“This is a big day. Twenty-six years ago my father made me a promise that there would be a cure for paralysis. Today we are taking a huge step to make it happen.”
— Marc Buoniconti, president of The Miami Project
Marc Buoniconti demonstrates the Lokomat locomotor training machine.
On July 31, 2012, Marc Buoniconti and other principals of The Miami Project to Cure Paralysis, The
Buoniconti Fund and the University of Miami, gathered at The Miami Project to trumpet the news: The FDA had given the Project the go-ahead to conduct a phase I human Schwann cell clinical trial. Slightly less than six months later, the first Schwann cell transplantation took place at the University of Miami/Jackson Memorial Medical Center.
The trial, which Neurology Today called “a landmark study,” is the only approved cell therapy trial for spinal cord injury in the United States and the first for Schwann cell transplantation in humans. And, while its focus is on safety, its successful conclusion will help open the way to further, more advanced trials.
No one is proclaiming to be close to a cure for SCI — yet. Still, an air of celebration surrounds the beginning of the trial, and deservedly so. The Miami Project team’s big moment has been a long time coming [see sidebar, “The Quest: The Miami Project — A Brief History,” below].
Why Schwann Cells?
Schwann cells are not stem cells. First discovered by German scientist Theodor Schwann in the mid-19th century, they make up the myelin sheaths that insulate and protect the nerve fibers in the peripheral nervous system. Other cells, oligodendrocytes, perform a similar function in the central nervous system.
But oligodendrocytes can’t do anything to repair or regrow damaged nerve fibers in the CNS, while Schwann cells can do both for damaged PNS nerve fibers. In 1975, those facts led Dr. Richard Bunge to propose that transplanted Schwann cells could be used to improve repair in the CNS — which, of course, includes the spinal cord.
The hope is that transplanted Schwann cells will perform the same repair function with damaged spinal cord nerve fibers as they do with damaged PNS fibers. Based on decades of research and extensive animal studies, it is a reasonable hope. And, because the Schwann cells being transplanted are the subject’s own, they’ll run very little risk of rejection.
The Clinical Trial
“This trial is a critical step in moving our basic science discoveries into people with acute spinal cord injury,” says W. Dalton Dietrich, Ph.D., scientific director of The Miami Project. “It will serve as a basis for future treatments that include combination approaches that should enhance the beneficial effects of Schwann cell transplantation and provide better functional improvements in people living with spinal cord injuries.”
Research participants manipulate various objects as part of a hand function study at The Miami Project.
All procedures of this phase I trial will take place in Miami at the University of Miami Hospital, Jackson Memorial Hospital and The Miami Project. Only newly injured paraplegics, from T3 to T11 complete, 18 to 50 years old, will be screened to see if they qualify for the trial. Only eight people will be selected. And while the selection process has already started, no names have yet been announced as of the writing of this article.
Why only paraplegics? “There’s less risk,” says Kim Anderson-Erisman, Ph.D., the project’s director of education and a researcher heavily involved in the clinical trial. “For a phase I trial, the FDA requires a conservative approach. If something happened that caused a thoracic
injury to worsen, it wouldn’t cause that much functional deficit.”
Those chosen must commit to it within five days of injury. A small portion of a sural (sensory) nerve in the lower leg will be taken by incision, under local anesthetic, from those who agree to participate. The Schwann cells taken from it will be grown and purified for the next three to five weeks until there are batches of 5, 10 or 15 million cells available for transplantation. At that time, if the participant still agrees to go forward, there will be surgery to open the injury site and injection of the Schwann cells into the center of the injury site using a mechanically stabilized needle. By that time the subjects will be from 26 to 40 days post-injury.
All subjects will be closely monitored for their first year after transplantation and followed for the next four years after that. The Project estimates that two or three years might pass from the time the first person is chosen to when the last one completes his first year.
If early results go well, and the procedure proves safe, the Project plans to move forward with other trials involving chronic injuries, cervical injuries and incomplete injuries. Researchers are already preparing for this expansion with chronically injured animal studies. After that, the hope is to possibly move on to tests of combined treatments. One using Schwann cells, plus cyclic AMP, a messenger molecule, plus Rolipram, an anti-inflammatory, has garnered good results in animal tests.
