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Analysis of phase 1 and 2 trials testing the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers.
Links to some earlier articles:
- First U.S. stem cells transplanted into spinal cord | CNN.com (January 2010)
- Stem cell treatment goes from lab to operating room | CNN.com (May 2010)
Transplantation of spinal cord–derived neural stem cells for ALS
Analysis of phase 1 and 2 trials
Authors: Jonathan D. Glass, MD; Vicki S. Hertzberg, PhD; Nicholas M. Boulis, MD; Jonathan Riley, MD; Thais Federici, PhD; Meraida Polak, RN; Jane Bordeau, RN; Christina Fournier, MD; Karl Johe, PhD; Tom Hazel, PhD; Merit Cudkowicz, MD; Nazem Atassi, MD; Lawrence F. Borges, MD; Seward B. Rutkove, MD; Jayna Duell, RN; Parag G. Patil, MD; Stephen A. Goutman, MD; Eva L. Feldman, MD, PhD
Objective: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers.
Methods: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale–Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups.
Results: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression.
Conclusions: Intraspinal transplantation of human spinal cord–derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers.
Classification of evidence: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.
Imagine having your back cut open, part of your spine removed, a stabilizing device that resembles a mini oil rig mounted on your back, the outer membrane of your spinal cord sliced open and experimental stem cells injected into it -- all for the advancement of science because it's not expected to benefit you.
Atlanta, Georgia — Imagine having your back cut open, part of your spine removed, a stabilizing device that resembles a mini oil rig mounted on your back, the outer membrane of your spinal cord sliced open and experimental stem cells injected into it — all for the advancement of science because it’s not expected to benefit you.
John Cornick, 51, did just that earlier this month as part of a groundbreaking clinical trial.
Almost a year ago, Cornick was told he had ALS — better known as Lou Gehrig’s disease. The diagnosis left him “fairly devastated,” he says.
He knew the prospects were grim because there is no cure.
But John wasn’t giving up so quickly, nor was his wife, Gina.
“I knew he was a fighter from the beginning and he really wanted to do something,” Gina Cornick says. She found information about a clinical trial on online and immediately signed him up, even though she had no idea where it was being held.
ALS destroys the nerve cells in the brain and spine which control muscle movement. When the brain can no longer tell muscles to move, they eventually die, depriving the patient of the ability to move arms and legs and eventually breathe.
The goal of this phase 1 trial is to determine whether fetal stem cells can safely be injected into the spinal cord. Ultimately, researchers hope to show that these cells may slow or halt the progression of the fatal disease.
But for now, the only goal is establishing safety.
The Cornicks live in North Carolina, just a few hours from Atlanta, Georgia’s Emory University, the site of the trial. It is the first FDA-approved clinical trial to inject fetal stem cells directly into the spinal cord of an adult.
Dr. Jonathan Glass, director of Emory’s ALS center, is overseeing the trial. Cornick and two previous patients in the trial are heroes, says Glass, because at this point, the trial will likely produce only information, not results.
“In reality what do these patients have? Time, families and their life and we’re putting all of these at risk,” says Glass.
Dr. Lucie Bruijn, science director of the ALS Association, says the progress being made in this clinical trial is exciting. “We’ve been able to move it forward … from animal testing now into actual patients.” The treatment had not been tried in humans before.
Glass hopes this trial will lead to a new form of treatment for people with ALS. “We’re testing multiple things: We’re testing the safety of the surgery; we’re testing the cells; we’re testing immunosuppressants[because scientists do not know whether the body will reject the cells].” They are also testing how well Cornick handles this major surgical procedure, says Glass.
“After we’re finished with the first 12 or 18 patients we will know whether this is surgery that patients can tolerate.”
As he was prepped for surgery, Cornick was hopeful but realistic. “Well, of course you’d like to get up and walk … but I know that’s not going to happen.”
The stem cells used in the surgery are shipped overnight from Maryland, where Neuralstem, the company funding the trial, is based. The stem cells’ source is donated tissue from the spinal cord of an 8-week old aborted fetus, which was donated to the company. The company has developed a method that enables growth of millions of stem cells from this single source of human nerve stem cells.
Before the surgery can begin, a technician at Emory has to verify that a majority of stem cells made it to Atlanta alive. At least 70 percent have to be viable. In this case three samples under the microscope showed 85 percent of the cells arrived alive.
Lead researcher Dr. Eva Feldman, a neurologist at the University of Michigan, designed the trial just four years ago. After a lot of animal testing, her team determined that using fetal nerve stems rather than human embryonic or adult stem cells (such as bone marrow stem cells) was most effective, she says.
Stem cells have the ability to turn into different cells in the body. However, human embryonic stem cells, which come from 4- or 5-day-old embryos, also been found to sometimes turn into cancer cells. Fetal stem cells, such as those used in this trial, are a few weeks older and have already taken on a specific identity — in this case nerve cells.
Feldman says the fetal stem cells used in this trial did not become any of the unwanted cell types. “That’s very, very important,” she says.
Animal testing also proved very useful when it came to figuring out how to actually inject the stem cells. Emory University’s neurosurgeon Dr. Nicholas Boulis invented the device that holds the needle that injects the stem cells. The goal is to inject the cells without injuring the spine and causing even more paralysis. He practiced on 100 pigs before attempting the procedure on a human.
Boulis says it’s critical that the injection be done in a very slow and controlled way.
“If you inject quickly, you’re going to create pressure at the head of the needle and that can cause damage,” Boulis says. That pressure can also inflate an area in the spinal cord which could cause the stem cells to seep back out of the cord when the needle is pulled out, he says. “So by pumping [cells] in slowly you have more security that you are not going to have reflux and you’re not going to have damage.”
