For more than a century, neuroscientists have been trying to figure out how to repair broken nerves in the spinal cord–and the rest of the central nervous system–after injury. They’ve produced a steady stream of promising discoveries–treatments that promote nerve growth in the laboratory dish and animals, even some reports of paralyzed rodents regaining motor function. So why are people with spinal cord injury (SCI) still without therapies that repair their nerve damage?
To find out where the research currently stands, I spoke to Naomi Kleitman, PhD, the program director in Repair and Plasticity at the National Institute of Neurological Disorders and Stroke, as well as Children’s neurobiologists Zhigang He, PhD, Larry Benowitz, PhD and Yang (Ted) Teng, MD, PhD. Here are eight take-home points from our conversations:
1. So far there’s no concrete evidence that a treatment has produced central nerve regeneration in humans. While there are many reasons to believe that regeneration is possible in humans, scientists are still hard at work studying this topic in animals, and figuring out how to translate new findings in animals into clinical trials.
2. Thanks to advances in the basic science, researchers can regenerate central nerves in rodents. About ten years ago, the lab of Clifford Woolf, MD, PhD, currently director of the Program in Neurobiology at Children’s, found in a landmark study that axons (individual nerve fibers) in the adult rat spinal cord can regrow after injury, if subject to conditions that activate their intrinsic growth potential. While the conditions in this study would be hard to apply clinically, Dr. Woolf and other researchers have since made tremendous strides in identifying the molecular gates to this growth potential—particularly, Drs. He and Benowitz, who have been able to induce robust regeneration of injured nerves in the mouse spinal cord and optic nerve (the nerve which connects the eye to the brain).
3. Nerve regeneration doesn’t equal functional recovery. After achieving nerve regeneration, the next big challenge is getting injured nerve cells to regain lost functions, such as limb movement or vision. For this, the nerve cell has to do a lot more than regrow its axon. That axon has to grow to the right place, form functional connections with other cells in the right pattern, and be wrapped properly in myelin—the insulation material that helps it efficiently transmit electrical signals. All this has to happen for lots of axons, over long distances. Some encouraging news? The spinal cord axon regeneration that Dr. He and collaborators recently reported included the formation of some functional connections. And Dr. Benowitz’s lab just reported long distance regeneration in the optic nerve.
4. It’s possible to get functional recovery without regenerating injured axons. Here’s a positive flip side: If a SCI is not complete, axons of uninjured nerve cells in the vicinity might be induced to branch out and take over the duties of their injured neighbors. This plasticity—the ability of the nervous system to adapt to change—can be enhanced by rehabilitative exercises and, sometimes, electrical stimulation of nerves or muscles.
5. Timing matters. Many experimental treatments are designed to limit nerve damage after the initial injury. So-called “neuroprotective” interventions aim to reduce the additional cell death and axon damage that—often due to inflammation—follow an acute CNS injury. (Just like the clot-busting agent tPA, which reduces the damage caused by stroke if patients get it within the first three hours.)
6. What works in rodents doesn’t always work in humans. In fact, what works in mice might not even work the same way in rats. And sometimes, the promising findings in animals have simply not been reproducible. “In some cases we’ve out-and-out not been able to repeat what’s been published,” Dr. Kleitman says, “And we’re working to figure out why.”
7. It can be really hard to figure out if a treatment works in humans. There’s often some improvement in nerve function that occurs naturally after an injury—improvement that can be hard to separate from the benefits of an experimental therapy. “People who are spending a lot of money on a procedure that’s not proven, or are traveling around the world to get it, are highly motivated to feel that something has improved,” Dr. Kleitman observes. What’s more, researchers can’t perform the invasive experiments they would in rodents to see what’s actually going on in patients’ nerves. But an ongoing observational study of patients receiving standard treatments, including rehabilitative therapies, for SCI—coordinated by the North American Clinical Trials Network—is expected to yield baseline information that will improve the quality of future clinical trials.
8. Because stem cells can become any type of cell in the body, they hold great promise for regenerative medicine. But it’s still very early days for stem cells in SCI. (In October, a patient with paralysis recently became the first clinical trial subject to receive a stem-cell-based treatment.) One thing we do know—thanks to Dr. Teng, who also directs SCI research at VA Boston Healthcare System, and his colleagues—is that stem cells don’t necessarily work by replacing dead nerve cells. In 2002, they devised a unique way to deliver neural stem cells to rats with SCI, restoring some walking ability. Surprisingly, these stem cells seemed to work by promoting neuroprotection and plasticity. Now the neuroprotective potential of stem cells is being explored as a therapy for SCI and other conditions.
The bottom line is there’s much hope, but in most cases—as for other CNS diseases, such as Alzheimer’s or Parkinson’s—we’re still waiting for that hope to be translated into treatments for patients. “We have a lot of evidence developing from human studies that the nervous system is sensitive to change and may actually change by growing new nerve connections,” says Dr. Kleitman. “But harnessing that, getting a therapy to do that reliably? We’re not there yet.”
Asked to venture a guess as to how long it will take, Dr. Benowitz predicts 5-10 years—and adds that effective therapies will likely require a combination of treatments.
For more on current experimental approaches to treating SCI in humans, see this excellent report by Dr. Kleitman and others, prepared for the International Campaign for Cures of Spinal Cord Injury Paralysis.
For an example of how researchers can tap into the spinal cord’s plasticity to drive functional recovery in rodents, read this FOCUS article on promising findings from Dr. Teng and his postdoctoral fellows. These findings connect and provide new insight on a number of the points above, from how we might take advantage of stem cells to why the timing of treatment matters.