11.18.11

After Geron, Stem Cells’ New Saviors

The biotech Geron may have abandoned its famous effort to treat paralyzed patients with stem cells—but two rivals are swooping in to do groundbreaking trials, Sharon Begley reports. So far, their results are even more promising.

When the biotech company Geron announced this week that it was halting its pioneering stem-cell program—whose centerpiece is a clinical trial in which four paralyzed patients with spinal-cord injuries were injected with cells derived from embryonic stem cells—the chief scientist at a rival firm had one thought: “I guess that leaves us holding the flag,” Robert Lanza of Advanced Cell Technology told me. “There’s a lot of weight on us to deliver now.”

The Geron study was famous for being the first to treat patients with cells taken from human embryos, and its premature end, due to financial concerns, may seem like a disappointing finale. Fortunately, at least two lesser-known firms are swooping in to continue similar groundbreaking research—perhaps with even more promise and practical applications—and with the potential to revolutionize medicine. One is forging ahead with an extraordinary new test today.

The better known of the two, ACT, has the only other Food and Drug Administration–approved clinical trials using embryonic stem cells, as Newsweek recently described: one trial is for patients with Stargardt’s macular dystrophy and one is for age-related macular degeneration. Both diseases cause blindness. (The studies are notable because Catholic nuns are among the patients, even though the Vatican has condemned stem-cell research.)

But there’s also Neuralstem Inc., which is in the midst of a clinical trial for ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease). Today, if all goes as planned, the first ALS patient will receive an injection of stem cells into the upper part of his spine—the first step toward determining whether the experimental therapy can save ALS patients from dying when their motor neurons, which control muscles, become too weak to maintain breathing.

In ALS, motor neurons in the spinal cord and brain deteriorate to the point where, eventually, they can no longer signal muscles to move. As a result, patients become paralyzed and, when motor neurons controlling respiration die, unable to breathe; most die within three to five years of diagnosis, and only one quarter survive at least five years. There’s currently neither a treatment nor a cure for ALS.

Neuralstem, based in Rockville, Md., uses cells slightly older than the days-old embryonic stem cells Geron used, opting for “neural” stem cells. Unlike embryonic stem cells, which can differentiate into the 200-plus kinds of human cells, neural stem cells have already chosen their fate; they can become any of three kinds of cells in the central nervous system (neurons, astrocytes, or oligodendrocytes). Neuralstem obtained all the cells it has needed so far from an eight-week old fetus that was aborted in 2000.

The procedure has been attempted on 12 ALS patients so far, starting in January 2010. They received either five or 10 injections of 500,000 or 1 million neural stem cells, respectively, into the lower (lumbar) region of the spine, in a procedure developed and performed by neurosurgeon Nicholas Boulis of Emory University, under the direction of Emory neurologist Jonathan Glass. The patient lies on his belly, and Boulis makes an incision and removes two layers of bone covering the cable of nerves that is the spinal cord. Then, guided by an MRI that shows where the motor neurons are, Boulis injects the stem cells, which takes about two minutes.

Although the goal of this early trial is to determine whether the procedure is safe—which it seems to be, although two patients have since died of ALS—the scientists have also seen hints that the cells benefit the patients. Ted Harada, 39, was a manager at Shred-It, a mobile shredding service based near Atlanta, when he was diagnosed with ALS in 2010, and by the time he enrolled in the study he was able to walk only with the help of a cane. Climbing stairs was difficult, he recalls, and he was easily fatigued and often out of breath. He was unable to raise his left leg while sitting if someone pressed on it even lightly, and his left arm was also losing strength.

Since receiving 10 stem-cell injections last March, Harada has improved enough to complete Atlanta’s two-and-a-half mile Walk to Defeat ALS on Oct. 22. “I still have ALS, but I’m starting to see signs of hope,” said Harada.

Studies of lab animals suggest how the neural stem cells might be benefiting Harada and other patients. The cells remain where they are injected in the spine, says Karl Johe, chief scientific officer of Neuralstem, right beside a high concentration of the motor neurons that are being killed by ALS. There, although the stem cells cannot resurrect dead motor neurons, they can keep additional ones from dying, explains Johe: they produce protective molecules.

Protecting neurons only keeps ALS from getting worse, however—they don’t reverse it. One reason Harada regained movement and strength might have been that the injected stem cells also cause axons—the long tails on neurons that connect neuron to neuron as well as to muscle—to regrow. “The connection that the motor neuron makes to the muscle is the first thing that goes in ALS,” explained Glass, possibly because the neuron becomes too weak to support the long axon that connects to the muscle. “It might be that if you can rescue the cell body [with neural stem cells], you can rescue that connection,” said Glass.

Animal studies suggested just that, said Eva Feldman, director of the A. Alfred Taubman Medical Research Institute at the University of Michigan and an unpaid adviser to Neuralstem: “You can hypothesize that if the nerve cell is just about to give up the ghost, the stem cells preserve it and the axonal connection is restored, with the result that the patient has a restoration of function.”

Today, for the first time, Boulis is scheduled to inject neural stem cells not into the lower part of his patient’s spinal cord, to restore movement in the legs, but into the upper region, to target motor neurons that control respiration.

Neuralstem believes that neural stem cells could also treat spinal-cord injury—the condition Geron targeted—and Huntington’s disease, in which neurons in the brain are killed much as they are in ALS. The company has requested FDA permission to launch a spinal-cord injury trial.

‘Many of us were surprised Geron selected spinal-cord injury in the first place,’ said Lanza. ‘It didn’t really make a lot of sense, either commercially or biologically.’

ACT, too, “remains committed to embryonic stem2cell research,” said Lanza. “We have no intention of letting [Geron’s decision] interfere with our mission.” The company’s clinical trial, at UCLA, uses what are called retinal pigment epithelial cells, grown from embryonic stem cells, to treat two causes of blindness, Stargardt’s disease and macular degeneration. (Stem cells from a human embryo are grown in the lab, and after they differentiate into the kind of cell needed for the disease being targeted, they’re injected into patients.) “We’re moving full steam ahead,” said Lanza, making final arrangements for other sites to enroll patients. Although results have not been formally reported yet, the first patients—who received stem cell–derived treatment this summer—are doing well enough, Lanza said, that “both want us to treat their other eye.”

In contrast, it would have taken years for Geron to see whether the cells it had derived from embryonic stem cells helped spinal-cord patients regain movement. “Many of us were surprised Geron selected spinal-cord injury in the first place,” said Lanza. “It didn’t really make a lot of sense, either commercially or biologically. So it’s not too surprising they didn’t obtain any biological effect. Although treating spinal-cord injury has a kind of sex appeal, you have to take reality into account, including not only the market but the chances of success.”