ARTICLE IN BRIEF
The FDA has approved the first phase 1 trial to transplant autologous Schwann cells in people with severe spinal cord injury.
THE MIAMI PROJECT TO...Image Tools
Researchers at the Miami Project to Cure Paralysis, part of the University of Miami Miller School of Medicine, have spent decades studying the potential power of the Schwann cell to help repair and regenerate damaged spinal cord tissue. They moved from the lab to animals, successfully growing and transplanting Schwann cells into injured spines. Now, after careful analysis of the science, the US Food and Drug Administration (FDA) has approved a small trial to test the potential treatment in people who have had a spinal cord injury.
The landmark study will be the first FDA-approved trial to cull a person's own Schwann cells, grow them, and inject them into the damaged cord. If it works as it does in animal models, it could mean that the transplanted Schwann cells would help repair the damaged axons and allow information to flow more effectively from the muscle and straight up the cord into the brain and vice versa.
The first step is a phase I safety trial with eight patients who have sub-acute injury and do not yet know that they will be paralyzed. They will be identified within the first five days of the injury and, if they qualify and consent to participate, the doctors will biopsy the sural nerve in the lower leg from which they will obtain Schwann cells. About a month later, when the population of cells is large enough and pure enough to transplant, the participants will undergo another consent process to see if they are still interested in being in the study. If they are, the doctors will transplant the participant's own Schwann cells into the center of the site of the spinal cord injury.
Barth Green, MD, co-founder of the Miami Project and chairman of neurosurgery at the University of Miami, said the hope is that the cells will insulate the damaged axons and encourage growth and “give the area an opportunity to heal.”
The study was carefully designed to maximize the safety of the transplanted Schwann cells, said Dr. Green. “Transplanting autologous cells added a level of comfort and security,” he added, “because we do not have to worry about immunosuppression.” In addition, the waiting period between obtaining the cells and transplantation gives investigators an opportunity to confirm that it is a complete paralysis.
The Miami investigators decided to select participants with a complete neurologic injury to the thoracic cord, anywhere between T3 to T11. These people will have lost sensation and movement below the chest because of the injury they sustained. They chose this level of injury because the upper extremity circuits have already left the cord so the potential of losing more feeling or movement is small, explained Dr. Green. “Hundreds of scientists thought about this design and this is the right first step,” he added.
They will begin looking for their first participant once the hospital's institutional review board (IRB) approves the study. The IRB was awaiting the FDA's green light before making its decision, said Dr. Green, but now it could be a matter of weeks before the first patient is enrolled.
The peripheral nervous system has the potential to recover, the investigators say. Studies from animals have demonstrated that transplanted Schwann cells make myelin that wraps the injured axons and allows for more normal functioning. W. Dalton Dietrich, PhD, scientific director of the Miami Project, said that the study is designed to grow and deliver from 5–15 million Schwann cells to the damaged area. They are hoping that the cells also recruit other Schwann cells. In addition to myelination, the Miami Project scientists have found that the cells release growth factors that promote recovery of injured axons.
The Miami scientists have tested transplanted cells on half a dozen animal models — from rats to pigs to non-human primates — and have shown that the cells lead to functional recovery of the paralyzed animals. Many of the cells do not divide and don't live beyond six months of the transplant. But the Miami scientists think that the autologous cells from the spinal cord victims will live longer.
There are about 4,000 new thoracic spinal cord injuries a year and generally centers that specialize in these injuries might only see a handful of cases. The Miami team is looking to recruit patients from all over Florida and in Southeastern states.
Dr. Green said that he is “cautiously optimistic” that the approach will work in patients. “When you introduce an experimental treatment into patients there is always the potential to harm and to heal. I hope that we will find that the treatment is safe and that we can then in short order do studies to test whether it will be effective.”
The neurosurgeon said that this first step is part of a master plan to improve the damaged environment using a combined therapeutic approach. Their best model so far was a mix of transplanted Schwann cells, an anti-inflammatory agent called rolipram, and cyclic-AMP, a messenger molecule inside cells that stimulates a cascade of molecules that promote regeneration. But the FDA requires a pure study with only one treatment before they can test a combination approach.
Participants in the phase I study will be followed for one year and assessed for neurological and medical status, pain symptoms, and muscle spasticity.
“The scientific background is unbelievably intricate and lays the groundwork for this study in patients with spinal cord injuries,” said Nicholas M. Boulis, MD, an associate professor of neurosurgery at Emory University in Atlanta. “It's great that they will be moving towards a clinical trial. They have done everything possible to make this happen. This is a huge milestone.”
Michael Fehlings, MD, PhD, professor of neurosurgery at the University of Toronto and director of the Krembil Neuroscience Centre at Toronto Western Hospital, agrees. “The field is definitely ready for this clinical trial.”
He added that while people with a complete thoracic injury should be the first to receive the transplanted Schwann cells, for the safety reasons discussed above, the downside of this is that they are much less likely to respond because of their complete break. “Still, this is a safety study and even if they don't show a benefit they should move on to the next phases of testing.”
Robert G. Grossman, MD, chairman of the department of neurosurgery and co-director of the Methodist Neurological Institute in Texas, will chair the data monitoring and safety board for this study.
“Spinal cord injury will not have a magic bullet,” he said. “There are so many things going on that it will call for a series of treatments delivered during specific times in the post-injury process.”
He added that Schwann cells “have a definite role in supporting the axon and there is every reason to think that they will be of benefit to spinal cord patients. This is a logical progression from lab work to a clinical application. It is important to demonstrate that cell transplant injections into the spinal cord can be done without causing harm.”
WHY THE FOCUS ON SCHWANN CELLS
What prompted the interest in Schwann cells? By the mid-1980s, it was becoming clear that the spinal circuits below the injury controlling movement and coordination were not damaged. It was the “telephone cable” — the axons carrying the information from the cord to the brain — that had lost its signal.
Scientists began using neurotrophic factors to coax nerve cells to grow. But Mary Bartlett Bunge, PhD, and Richard Bunge, PhD, neuroscientists at the University of Miami, were focusing on a cell outside of the central nervous system that they believed was critically important in fixing the damaged axons. Knowing that Schwann cells make myelin that insulates the axons, the Bunges began testing their idea that these cells could repair the downed wiring below the injury that made it impossible for signals to get from the cord to the brain.
They removed the peripheral nerve cells from the legs in animals and in humans and let them multiply in test tubes. They placed millions of these cells in a small casing (scaffold) and laid it across the lesion in animal models, added growth factors, and watched as the axons grew across the damaged site and made connections outside of the lesion. Richard Bunge passed away in 1996 and Mary Bunge, a professor of cell biology & anatomy, neurological surgery and neurology, has continued the work in her lab.
Barth Green, MD, co-founder of the Miami Project and chairman of neurosurgery at the University of Miami, talks with Neurology Today about the opportunities for neural stem cell transplantation to cure paralysis — what investigators have learned to date and what lies ahead: http://bit.ly/dy2KLx.