Dr. Karussis Using Stem Cells to Treat MS
In 2007, Canadian golf pro Louise Zylstra was given the grim diagnosis that she had multiple sclerosis. By early 2008, she was not only unable to play 18 holes, she could scarcely walk 50 yards. Her doctor in Ottawa told her she would likely be in a wheelchair within two years.
“It was a disaster,” Zylstra told Canada’s CTV National News. “When you think you might not play golf again and that’s what you do….” She was speaking in mid-November 2008, soon after returning to Canada from eight months of treatment at the Hadassah–Hebrew University Medical Center in Israel. Not only is she walking easily again, she is back on the golf course. “It’s night and day,” she told CTV. “It’s a complete 180-degree turn from where I was.”
Neurologist and multiple sclerosis specialist Dr. Mark Freedman of the Ottawa Hospital, who had diagnosed Zylstra and told her there was no cure for her illness, acknowledged to CTV that she had “recovered substantial function very quickly…. She’s out golfing, and out-golfing most people, which is quite incredible.”
Zylstra is one of 35 people to undergo the world’s first adult stem cell therapy. “Until recently, stem cell therapy was a theoretical treatment, still more science fiction than fact,” says Dr. Dimitrios Karussis, neurologist and neuroimmunologist in Hadassah’s neurology department. “The trial in which Louise Zylstra took part is the first time that adult stem cells have ever been clinically transplanted anywhere in the Western world.”
The results of this transplant are so exciting that representatives of major medical centers from Europe and North America are meeting in London in the next few months to discuss the Hadassah protocol directly with Dr. Karussis and his collaborators—Hadassah neurology head Dr. Tamir Ben-Hur, former Hadassah bone marrow transplantation head Dr. Shimon Slavin, Hebrew University of Jerusalem biophysicist Dr. Adi Vaknin and Dr. Celementine Karageorgiou, an associate at the Neurological Center of the G. Gennimatas General Hospital in Athens.
“We’re planning to set up an international multicenter Phase 2 trial of this treatment with adult stem cells, to examine it further, improve it and hopefully make it more effective,” says Dr. Karussis.
This is encouraging news not only for the tens of thousands worldwide struggling daily with MS but also, potentially, for the many more afflicted with other devastating neurological disorders—among them amyotrophic lateral sclerosis (Lou Gehrig’s disease), Parkinson’s disease, Alzheimer’s disease, stroke and spine injuries.
Multiple sclerosis was, however, the first focus for Dr. Karussis. Born in Salonika, Greece, he has lived in Israel since 1988, researched bone marrow stem cells since 1990 and now heads Hadassah’s Multiple Sclerosis Center.
“Our department at Hadassah is one of the leading stem cell research centers in the world,” he says. “It made sense to combine my research with my clinical experience….”
The Hadassah center treats about a third of the thousands of Israelis battling the autoimmune inflammatory disease of the central nervous system. Most were diagnosed before age 40.
“MS is the commonest cause of neurological disability in young adults, occurring in about one in 2,000 people,” explains Dr. Karussis. “It’s more frequent in countries further from the equator and, in Jewish populations, is found more often in Ashkenazim than Sefardim, at a rate of three to one.”
In MS, the patient’s immune system goes rogue and attacks the fatty white myelin sheath that insulates the neurons or nerve cells. The result is functional deficiencies in vision as well as in the sensory, motor, balance and sphincteral areas.
While doctors know a great deal about the mechanisms of the disease process, its cause or causes have yet to be found. Medications that ease symptoms, return function and prevent new attacks help some patients, but in others are ineffective or produce adverse effects. Until, perhaps, now.
“We’re exploring how stem cells can be used to regulate or reprogram the malfunctioning immune-system cells that destroy myelin and perhaps even to enhance regeneration of both myelin and neuroprotective mechanisms,” says Dr. Karussis. “What’s new is that we’re using the patient’s own stem cells to do so.”
It was only recently that researchers at Hadassah and major medical centers in the United States and Europe discovered that each of us carries small reserves of a different type of stem cell, one known as mesenchymal. These are flexible young cells, as yet uncommitted to turning into the many different types of human tissue—but, importantly, with the potential to do so.
