Two teams of scientists have made significant advances in potential technology to re-grow nerves after spinal cord injuries. Both studies also highlight the formidable obstacles that researchers in this field still face, even though one of the techniques is likely to soon enter clinical trials in paralyzed humans.
“They’re both exciting pieces of work. We’re getting closer,” says Jerry Silver, a neuroscientist at Case Western Reserve University in Ohio who didn’t participate in either study but is a prominent researcher in the area.
The two papers describe techniques to overcome nervous system features that normally prevent spinal nerves from regenerating in adulthood. In most animal species, basic central nervous system pathways are almost entirely set before birth.
As this process is completed, genetic programs that produce some nerve-growth factors (the term for special proteins that promote neuronal growth) are switched off, and other programs are switched on to suppress the growth of new nerves and protect the basic architecture of the brain and spinal cord. Nerve repair researchers therefore have sought to restore the nerve-growth-friendly environment of fetal life to the extent needed to heal severe spinal and brain injuries.
Sprouting across the gap
The more ambitious of the two studies, by a group of University of California, San Diego, scientists from the laboratory of Mark Tuszynski, appeared online on August 2 in Nature Neuroscience. In rats whose spinal nerves had been severed, the group tried to regrow sensory nerve output fibers, known as axons, across the lesion and into the appropriate clump of target neurons in the brainstem.
The effort combined several techniques that had been described before, including the packing of bone marrow “stromal” cells, which produce nerve growth factors, into the site of the lesion to serve as a bridge for regrowing, brain-bound axons. The team also used a gene-therapy technique to deliver a nerve-growth factor known as neurotrophin-3 (NT-3) to the target zone in the brainstem.
Six weeks after the spinal cord injury, treated rats had regrown sensory nerve fibers across the cut spinal cord and into the NT-3-labelled target zone, called the nucleus gracilis. (When a different, inappropriate region was labelled with NT-3, the axons homed in on it, too.) With the highest dose of NT-3, the nucleus gracilis recovered about a quarter of its usual axon presence, and these axons terminated at normal-looking synapses.
There was just one problem: When the researchers tested these new synapses by stimulating the nerves, they found that the synapses were silent. After further evaluation they concluded that the new axons had grown without their usual myelin sheath – a protein coating that promotes nerve-signal conduction.
“This is very important,” Silver says. “It means that even a very short distance in which a normally myelinated fiber is unmyelinated will essentially block all function of the regenerated fiber.”
Ordinarily, neural cells known as oligodendrocytes keep central nervous system axons myelinated. In the peripheral nervous system, where regrowth is somewhat easier during adulthood, cells known as Schwann cells myelinate axons.
To get around the myelination problem, the group now plans to try implanting both kinds of cell in the spinal lesion. “We will examine the ability of either neural-restricted oligodendrocytes or co-grafted Schwann cells to remyelinate regenerating axons,” Tuszynski says.
In the second experiment, researchers in the Cambridge University laboratory of James Fawcett took a different approach. They promoted the ability of axons spared by a spinal injury to shift to new connections, creating detour pathways that enabled the recovery of lost skills.
In the study, described in the online version of the August 9 Nature Neuroscience, the Fawcett team used motor-skill training, combined with a special enzyme treatment, to improve manual dexterity in rats whose nerves controlling fine motor skill had mostly been severed.
The enzyme, known as chondroitinase ABC, breaks down nerve-growth-suppressing proteins called proteoglycans. These are secreted in spinal lesions and also form a “perineuronal net”—a matrix of supporting proteins located outside brain cells—to protect clumps of spine and brain neurons from inappropriate invasion by nerve fibers.
Fawcett’s team hypothesized that the chondroitinase treatment would “open a window” of axonal sprouting, enabling the motor neurons needed for a given skill to reconnect to their targets in the spinal column via the relatively few remaining axons that had not been severed.
The scientists also judged that this burst of neural “plasticity” would enable optimal connections only if the animals were simultaneously trained in the desired skill, thus driving the new connections in the proper directions. And indeed they found that chondroitinase plus specific training for an hour a day (starting seven days after the injury and lasting six weeks), greatly improved the manual dexterity of the spine-damaged rats on a grasping task, compared with the use of either approach alone.
Surprisingly, however, when the rats were given chondroitinase plus non-specific physical training, their grasping skill didn’t just fail to improve; it disappeared almost entirely, and skills such as ladder walking improved. The result suggests that the new connections formed during the period of chondroitinase-enabled plasticity are apt to take over axonal pathways once used for other skills.
To Fawcett, the lesson is that “if you make the central nervous system plastic, it’s very accessible to good rehabilitation but is very vulnerable to bad rehabilitation. And so you’ve got to get [the rehabilitation] right.”
Considering that people with spinal injuries have few treatment options and that chondroitinase appears non-toxic, Silver finds the result quite promising on the whole. “It gives a huge amount of hope for a clinical application that’s pretty close,” he says. “It’s not going to help everybody with complete lesions, because there’s no bridge building. You’re talking about people who have some spared fibers.”
Fawcett too is optimistic, and is currently working with Hawthorn, N.Y.-based Acorda Therapeutics to get the chondroitinase-plus-rehabilitation treatment into clinical trials. Since completing the work described in his recent paper, he says, his team has found that the recovery of a specific skill in rats can occur even if the treatment regime is started 30 days after the spinal injury. “So that’s certainly brought the possibility of clinical trials a lot closer,” he says.