Dr. Jeffrey Rothstein, who heads the ALS research center at Johns Hopkins University and is not connected to this trial, said work on this method is a big achievement. “This is purely about how to surgically deliver cellular therapy to spinal cord,” he says. “It’s never been done before.”
After the spinal cord was exposed, the injections began. Cornick got five — each one contains about 100,000 stem cells.
The four-and-a-half hour surgery went smoothly, Boulis, says. “There were no surprises.”
A day after surgery, Cornick was lying flat in a hospital bed, chatting and laughing with some friends from North Carolina.
One week after surgery, he says he felt amazingly well and was still hopeful the cells would do some good for him.
Two weeks later Cornick’s stitches were removed and he was able to drive home. But he will be making frequent visits back to Atlanta as Glass and his team continue to monitor him.
Neuralstem’s Chief Scientific Officer Karl Johe says after the trial’s safety board reviews all existing data, including Cornick’s results, a fourth patient can be treated with the stem cells.
“Patients Four, Five and Six will receive twice as many [stem cell] injections,” Johe says. They will get five more injections on the other side of the spinal cord compared with Cornicks’s surgery.
Cornick expects the researchers will follow his progress for a long time. He says he understands the need for people to be willing to participate in experimental research like this.
“For me it just seemed like the right thing to do. I almost felt I had an obligation to do this,” he says. “To help other people and myself.”
For the first time in the United States, stem cells have been directly injected into the spinal cord of a patient, researchers announced Thursday.
ATLANTA, Georgia (CNN) — For the first time in the United States, stem cells have been directly injected into the spinal cord of a patient, researchers announced Thursday.
Doctors injected stem cells from 8-week-old fetal tissue into the spine of a man in his early 60s who has advanced, or amyotrophic lateral sclerosis. It was part of a clinical trial designed to determine whether it is safe to inject stem cells into the spinal cord and whether the cells themselves are safe.
ALS is a fatal neurodegenerative disease that causes the deterioration of specific nerve cells in the brain and spinal cord called motor neurons, which control muscle movement. About 30,000 Americans have ALS at any given time, according to the ALS Association.
There is no cure for ALS, which is better known asdisease, named after the New York Yankees’ first baseman and Hall of Famer who retired from baseball in the 1930s after being diagnosed with the disease.
As the illness progresses, patients lose their ability to walk, talk and breathe. Patients usually die within two to five years of diagnosis, according the ALS Association.
Neuralstem Inc., a Rockville, Maryland-based biotech company, received approval from the U.S. Food and Drug Administration to conduct the clinical trial in September. The company is fully funding the research and provides the stem cells that are being injected into the patients.
Neuralstem announced the start of the clinical trial in a news release Thursday.
Longtime ALS researcher and University of Michigan neurologist Dr. Eva Feldman is overseeing the first human clinical trial of a stem cell treatment in ALS patients.
“We are entering a new era of cell therapeutics for ALS, and in my opinion, it is an new era of hope for patients with ALS,” Feldman said.
At least 12 patients are expected to participate in this early research. They are to receive the stem cell transplants at Emory University in Atlanta, Georgia.
“This is the first study to see if the invasive injection into the spinal cord is safe for the patient,” said Lucie Bruijn, science director of the ALS Association.
This first patient in the clinical trial received several injections of stem cells into the lumbar region of the spinal cord, the area that controls leg function, because most ALS patients first lose muscle function in their legs, according to Karl Johe, Neuralstem’s chairman and chief scientific officer.
Bruijn says there have been a few other occasions outside the United States in which fetalhave been injected into a patient, “but not necessarily using a very [rigorous] trial design.” She adds that there were also a couple of small studies in Italy that injected other types of stem cells into a few patients but that this is the first FDA-approved trial in the United States.
“Our biggest hope for stem cells is to significantly slow the progression the disease,” Bruijn said.
The ALS Association is not providing funding for this clinical trial, but it has supported the work of Dr. Nick Boulis, the Emory neurosurgeon who developed the surgical technique used to inject the stem cells.
Johe invented the technology that allows the company to manufacture billions of copies of stem cells that are taken from a single source of spinal cord cells: cells that were extracted from fetal tissue, which was donated to the company.
“The cells are human neural stem cells,” Johe said, acknowledging that the introduction of stem cells is a very invasive procedure.
“What we are attempting is a novel approach by directly injecting them into the middle of the spinal cord, which to our knowledge has never been done before,” Johe said.
Researchers plan to follow this and future patients participating in this trial for a long time to determine the safety of the procedure.
These particular stem cells — which came from the spinal cord of an 8-week-old fetus — are neural stem cells, which have the ability to turn into different types of nerve cells. These are not the same stem cells as the controversial human embryonic stem cells, which destroy the embryo when the stem cells are removed.
Johe says that once the safety of this type of transplant is determined, he and his colleagues hope to see whether this is a possible treatment for ALS.
“This is not a cure. We are not replacing those motor neurons [nerve cells which tell muscles to contract]. These stem cells don’t generate motor neurons. Instead they protect the still-functioning motor neurons,” Johe explained.
Bruijn says that injecting stem cells into the spinal cord — in the region where the motor neurons are located that affect ALS — is a breakthrough. But she cautions that this is only the first step in the first part of this clinical trial. It’s too early to draw any conclusions about the effectiveness of this treatment, especially since the trial has only just begun.
She notes that everyone involved with the study and other ALS patients have to wait and see what the results of the clinical trial will be.
The FDA granted the first approval for injecting human embryonic stem cells into humans to Menlo Park, California-based Geron Corporation in January 2009. Their trials were expected to start last summer but have yet to begin.