http://www.crainsdetroit.com/article/20121028/SUB01/310289962/advancing-on-als
October 28, 2012 8:00 PM
Advancing on ALS
Stem cell research nears next phase; trials may come to Ann Arbor
By Tom Henderson
Approval by the U.S. Food and Drug Administration is expected any day for researchers and physicians at the University of Michigan to begin a second round of Phase 1 stem cell trials on patients with amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.
ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. It usually leads to death within three to five years. Currently, there is no cure.
The first round of Phase 1 trials, which lasted 21/2 years and concluded Aug. 22, involved 18 operations that injected stem cells into the spines of 15 patients, three of whom were injected twice. The operations were conducted at Emory University Hospital in Atlanta by Nicholas Boulis, M.D.
Eva Feldman, M.D., director of the A. Alfred Taubman Medical Research Institute at UM and director of the ALS clinic at the University of Michigan Health System, helped design the study. Boulis is one of her former colleagues at UM.
The first study was to test safety only. and it passed with flying colors, according to a report Feldman issued this month at the annual meeting of the American Neurological Association in Boston, held in cooperation with the British Association of Neurologists. Feldman is president of the American group.
Four of the study patients died, three from ALS complications and one from a heart problem. But no safety issues arose from the study itself.
“It went better than I anticipated and could have ever hoped for,” Feldman said of the Phase 1 trial. “There were no adverse affects.”
The Phase 1B trial, which could begin as early as December, will involve injecting just three patients and will be conducted, pending FDA approval to move the trials to Ann Arbor from Atlanta, by Parag Patil, a UM physician.
The first trial involved injections of 500,000 stem cells. This trial will inject at least 1 million cells. The trials use a stem sell line derived at Rockville, Md.-based Neuralstem Inc. after a a patient donated spinal cord tissue in 2002.
If there are no ill effects from doubling the amount of stem cells, a Phase 2 study of 32 patients to test efficacy could start as early as next summer.
“It’s really exciting to bring this back to Michigan,” Feldman said. “The climate now for this is very embracing — not just in the state but in the university, too.”
Feldman was referring to the contentious climate for stem cell research in Michigan that culminated in voters’ approving embryonic stem cell research in 2008. One reason that the first trial was in Atlanta and not Ann Arbor was that all stem cell work got tarred with the same brush, she said.
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Although Feldman’s trials didn’t use embryonic stem cells, it was thought that Atlanta was a better place to start them. “I used to get these letters and emails against what we were doing,” she said, “but that’s stopped.”
Feldman said that while the primary purpose of the Phase 1B trial will be to test safety, it has been designed to test efficacy, too.
One post-surgery test on the three patients will use ultrasound to evaluate the movement of the patients’ diaphragm. Other tests will investigate how forcefully patients can expel their breaths and how much oxygen they can inhale.
“One of the purposes of the injections is to protect the large nerve cells that control breathing,” Feldman said. An inability to breathe is what ultimately kills many ALS patients.
Based on anecdotal evidence of improvements in some patients in the first round of safety tests (see story, Page 11), Feldman expects to see dramatic results in at least some patients — if not in the upcoming three-patient trials, then in the Phase 2 trials to follow.
The exact mechanism behind why stem cells helped rats and pigs in animal studies and now seem to have helped some patients is unclear. Feldman theorizes that the cells turn on repair signals inside the body, act as nursemaids for the damaged cells and slow, if not halt, the progression of the disease.
“This was something that had never been done before, and there was a lot of skepticism in the medical community — and ‘skepticism’ is a pretty polite word,” Feldman said of a procedure to inject stem cells into the spine of patients.
“Now that we’ve taken this idea and not only shown it’s feasible but safe, it’s opened up doors.”
In July, Clive Svendsen, Ph.D., director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, was awarded an $18 million grant from the California Stem Cell Agency to do a Phase 2A study of 18 patients patterned after the UM-Emory study, using a stem cell line he derived.
The study, designed to test both safety and efficacy, will be done at three sites, including six operations by Boulis at Emory.
Svendsen, with Boulis, had begun work on the line in 2003 at the University of Wisconsin before Boulis’ partnership with Feldman. Troubles with that line, which included a drug that was genetically engineered into the stem cells, took years to surmount.
Svendsen’s stem cells are engineered to use a drug called glial-derived neurotrophic factor, a growth factor designed to help protect neurons from the effects of ALS.
Feldman is optimistic that Phase 2 trials on ALS patients will be so successful that she will be able to get funding and gain FDA approval to begin similar stem cell trials on patients with Alzheimer’s disease. She has been working on a grant from the National Institutes of Health to fund an Alzheimer’s study.
“We shouldn’t limit this technology to one disease,” Feldman said.
In part, that’s because there is a far larger population of Alzheimer’s patients than ALS patients, and in part because the brain can be injected with far more stem cells than can the spinal cord.
As a result, trials should be easier to conduct and therapies easier to devise.
Said Feldman: “Alzheimer’s is going to be easier than ALS.”