Just as vital, exercise studies, aggressively named Boot Camp, have already started — to establish what
exercise and rehab is needed to get long-term wheelers in shape so they can benefit. “Initially,” Anderson-Erisman says, “They’ll start with chronic, motor-complete thoracic injuries, T5-12. The subjects will do circuit training for their upper extremities, functional electric stimulation cycling and Lokomat treadmill training. As more funding comes in, they’ll add cervical injuries and give them circuit training as well as fine
motor training for their hands.”
A C5-6 quad herself, Anderson-Erisman says, “I’m glad to see that there are several clinical trials developing around the world. And more are in the works. We don’t think it’s a race. We’re all hoping for the best outcome. But it’s important to note, there will be multiple outcomes.”
In other words, there’s no guarantee that Schwann cell transplantation will be the one essential element in any eventual cure. Some at the Project are doing stem cell research, too. But who knows? While The Miami Project was once almost a sole voice in the wilderness, they aren’t alone anymore.
Geron, a biopharmaceutical corporation based in Menlo Park, Calif., was in the forefront of the quest for a cure when they received FDA approval, in early 2009, for the world’s first clinical safety trial utilizing human embryonic stem cells for treatment of SCI. Four subjects were selected and injected in 2010. A fifth participant was added the following year. But Geron, citing financial problems and the need to focus on other ongoing research, discontinued the program. The company will continue to follow all the participants, as required. And Geron has announced a nonbinding agreement to transfer its embryonic stem cell programs to BioTime. As of this date no adverse reactions or surprising improvements have been reported.
StemCells, Inc., in Newark, Calif., another biopharmaceutical corporation, sponsored research into using human neural stem cells for SCI at the Reeve-Irvine Research Center at the University of California, Irvine. The animal data led to Swissmedic authorization (the Swiss equivalent of a FDA approval) in December 2010 for a phase I/II clinical trial. The trial began at Balgrist University Hospital, at the University of Zurich, in March 2011 with a goal of enrolling 12 participants.
To date four SCI subjects, four to eight months post-injury, have been injected with millions of human neural stem cells. So far none have shown any ill effects. But there are other early results that researchers at Reeve-Irvine characterized as “very surprising.” One participant, Knut Olsted, a Norwegian paraplegic, told CNN that he thought the stem cells had helped him. “Sometimes,” he said, “I can feel my girlfriend is squeezing my legs.”
Participants in a different Miami Project study work out in the cardio lab.
Results like that were “rather unexpected” according to the trial’s principal investigator, Dr. Armin Curt, who reported, “We are very intrigued to see that two of the three participants have gained considerable sensory function.” He went on to explain that sensory gains were first noticed three months after transplant and continued to evolve at six months.
These are very early results and the trial has a long way to go before they can reach any conclusions. Dr. Stephen Huhn, vice president and head of StemCells’ CNS program, says of the early results, “Very exciting. But we’re also very reassured by the safety shown in the six-month data outcomes.”
What’s next? “We’re going to be looking at incomplete subjects now,” says Huhn. “They may be more amenable to stem cell treatment. We’ve already dosed our first incomplete subject, who has an ASIA B with some sensory below the level of injury but no motor function.”
Even though StemCells is conducting its clinical trial in Europe, Curt says it is open to participants in Canada and the United States.
The most recent stem cell news? On Jan. 14, 2013, Neuralstem received FDA approval for a phase I safety trial for transplantation of neural stem cells into people with chronic, or longterm, SCI. In this study, eight people with ASIA A (complete lack of motor and sensory function) injuries between one and two years old will receive stem cell transplants from Neuralstem’s NSI-566 line. The participants will have thoracic injuries in the T2-12 range. Each will receive six injections in or around the injury site. Half will receive 100,000 cells per injection; the other half will receive injections of 200,000 cells.
As is the regimen for most SCI trials these days, rigorous post-surgery physical therapy will be conducted to help newly-forming nerves make functional connections. Each participant will be followed closely for six months to assess safety of the procedure.
At press time, the trial was estimated to begin in March, but locations were not yet disclosed. Neuralstem has reported encouraging results from the same NSI-566 line of stem cells transplanted into people with ALS in an already-completed phase I trial.
