Yale-New Haven magazine, a publication of Yale-New Haven Hospital
Fall 2001/Winter 2002
Researchers at Yale-New Haven have a long history of taking on giants in the realm of disease: fatal bacterial infections, heart failure, sick or premature newborns and diabetes are just a few of the areas where Yale doctors have been responsible for dramatic advances in medicine.
Today, Yale clinicians and researchers are building upon their long history of research into nerve repair and transplantation to aggressively wage war against multiple sclerosis (MS) and related diseases. One recently completed clinical trial tested the effect of oral interferon on patients with MS. Another ongoing trial is examining the use of the cholesterol-lowering drug, simvastatin. But, perhaps the most exciting project of all, involving cell transplantation in humans, has attracted international attention and doctors and patients around the world are awaiting its outcome.
Only July 18 and 19 , a team of Yale-New Haven neurologists and a neurosurgeon performed surgery at Yale-New Haven Hospital on a 53-year-old patient with an advanced form of MS. If the procedure proves effective and safe, they will have made a dramatic advance in the quest to repair the central nervous system of MS patients.
When Nerves Don't Communicate Well
MS affects as many as 350,000 Americans, two-thirds women, who as a result experience problems with muscle control and strength, vision, balance and sensation. In MS, recurring inflammation in the brain and spinal cord-the central nervous system-damages the "fatty" or lipid coating (myelin) that surrounds and insulates nerve fibers (called demyelination).
Myelin allows the conduction of impulses from one part of the body to another. It can be destroyed in acquired diseases such as multiple sclerosis and by hereditary metabolic disorders such as the leukodystrophies. A scar forms where myelin is destroyed, which disrupts impulses produced by the nervous system. These scars or lesions can occur randomly in a person's nervous system, but prove more disabling when they occur in the spinal cord or brainstem.
While MS is rarely life-threatening, its impact on a person ranges from mild to severely disabling.
What Could Be a Medical Milestone
In that Yale-New Haven operating room in July, YNHH neurosurgeon Dennis Spencer, M.D., transplanted myelin-forming Schwann cells into the central nervous system of a woman with a serious form of MS. Before surgery, Jeffrey Kocsis, Ph.D., professor of neurology and neurobiology, had already supervised preparation of the Schwann cells taken from the patient's own peripheral nerves, specifically the sural nerve. The cells were prepared for transplant in the Frisbee III Laboratory, a Class 10,000 clean room suitable for delicate manipulations of cells. The cells were isolated overnight and delivered on ice to the operating room ready for the surgery.
During surgery, these Schwann cells were transplanted into the right frontal lobe of the patient's brain using stereotactic technology that enables the surgeon to be extremely precise in positioning the transplanted cells. According to Dr. Kocsis, Schwann cells are implanted because they are generally considered safe for transplantation.
If the cells behave in humans as they have in animal studies, they will replace the damaged cells and begin to re-coat, or remyelinate, nerves in the brain and spinal cord. Dr. Timothy Vollmer, YNHH neurologist and associate professor of neurology at Yale School of Medicine, is the study's principal investigator. He points out that the current study, while groundbreaking and receiving much international attention, is really the progression of the school's long history of research into neurological repair and nerve transplantation.
It All Begins in the Lab
Research involving humans is never begun without a tremendous amount of basic research in the laboratory. And between basic science discoveries and improved patient care lies a gulf that many universities and companies struggle to bridge.
"This research project stands out, not only for what we are trying to accomplish, but also for the fact that our team of neuroscientists, clinicians, neurosurgeon, imaging experts, Frisbee Lab staff and a great support staff worked so effectively together to bridge that gap," said Dr. Vollmer.
In a series of experiments involving rats, Dr. Kocsis had already proven that enough Schwann cells could be extracted for transplantation, that transplanted cells could lead to remyelination of MS-type lesions and that impulse conduction improved in the transplanted nerves of the rats.
Based on this research and a resulting paper, a protocol for research conducted in humans was developed that attracted the attention of The Myelin Project based in Washington, D.C. While some earlier studies in neural cell transplantation in Parkinson's disease had been disappointing, the Yale team felt that the controls in these earlier studies had been weak. They would correct for that in their own study.
The Myelin Project was the logical organization to be interested in this type of research. The Project limits its funding to clinically oriented experiments on the cutting edge of remyelination research. The organization represents a multinational group of families whose lives have been affected by demyelinating diseases. Its stated purpose is to accelerate research on myelin repair by "giving scientists adequate, prompt financing and by continuously interacting with them."
The project was founded by Augusto and Michaela Odone, whose son Lorenzo is afflicted with an inherited demyelinating disease, adrenoleukodystrophy. Their story was dramatized in a 1992 movie, "Lorenzo's Oil."
Drawing upon the expertise of the world's top laboratories engaged in myelin repair, The Project has formed a work group that includes researchers from Mount Sinai Medical Center, the Istituto Superiore di Sanitá in Rome, the Collège de France, the University of Wisconsin at Madison, the Hopital de la Salpêtrière and the Institut Pasteur in Paris, the Queen's University at Kingston in Canada, the University of Cambridge in the UK, and the Max-Planck Institut in Germany. Researchers at Yale had an opportunity to discuss their protocol and receive input with other members of the work group.
The Yale Protocol
Every element of the protocol, or the procedure for how this research would be conducted, was carefully designed to guard the patient's safety, while producing meaningful results. "We're taking a very conservative approach," said Dr. Kocsis. "We are transplanting a small number of cells using minimal surgery." Doctors chose the right frontal lobe of the brain because it is the safest area of the central nervous system for the patient to undergo this type of transplant surgery, as well as an easier area to monitor.
Schwann cells taken from the patient herself, rather than a donor, reduced the risk of rejection. And because MS does not attack Schwann cells and the myelin they produce, they are likely to better withstand any future attack from the disease. In January 2002, a biopsy of tissue at the site of the implant will be examined to determine the following:
Watch and Wait
If nerve impulse conductivity is improved in humans thanks to the transplanted cells, researchers are optimistic this may lead at some point to an improvement in function. However, functional improvements are not being measured by the current clinical study-which is engaged in what researchers refer to as proof of concept.
"If we can show even modest remyelination," said research associate Jana Preiningerova, M.D., the project manager, "then we can proceed to the next phase of clinical studies and see if transplantation of Schwann cells into critically located lesions may bring back some function to our patients."
While they await the biopsy that will prove or disprove their theory, doctors monitor the patient closely and follow her progress via MRI scans of the brain and clinical examinations. Currently, no complications have been encountered and the patient is doing well. Only time will tell.
If the outcome is encouraging, this trial represents a small-but very significant step-along the road to finding a cure or more effective treatment for the disease whose cause is still unknown.
"If it works," concluded Dr. Vollmer, "it may be a model of how to test other cell types and will encourage new studies."
And medicine will have been advanced, one small victory at a time.
©Yale-New Haven Hospital 2001-2002