Until this discovery, the only adult stem cells to be therapeutically exploited were blood-forming or hematopoietic stem cells. Generally provided by matched donors, they have been used in bone marrow transplantation for over 30 years to repopulate blood. Other than this, however, cell therapy research has focused on the ethical minefield of stem cells from embryos.
The adult mesenchymal cells, however, have several important advantages over the embryonic kind, as the Hadassah team learned. First, because they are harvested from the patient, there are neither ethical issues to limit their use nor rejection problems, making treatment safer. Second, there is little danger of this type of cell turning malignant after transplantation. And third, they can be cultured and expanded easily: within two months, a purified population of up to 100 million adult stem cells can be produced from a single patient.
A further plus is that these reserves of adult stem cells have turned out to be more plentiful than once thought. Scientists have found small quantities of them (roughly one stem cell per million cells of tissue) in brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin and liver. Their probable function: repair of damaged tissue.
“You may question, as we did, why we need to graft these cells if they already exist in the body,” says Dr. Karussis. “We don’t have a firm answer, but it could be their small numbers limit their ability to migrate to damaged areas, or they don’t receive the signals to migrate.”
Whatever the reason, Hadassah physicians decided to give nature a hand and move these healing cells to where they were needed. In mid-2006, Drs. Karussis and Slavin launched the world’s first clinical trial with adult mesenchymal stem cells.
“Seven years of research in animal models of MS and in the lab with human tissue, together with Hadassah’s clinical bone-building and bone marrow transplantation programs, convinced us that a clinical trial was both safe and justified,” says Dr. Karussis. “We examined two very disabling conditions in this trial: multiple sclerosis and amyotrophic lateral sclerosis. The former is an inflammatory disease in which neurodegeneration is secondary, resulting from the inflammation. In the latter, degeneration of central nervous system cells is the primary pathogenic [disease] process.”
During the two and a half years that followed, 15 patients with MS and 20 with ALS joined the study, over half from outside Israel. “There’s no effective treatment for either ALS or the progressive phases of MS,” says Dr. Karussis. “When patients, such as Louise Zylstra, heard about the trial, they were anxious to be included.”
In this Phase 1 study, 35 were dosed with their own stem cells. Some 25 million cells were administered to each intravenously and another 60 million by lumbar puncture, directly into the spinal fluid.
“Our aim was to see whether therapy was feasible and that it caused no harm,” says Dr. Karussis. “Both were demonstrated. The sole side effects were mild headache and a three-day fever.”
Although evaluating efficacy was not a study aim, the investigators naturally made preliminary clinical observations. And it’s these, combined with the protocol’s feasibility and safety, that have excited the medical world.
“In the trial, the cells showed special properties,” says Dr. Karussis. “They reduced the destructive inflammatory process and so prevented further injury, and they also appeared to promote recovery processes in the brain.”
In practical terms, the stem cells stabilized the neurological condition of the ALS patients. Among the MS patients, some, like Zylstra, showed an impressive response, recording an improvement of about one degree in their functional score. Among the very severe and chronic MS patients, however, there was no such response—perhaps because years of degeneration have created damage beyond repair.
The Hadassah researchers have planned two further clinical trials. One is the extensive multicenter Phase 2 trial to be set up at the London meeting. “One modification we’ll suggest is multiple injections of stem cells, as there were indications that efficacy decreased over time,” says Dr. Karussis.
Another is testing other types of stem cells. “Experience gained in this first clinical trial with adult mesenchymal stem cells is providing a critically needed platform to advance our work with different types of stem cells currently in the development pipeline,” adds Dr. Ben-Hur.
For the past eight years, Dr. Ben-Hur has been working with Dr. Benjamin Reubinoff, director of Hadassah’s Human Embryonic Stem-Cell Research Center, to develop the use of neuronal precursor cells (infant nerve cells) derived from human embryonic stem cells. They are planning a clinical trial, substituting these neuronal cells for the mesenchymal cells used in Dr. Karussis’s trial.
“We’re excited, but we’re realistic,” says Dr. Karussis. “We still have a lot to learn. We’re working with the building blocks for all human tissue, and I don’t think any of us would care to predict, at this stage, how far this may take us.”