Super-charging research on spinal cord injury
New VA initiative brings together key groups working toward a cure
When physician-researcher Mark Tuszynski, MD, PhD, talks with patients who have spinal cord injury, he advises them to "have a positive outlook and keep their bodies in the best shape possible. With much hard work and some luck, we hope to have truly promising therapies to deliver in the future."
A new VA initiative aims to put researchers on the fast track toward that future. The VA Spinal Cord Injury Collaborative Translational Consortium is building teams of leading investigators—almost a "Who's Who" of spinal cord research in the U.S. today—to nurture high-risk, high-return ideas that would likely not get funded through other programs, and to create synergy among scientists who are in hot pursuit of the same goal.
One lead group in West Haven, Conn., and another in San Diego have already begun a dialog that will have them sharing data, techniques and experimental therapies; replicating each other's results; and propelling the research forward at a pace that would otherwise be hard to attain.
"Right now we are still working in animal models," says Audrey Kusiak, PhD, the scientific program manager for VA who designed the consortium and oversees it. "The hope is that after 10 years of research and funding, the consortium will have the data and expertise to translate the methods and results to humans. Toward that goal, I have already started talking with the Food and Drug Administration so they can help us design the experiments to make the data more meaningful during the preclinical phase."
Academia, private sector to
help guide effort
Tuszynski, with VA and the University of California, is at the helm of the San Diego team. The West Haven group is led by Jeffery Kocsis, PhD, of VA and Yale University. As the two groups build their partnership, they will also reach out to other collaborators—both in and outside VA—to bring additional expertise into the consortium. Kusiak says VA's Rehabilitation Research and Development Service also expects to fund pilot studies by other VA investigators who can become part of the consortium by contributing tools to further its work. Examples include cells for transplantation or new drug-delivery methods.
Two advisory committees and a central advisory board that includes top names in spinal cord research from academia, government, private industry and the Veteran community will help guide the overall effort.
Veterans and spinal cord injury
Much of the work in Tuszynski's lab will focus on pinpointing networks of genes that trigger nerve regrowth. "We can then isolate these genes and introduce then into a non-regenerating cell to convert it into a regenerating cell," explains Tuszynski. Another area of interest is using proteins called growth factors, namely BDNF and NT-3, to coax nerve cells to sprout new axons. Axons are the long, spindly part of the neuron that connects with other neurons to transmit impulses from the brain.
The San Diego lab is also exploring the use of scaffolds made of a natural sugar-based substance called agarose. A damaged spinal cord has gaps above and below the injury that prevent nerve impulses from traveling through. The implanted scaffold acts like a bridge for regenerating axons to grow across the injury site.
Combination therapy nets
strong results in lab studies
Tuszynski believes in a combination approach, and his lab has had a string of successes along that line. Kusiak notes that recent studies from the San Diego team "have shown that combinations of cells, drugs and growth factors result in regrowth of nerve fibers past the site of injury twelve months after the injury. Similar combinations have resulted in recovery of function in rodents as well as non-human primates."
Some experimental therapies for spinal cord regeneration must be used within hours of the initial injury. Others, targeted to "subacute" injuries, must be used within a week or two. That's the case with a therapy now being tested in a small safety-and-tolerability trial just begun by Geron Corporation, whose medical director sits on the advisory board of the VA consortium. In that trial, for the first time ever, human patients are being injected with human embryonic stem cells, which are still highly controversial. The VA consortium, though, will seek to develop therapies that will work even months after an injury. "That's more relevant to our Veteran population than acute or subacute therapies," says Kusiak.
Kocsis, who for many years has partnered with well-known VA-Yale neurology researcher Stephen Waxman, MD, PhD, is working on methods that will complement those of the San Diego group. One area is the development of imaging techniques to track the survival of transplanted cells and to show how nerve fibers are growing inside the live organism. Currently, researchers rely on examining tissue under a microscope to gauge the success of a therapy. Kocsis' team is now working with a commercially available system that had previously been used mainly by cancer researchers to view tumor progression. "The resolution is not great, but it gives us good correlation with cell survival," he says. His team is also looking to take advantage of sophisticated scanning tools such as positron emission tomography and diffusion tensor imaging.
Adult stem cells show
promise
The West Haven group has also been testing adult stem cells for spinal cord regeneration. In one recent study, they and Japanese collaborators infused mesenchymal stem cells—which can be derived from bone marrow or umbilical cords—into the bloodstream of rats with damaged spinal cords. The stem cells turned into neurons at a significant rate. The result was improved movement in the animals. Because the delivery method was non-invasive—it involved no surgery—Kocsis believes it holds promise for eventual human trials. A twist on this approach is now in the works in the West Haven lab: genetically engineering the stem cells to produce "trophic factors," or growth-stimulating proteins, which should further boost regeneration.
Through consortium funding, Kocsis and colleagues are also continuing their longstanding work on remyelination—restoring the waxy insulation around damaged axons so they can once again conduct electrical impulses. The team is one of many worldwide that is experimenting with olfactory ensheathing cells, which can be harvested from the lining of the nose. Transplanted into the spinal cord of rats, the cells have triggered remyelination and axon regrowth in several experiments.
It's hard to predict right now which therapies will emerge as the most practical for human trials, but Kusiak believes the consortium will speed progress toward that goal. She says she's gotten excellent feedback on the overall plan from her counterpart at the National Institutes of Health—particularly on the built-in checkpoints that require careful validation by collaborating groups before a potential therapy can advance from rodent to primate testing, and from primates to humans. The field of spinal cord research is at a crossroads, she says, and aggressive, wide-reaching approaches are needed more than ever to move discoveries from labs to clinics. She hopes the new consortium will do just that.
"It is truly unique to VA," says Kusiak "We think it's a model system for translation."
This article originally appeared in the October-November 2010 issue of VA Research Currents.