Spring and summer have been humdinger seasons for news about repairing spinal cord injury — and not just because of the encouraging research about cord stimulation I reported in April and July. This month’s story involves giving the brain a chance to reconnect to the cord below the injury site in a different, and potentially more exciting, way. I’m talking about corticospinal regeneration — the holy grail of SCI research for as long as scientists have been trying to repair damaged cords. To be brief, corticospinal regeneration is the process by which damaged axons that are attached to healthy neuron cell bodies grow past the site of injury and restore lost connections with cells below that lesion.
A quick refresher might be useful.
In a functioning central nervous system, there’s a group of brain cells called corticospinal neurons. They have three main physical parts: a cell body, a forest of dendrites and a single slender axon with exquisitely tiny nerve endings at the far end. The cell body holds the DNA and builds proteins as needed. The dendrites are message receivers, and the axon is the message sender.
Collections of these axons, in long, dense bundles commonly called spinal nerves, are the “white matter” of the spinal cord. These axon bundles are part of what has been damaged in a spinal cord injury. Their cell bodies and dendrites, safely tucked away up in the skull, are fine.
Axons famously don’t grow and reconnect after injury, for lots of reasons. One is that a newly damaged spinal cord isn’t anything like a cleanly broken bone; it’s more like a toxic waste site, where decay is ongoing. The cord is supposed to be permanently walled off from intrusion, and it sees trauma as an invasion. When the cord is breached by broken vertebrae, inflammation follows, which leads to cell death, which leads eventually to a glial scar — an impenetrable wall that growing axons can’t ever get through.
At least, that’s the conventional wisdom.
But on May 29, 2018, a new study from the lab of Dr. Xiaoguang Li in Beijing described a successful attempt to regenerate corticospinal axons in rhesus monkeys. There are two reasons why this information from the journal Proceedings of the National Academy of Sciences of the USA should startle you. First, rhesus monkeys are primates, closely related to humans. They share 93 percent of our DNA, as compared to rats, which share only 80 percent. Interventions that work for these monkeys are far, far more likely to work in humans than procedures that work in rats. Second, successful regeneration of corticospinal axons means functional return of both muscles and sensation. And that’s what happened in Li’s study.
Decades of unsuccessful lab work all around the world show just how difficult it has been to coax those axons to grow across an injury site, even in rodents. It’s simply an enormous victory to have managed it with primates. How did Li’s team get it done?
First, they caused T8 SCIs in these animals by creating hemisections, removing a 1-centimeter-long section from half of the cord — a half-cylinder-shaped piece about as long as a pencil is wide. Then, with the animals still in the acute post-injury stage, they inserted a tubular scaffold at the lesion site that was made of biodegradable material, like those stitches that eventually dissolve. Most critically, this bridge was infused with a slow-release molecule long known to be an irresistible lure for the broken ends of axons.
The bridge was made of chitosan, a type of fiber derived from the hard, outer shells of crabs, crayfish and lobsters. Chitosan has been studied, and used, as an excellent vehicle for sustained-release drug delivery in humans for more than a decade. Not only is it biodegradable, it does not form tumors and is nontoxic. These same Beijing scientists had used chitosan back in 2015 to test whether rats with completely transected cords could recover. They could, which is why it made sense to take the next step and test nonhuman primates.
The growth-attracting molecule in the chitosan tubes is known as NT-3 (neurotrophin-3), and we’ve known since 1994 that growing axons love it. Way back when that discovery was new, it seemed like the path to functional recovery was clear. For lots of reasons, it hasn’t been that easy. Li’s study is the very first time NT-3 has been shown to restore function in nonhuman primates, 24 years after the original work was published.
What Did the Recovery Look Like?
There were 32 animals in this study, and all of them were given the exact same T8 hemisection injury. After that, 20 of them had the NT3-chitosan tube inserted, and the other 12 were cared for as controls. Here, directly quoted from the paper, are the key data points:
• Over one year after the surgery, a neural cable-like “bridging” structure connecting the … ends of the severed right side of the spinal cord appeared in the NT3-chitosan matrix, whereas only scar tissues were found in the lesion control group.
• In the lesion control group, animals dragged their right legs most of the time. In the NT3 group … we selected the 12 clinically most relevant parameters and showed good walking recovery.
• Compared to the lesion control group, the NT3 group displayed evident restoration of temperature sensation.
• NT3-chitosan significantly reduced the incidence of bedsore [yes, monkeys do get bed sores], with a 58.3 percent occurrence rate in the lesion control group reduced to 10.5 percent in the NT3-chitosan group.
The data in this paper is well worth looking at, even if scientific papers make your eyes glaze over. It gives me hope for a number of reasons. One is the meticulous nature of the work. Another is that it’s published by one of the most reliable journals, meaning that it’s been very carefully and thoroughly vetted by experts.
And finally, the authors are already focused on the next step: testing this product and process on nonhuman primates with chronic injuries. This is from the conclusion of the paper:
“While this study is mainly focused on acute injury repair, we hypothesize that for treatment of chronic injury, removal or at least partial removal of glial scar tissue will be needed … of course, studies using NT3-chitosan to repair chronic lesion models … are currently ongoing [emphasis mine].”
They’re already working on a chronic injury model! Let’s allow ourselves to assume the best possible outcome: that the work Li is doing right now with chronic injuries on rhesus monkeys is successful. Let’s assume that he is able to safely remove enough of the glial scar to allow the axons to regenerate and the test animals to recover some function. It’s a big assumption and it would be fantastic, but it wouldn’t be the end.
We can all see what the next questions would be. Could this work on chronic injuries that more closely match what most of us are up against — not nice clean hemisections, but messy contusions? Could it work if there was damage not just at the level of a single vertebra, but in more complicated situations with several sections involved? How might it be combined with one of the stimulation interventions, or with gait training or with cell transplants? Is there some point where an injury is “too chronic” (meaning, too far in the past) for this to be effective? At what point does it become risk-free enough for testing in humans?
The day is coming when we’re going to find out all of that and a lot more. The only question is when.
• Proceedings of the National Academy of Sciences of the USA, May 29, 2018, pnas.org/content/115/24/E5595
• Proceedings of the National Academy of Sciences of the USA, Oct. 27, 2015, ncbi.nlm.nih.gov/pubmed/26460015
• Nature, Jan. 13, 1994, ncbi.nlm.nih.gov/pubmed/8114912