Elsewhere, TCA Cellular Therapy, a small privately held biotherapeutic company in Covington, La., began the first FDA-approved clinical trial for chronic complete SCI in 2010. The trial, assessing the safety and potential of harvesting adult stem cells developed from an injured person’s bone marrow and injecting them by lumbar puncture into the subject’s spinal fluid, started off by dosing a disabled Marine who’d been injured in Iraq five years before.
The company posted good news within a few months. The marine had reported some sensation returning to his lower legs. But TCA also moved forward on offering tests, reportedly for $20,000, to individuals who might not qualify for the trial. The FDA was not pleased and issued a warning to Dr. Gabrial P. Lasala, a cardiologist and president of TCA Therapy and the principal investigator of the trial, citing TCA for research violations that included “failing to test specimens from donors for communicable disease and treating patients outside of the trial protocols.”
The Louisiana Board of Medical Examiners acted on those warnings and Lasala subsequently signed a consent order agreeing to, among other things, pay a $5,000 fine, divest himself of any interest in TCA and any other stem cell labs, accept a five-year probationary period and attend ethics and professionalism seminars. TCA’s website currently shows the clinical trial on hold.
The TCA flap should be instructive for those considering getting into a clinical trial. Eyes wide open and plenty of questions should be the rule. And watch out if they ask you to pay for it, especially in far-flung locales like China and Iran. It might be wise for those who are tempted to venture so far afield to take heed of the old cartographers’ warning: “Here be dragons.”
The Miami Project — A Brief History
When the University of Miami Medical School recruited Dr. Barth Green, a talented neurosurgeon and researcher, to establish a spinal cord injury center at Miami’s Jackson Memorial Hospital in 1975, they set in motion the beginning of what would eventually become the largest comprehensive SCI research center in the world.
Green’s work in a SCI research lab during medical school had left him with a focus on improving treatment for paralysis and a burning desire to seek its eventual cure. He brought that focus and dream with him and soon started up his own fledgling SCI research project. But by August 1985, stymied by the lack of support and funding, he confessed to Donald Misner, a successful Washington, D.C., developer who’d recently been injured in a car accident, that he was, “ready to give it up.”
“Well it’s a bad time,” Misner said. “Because I just became paralyzed this week. What can we do to change your mind?”
“If I could raise a million dollars,” said Green, “I could go out and hire the most fabulous scientists and get them equipment and we could be well on our way to curing paralysis.”
Misner signed on to that dream. Beth Roscoe, a local businesswoman who’d recently become a paraplegic, did the same and, together with Green, the three of them set up the nucleus of what would become The Miami Project to Cure Paralysis. But fundraising was a challenge, totaling less than $100,000 over the next two months.
Then on Oct. 26, 1985, a disastrous tackle on a Tennessee football field left Marc Buoniconti, 19 at the time, a C3-4 quadriplegic. His misfortune was devastating, but proved to be a game changer for The Miami Project. Marc’s father, Nick Buoniconti, an NFL Hall of Famer, attorney, businessman and broadcast personality, promised his son, “I’m going to do everything in my power to get you better again. To see you walk again.”
It was no idle promise. “I realized that there was nothing I could do to make him better,” he said. “But I knew I could raise the money and awareness to at least give the scientists a chance to find this cure.”
Marc was flown to Miami for treatment and Nick came aboard as the other cofounder of the Miami Project. The fundraising total soon jumped past $400,000. In December, after Nick spoke to a sellout Orange Bowl crowd, it blew by $600,000, rising past $800,000 by early January.
The Project’s first scientific director, Dr. Ake Sieger, cobbled together a group of basic and clinical researchers and housed them in 800 square feet of offices. Clinical trials in biofeedback, FES and rehabilitation strategies soon followed. Fundraising continued to accelerate, grant money started to flow and by April 1987 the Project had added more researchers and 6,000 more square feet.
In 1988, when Sieger decided to move on, Dr. Richard P. Bunge and his colleagues at Washington University in St. Louis were already beginning to explore the possibilities that Schwann cell transplantation might offer for SCI. Bunge agreed to become the Project’s second scientific director. By 1996, when cancer cut short his tenure, the Project research team had doubled in size and gained national recognition for its scientific work.
