Chondroitinase ABC (ChABC) is a type of enzyme drug that eats up certain sugar chains that form scars and block regeneration after spinal cord injury. ChABC, in combination with rehabilitation, boosts functional recovery in acute SCI. Now there is data to show that ChABC, plus rehab, works in a chronic injury model too.
This work, just published in the Journal of Neuroscience, comes from the lab of James Fawcett and was partly funded by the Reeve Foundation. Fawcett directs one of six labs in the Reeve International Research Consortium on Spinal Cord Injury. His lab is located at the University of Cambridge, in England.
For some background, here’s an interview
I did with Dr. Fawcett earlier this year.
For the new study, Dr. Fawcett, using a rat model, clearly has an eye on human application. He administered the drug about the same time rehab starts – four weeks post injury. Rats that got ChABC plus rehab did much better in pellet grabbing and grid walking than animals that got no drug, or got the drug but no rehab. From the paper:
There was significant functional recovery in skilled paw reaching and other forelimb motor functions accompanied by increased spouting and synapse formation by corticospinal and serotonergic axons. Our results suggest that delayed ChABC treatment would be effective if given to patients as they start rehabilitation after SCI.
How does it work? In the previously published acute data, it appears that ChABC encourages axons in the area of injury to regenerate. At four weeks though, a spinal scar is well established, inhibiting regeneration. Benefits shown in the chronic model are probably due to enhancement of plasticity – sprouting of bypass circuits – rather than long-distance axonal regeneration
How might ChABC and rehabilitation work together to promote functional recovery?
The enzyme ChABC changes the central nervous system extracellular matrix, leading to three main effects.
After acute injury, there is increased axonal regeneration. However, in our chronic model the glial scar was firmly established and ChABC treatment did not produce cortical spinal tract (CST) regeneration past the lesion. The beneficial behavioral effects are therefore unlikely to have been caused by long-distance axonal regeneration.
The second effect is sprouting of axons above and below the injury. We saw CST sprouting of a similar magnitude to that in acutely treated cord, and also sprouting of serotonergic axons. These axon sprouts made more synapses in ChABC-treated animals. We did not see sprouting of unlesioned CST axons below the lesion, so the new connections and behavior must have been due to CST sprouts above the lesion synapsing onto propriospinal interneurons projecting below the lesion.
The third effect of ChABC is to digest perineuronal nets [cartilage type structures that form around some neurons] which may make it possible for new sprouts to access the surface of neurons, increasing their probability of forming a synapse. It is probable that the initial connections formed by axon sprouts are random, some functionally appropriate, some inappropriate. The situation is therefore similar to the exuberant connections formed during development.
What then, does rehab have to do with sprouting? Activity and training may help refine these new connections – strengthening appropriate ones, removing inappropriate ones.
Does this plasticity response cause pain? That is a worry with sprouting. In this study, it did not: “…neither ChABC nor task-specific rehabilitation affected the threshold for pain, temperature, and pressure sensation.”
Our experiment shows that delayed ChABC treatment remains able to induce sprouting of different spinal fibers in chronic SCI, and that this increase in sprouting is sufficient to drive functional recovery when combined with rehabilitation. The timing and methodology we used could be applied to human SCI patients.
Dr. Fawcett is of course eager to test ChABC in a human trial. Regulatory and safety tests are moving forward for that. "We still have to do a lot of safety work to determine the final formulation. And we have to figure out how to best administer the enzyme. Typically, in animals, we inject it either directly to the spinal cord or in larger quantity around the cord. In humans, though, the cord is much larger; the enzyme cannot diffuse very far, so you cannot put it in the fluid surrounding the cord and expect it to get into the middle. That means we probably have to inject it; one is cautious about putting needles into the injured spinal cord."
So, the drug worked on a chronic animal model. Does that mean it could be a potential therapy for chronic human SCI? That’s not yet clear, says Dr. Fawcett. He doesn’t know if it will work in a long-term chronic animal. “For people, our view is that chondroitinase needs to be given at the same time as rehabilitation is going on. The two have a positive interaction. Rehab usually begins at three weeks or so after injury, and that would be a good time to do the chondroitinase treatment."
Chondroitinase Combined with Rehabilitation Promotes Recovery of Forelimb Function in Rats with Chronic Spinal Cord Injury
Difei Wang, Ronaldo M. Ichiyama, Rongrong Zhao, Melissa R. Andrews, and James W. Fawcett