drugs toward a particular body part — eye drops for the eyes, inhaled medicines for the lungs and catheters for hard-to-reach tissues. A more biochemical approach would be to link the drug to signaling molecules or antibodies that home in on specific sites in the body. For example, Ding says, the bisphosphonate functional group targets bone.

Alternatively, Ding speculates that some ailments might call out for their own cure. If endogenous stem cells are already on high alert because of nearby tissue damage, they may be primed to respond to drugs, Ding says. And stem cells may be able to listen to the injured tissue's own signaling once small molecules jump-start the system. Adult stem cells elsewhere in the body, then, might be less responsive to the drug's effects.

Activating developmental pathways and stem cells systemically might not even be all that dangerous, Zon says. In an as yet unpublished study, his lab engineered zebrafish that turn on Wnt at high levels all over the body and have an increased blood stem cell population. "They seemed pretty normal, actually," he says. "Having more stem cells isn't that bad for you." The same will not necessarily be true in people; Wnt activation is implicated in many human colon cancers.

If Fate allows

The company's lead candidate is based on work from Zon's lab. His group discovered that a natural small molecule, prostaglandin E2, boosts haematopoietic stem (HS) cell numbers in zebrafish. When fish HS cells were destroyed by radiation, administration of a prostaglandin E2 derivative helped kidney marrow recover4. More recently, at the December 2008 meeting of the American Society of Hematology in San Francisco, California, Zon presented data suggesting that prostaglandin E2 acts by increasing the activity of beta-catenin, a player in the Wnt pathway, to stimulate transcription for cell growth and proliferation.

The drug candidate will, Fate hopes, help patients who need their blood-forming system rebooted. High-dose chemotherapy or radiation obliterates the body's immune cells, so patients require a transplant of bone marrow or umbilical cord blood to reconstitute their immune systems. But that process happens slowly, leaving patients vulnerable to life-threatening infections for weeks or even months. "The trick is to make sure that you not only get rapid engraftment of those haematopoietic stem cells, but to make sure that you get a durable engraftment," says Paul Grayson, chief executive officer at Fate.

Fate plans to pretreat transplant cells from cord blood with the drug candidate to boost their engraftment potential. One advantage of this approach is that only the transplant material, not the actual patient, is exposed to the drug, limiting risk. Adult transplant patients typically require the volume of cells from two umbilical cords, and this provides the researchers with a neat trick to measure the therapy's success. By pretreating only one batch of cord blood, the scientists will be able to follow the relative success of treated and control cells within the same patient.

The company aims to test this first potential therapy in clinical trials early in 2009. That's quick-paced, particularly considering that Fate began in 2007, when venture capitalists ARCH, Polaris Venture Partners in Waltham, Massachusetts joined forces with five big-name scientific founders — in addition to Zon, Ding and Moon, Philip Beachy of Stanford University in Palo Alto, California, and David Scadden at Harvard Medical School in Boston round out Fate's dream team. There are currently a dozen employees, and the company is growing fast.

"They're all extremely experienced," Mason says. "Those guys will come up with something, there's no doubt about it." Although a simple pill can't yet replace dialysis, it looks like patients won't have to wait until Star Trek's 23rd century for drugs that help the body heal itself. Someday pharmaceuticals may allow patients to regrow damaged tissues or even lost limbs like the starfish does. "I'm optimistic," Ding says. "Science fiction may happen."


Source:  Nature