When W. Dalton Dietrich, Ph.D., became the Project’s third scientific director in 1997, he focused relatively soon on speeding up the transition of new laboratory findings into clinical trials on humans — a lofty goal for a process that often moves at glacial speed. The application for the phase I Schwann cell clinical trial took three years to prepare, was submitted in September 2011 and was finally approved almost a year later.
Whatever the pace of the clinical trials, or their outcome, The Miami Project has much to be proud of — as does Marc Buoniconti. Initially the poster child for the Project, he became the public face and president of both it and the Buoniconti Fund. Fundraising now runs in the millions annually, and cramped offices have given way to a 105,000 square foot, seven-story building. Over 250 scientists now work there on dozens of projects. Many others have trained at the Project and moved on to do research elsewhere. Most importantly, many people with spinal cord injuries have already benefited from advancements pioneered at The Miami Project.
By Tim Gilmer
Clinical trials involving transplants of stem cells and Schwann cells are not the only game in town.
In September 2011, NEW MOBILITY reported exciting progress in functional return for Rob Summers, a quad, following locomotor training and epidural stimulation conducted at Frazier Rehab Institute in Kentucky, part of the Reeve NeuroRecovery Network, directed by Susan Harkema. Now comes word that two more trial participants are experiencing similar return of function.
“These two have gained voluntary control [with stimulators turned on] of ankle, knee and hip movement,” says Harkema. “They have gained muscle mass, improved circulation and can stand with no assistance with the stimulator on, all similar to Rob. But all have progressed at different rates. The main question now is, what accounts for these differences?”
All three underwent vigorous locomotor training prior to being implanted with stimulators. While the locomotor training conditions and coordinates spinal cord circuitry needed for voluntary movement and proves that the spinal cord is intelligent on its own, the stimulator is the switch that turns on measurable functional return.
“The state of excitability is critical,” says Harkema, “since the only difference between being able to move voluntarily and not move voluntarily is the epidural stimulator is on.”
Researchers hypothesize that even clinically “complete” injuries must involve some sparing of anatomical nerve connections. “The irony is that … people most in need of locomotor training are probably those who aren’t going to walk as a result of it,” says Harkema in a December 2012 interview with CRPF’s Sam Maddox. She’s referring to the full range of benefits that come with weight bearing and reactivating muscle mass, such as better circulation, cardiovascular fitness, protection against pressure sores, bladder control, sexual function, temperature regulation and more.
Kent Stephenson, 25, of Mount Pleasant, Texas, one of the latest trial participants, was injured at T4 in a motocross accident in June 2009. He rehabbed at Craig Hospital in Denver, doing mat exercises, swimming, and FES cycling. When discharged, he was a motor-complete T4, no return of function. He went to Frazier as an outpatient and did locomotor training for more than a year before entering the epidural stimulator trial. After 80 trial sessions with more LT, there was still no change, but he had kept his muscle mass. Then he was implanted with the stimulator followed by three to four weeks of complete bed rest.
Next, pre-stim evaluation went on for a few weeks as he tried to move his legs while lying down. He couldn’t. No movement, no control. Then the stimulator was turned on. “I could just feel a tingly rush all the way down my body,” says Stephenson. When lying down he was asked to move his knee toward his chest. “It just came right up. It was … insane, I was just smiling from ear to ear.” This was the beginning of his muscle movement regimen. In the standing part of the trial, it took him several times to stand independently with the stimulator on. “You can tell you are standing on your muscles, not just your bones. It’s like you’re just charged. The more I stood, the more my body got in tune with it.” In time he could stand with no help and sit down by relaxing and bending at the knees.
Now he does muscle movement exercises and stands at home and returns to Frazier for occasional evaluations. He says in the beginning all he hoped for was to keep his muscle mass. But he has gained more than the ability to move his legs and stand with the stimulator on. “I haven’t had any skin issues. My bladder control is better, no accidents, I can tell when I have to cath. And oh, man, it’s a 10 on erections and keeping it up,” he laughs. “I’d go back and do it over any day, any time.”