Stem Cell Treatment for Brain Disorder Appears Safe, But Efficacy Still Unknown

by Brenda Patoine

July 28, 2009

Transplanting neural stem cells directly into the brains of children with a rare, fatal neurological disease appears to be safe for at least a year, according to preliminary results from the first U.S. clinical trial of a stem cell-based therapy.  Whether the treatment is effective remains to be seen, however, as the trial was primarily designed to evaluate safety.  Nevertheless, experts say that the development marks a significant milestone in the clinical translation of stem cell research.

The ongoing study involves six children between the ages of three and nine with advanced neuronal ceroid lipofuscinosis, or Batten disease, an inherited condition that occurs in about two to four of every 100,000 U.S. births. Children with Batten disease suffer vision loss, seizures and progressive declines in cognitive and motor functioning. The disease is fatal in all cases, and there are no treatments.

Underlying the disease is a set of genetic mutations that disrupt enzymes performing critical “housecleaning” functions in nerve cells, such as clearing away leftover byproducts of cell metabolism.  As this cellular garbage builds up, it interferes with normal nerve cell function and eventually kills the cells, causing widespread brain degeneration. 

Evidence for engraftment

StemCells Inc., a biotechnology company in Palo Alto, Calif., launched the trial after developing a proprietary process for purifying and expanding neural stem cells from fetal tissue.  In contrast to embryonic stem cells, neural stem cells are a type of “adult” stem cell and cannot differentiate into any cell type in the body but are restricted to becoming either neurons or glial cells (cells that provide support and nutrition to neurons).

Preclinical laboratory studies showed that the stem cells produce working versions of the enzymes that are defective in Batten disease.  And when the cells were transplanted into animal models of Batten’s, brain levels of the functioning enzymes increased, the build-up of cellular trash decreased and some neurons did not die.

To test the concept, neurosurgeons at Oregon Health & Science University transplanted up to a billion of these cells into multiple sites in the brains of the six children, who also received immunosuppressive drugs to prevent immune system rejection. The results of the year-long human trial have not yet been published, but a company vice president, Stephen Huhn, presented some safety data (pdf) on June 6 at a scientific meeting in Germany.  In a press statement, the company said the cells showed a “favorable safety profile along with evidence of engraftment and long-term survival.”

The evidence for engraftment—or whether the transplanted cells remained in the recipients’ brains instead of dying off or being excreted out of the body—was based on a brain autopsy of the one child who died during the study due to the natural progression of the disease.  The other five children will continue to be followed for four more years.

Douglas Kerr, a stem cell researcher at Johns Hopkins University, says any evidence for engraftment is promising.  In an e-mail, he wrote, “One could turn this around and say that if the cells survived and the patient continued to die, then isn’t this bad news? But it’s not.  These patients were too far along for the cells to change the clinical course.”

Unsettled questions

On the other hand, Arthur Kriegstein, director of the stem cell research center at the University of California, San Francisco, says he is not sure how to interpret the company’s claim that the cells engrafted.  “What does that mean?” he says.  “I’d like to know where the cells have migrated, and exactly what’s become of them.  Did they turn into neurons or glia? Did any remain undifferentiated? Were [the researchers] able to track all of the cells?  Did some cells migrate to distant sites where they weren’t expected to go?”

In addition, Kriegstein says, he isn’t aware of any evidence that “the cells were able to do what they’re supposed to do” with regard to producing the corrected versions of the defective enzymes in children.  “Without that, and without a good understanding of where the cells went and what they’ve become, I think we’re still not as informed as we’d like to be about the trial so far.”

In an interview, Huhn, head of the company’s program for nervous system disorders, declined to offer additional details about the degree of engraftment, cell fate or migration patterns, saying the company’s analysis is still underway.  He added that the study protocol was not designed to identify the fate of the stem cells, because it’s not important to the purported mechanism by which the cells work.

“Based on our preclinical work, the cells produce the enzyme in their transplanted state; they don’t need to differentiate to be more or less effective,” Huhn said, adding that enzyme production levels in the treated children is not known because “the amount of enzyme that will be released by the cells cannot be measured in humans at the present time.”

Huhn also would not say whether researchers detected any hints that the therapy might have clinical benefit.  The company’s statement said that overall, the children’s medical, neurological and neuropsychological measurements after one year with the transplants “appeared consistent with the normal course of the disease,” suggesting neither improvement nor deterioration beyond what was expected.

Most experts agree that for regenerative medical therapies to have an effect, early treatment is critical.  Huhn said the company recognizes this and hopes to begin a second trial that targets a more initial stage of disease. “If your goal is protecting brain cells, you have to intervene earlier in the course of the disease to maximize the effect of the protection,” he said.  “If the host brain cells are so diseased that they can no longer be corrected, then you won’t have a benefit.”