One of the most compelling spinal cord research stories of the past year centers on an enzyme called chondroitinase. Its primary target is chronic SCI – that in itself is big news since most SCI science has been about acute care and almost never about long-term injuries.
Ch’ase seems to restore function, scientists seem to understand how it works, and a private company is involved in bringing it to market. Looks ready for people? Not quite, and here’s why, after a bit of background.
In animal models of spinal cord injury, ch’ase digests chondroitin sulfate proteoglycans (CSPGs), inhibitory molecules that form a sort of scar in the area of trauma. Getting rid of these inhibitors permits nerve growth (plasticity in the form of sprouting) and restores function. Numerous independent labs have confirmed the results. Ch’ase has worked on rats and cats; other larger animal studies are in the works. Several important research projects were published in 2011, all attesting to what might be a huge upside for the enzyme:
Ch’ase with NT3 and a nanofiber scaffold
Ch’ase promotes recovery in cat
Ch’ase with rehab training
, and again
Ch’ase with olfactory ensheathing glial cells
Ch’ase with stem cells
Ch’ase as a neuroprotective
Ch’ase with tissue plasminogen activator
Case Western Reserve scientist Jerry Silver reported last summer
that his team restored breathing in paralyzed rats using a nerve bypass and ch’ase. “It's pretty amazing,” said Silver. “Our work is to-date one of the most convincing demonstrations of the return of robust function after paralysis.” That work was funded in part by the Reeve Foundation. Silver was the first to identify CSPGs in the rat cord, more than 20 years ago. He’s been on the trail of ch’ase for most of that time.
In London, the James Fawcett lab, one of six labs that form the Reeve Foundation International Research Consortium on Spinal Cord Injury, reported significant plasticity of spinal cord nerves in a chronic model
. Fawcett’s group patented the form of ch’ase that relates to plasticity. That patent was licensed to Acorda Therapeutics, the New York biotech that brought the drug 4-AP to market as Ampyra.
The ch’ase clinical story picks up with Acorda
, founded on the basis of discovering therapies for spinal cord injury. The company likes ch’ase and its commercial potential. Said Acorda founder and CEO Ron Cohen: “I personally am the most excited about the potential for chondroitinase relative to other pipeline products at Acorda.”
But there are a few things to work out. I spoke with Chief Science Officer Andy Blight. He explained that the company first got interested in ch’ase because of Silver’s work. “Eight or nine years ago,” said Blight, “we asked the question, ‘what looks most promising to treat spinal cord injury, particularly other than immediately after injury.’ It was pretty clear to us, based on all the published data available, that chondroitinase really was a promising approach. Our concern is mainly on the practical side – it’s fine to have all the promising experimental data on rats but how do you actually produce this to use it in people, and how do you actually use it in people.? Those are far from trivial issues.”
Blight says ch’ase is normally made from bacteria. Until recently, a Japanese company called Seikagaku used this method to supply the native ch’ase enzyme to the research world; the company is longer marketing it. Acorda chose to go a different route: they obtained the DNA sequence for the enzyme and made it recombinantly. The idea, said Blight, is that the enzyme might be more controllable that way. (Acorda makes its version of ch'ase available to the research community.)
Said Blight: “We’ve gone off to play with the structure to see if we can identify parts of the molecule that are perhaps unnecessary – to trim in down a bit, or to make parts of it better as a therapeutic. One of our early tasks was to make it more stable. One of the problems with the native enzyme is that when you raise it to mammalian body temperature it tends to degenerate rather rapidly. That means if you want long-term digestion of the proteoglycans you have to keep dosing it repeatedly.”
Blight said the company has succeeded in making the enzyme more stable at physiological temperatures.
“The other issue now is that it’s hard to see how the enzyme will be usable in a large animal or human. The data show, and it’s not clear why, that the enzyme does not travel through the nervous system very effectively. From what people have been able to see so far is that chondroitinase really only moves a fraction of a millimeter through the tissue and then stops. We’re trying to understand how big an issue this is for potential therapeutic application. What stops the enzyme from diffusing into the nervous system? If you are dealing with a spinal cord that is several millimeters thick, then it’s hard to see how to get the enzyme where you need it, which is probably in the grey matter, in the middle of the cord.” This, said Blight, “remains a bit of a challenge.”
In some animals models ch’ase is injected directly into the spinal cord. There is a lot of concern about putting needles into the human cord.
What makes ch’ase so vital for the SCI community is that it’s intended for chronic injuries. Said Blight, “A number of studies indicate that this can produce beneficial effects in the chronic state. Dena Howland [University of Florida], for example, did some work with cats with spinal cord injury, looking at their locomotion; hers were quite chronic interventions that showed recovery of function. The work Jerry Silver is doing is also pushing the time [between injury and treatment] out. I think it is pretty clear that you can have long term effects with very delayed treatment, in the chronic situation, where people are very stable in terms of their neurological deficits.
“I don’t think there’s a huge limitation in terms of time after injury. The limitation is in terms of what you can expect with this. Early on I think people thought we were dealing with something that would enhance long distance regeneration. But the more people have looked at it, the real power of this enzyme approach is not so much in regeneration but in plasticity. It really seems to enhance the ability of the surviving pathways to do more. It removes some of the rigidity in the connections that are normally there, especially in the spinal cord. It allows more adaptive changes. And it goes along with what we’ve seen anatomically.
“I don’t think we’re looking at this as something that’s going to produce large-scale, long-distance regeneration as much as it’s going to enhance the ability of the nervous system to use what remains connected. Our original idea was that ch’ase would attack the scar tissue in the lesion area and thus allow the nervous system to grow back to its normal state. But I think that’s an ambitious reading of what it can do. Most of the behavioral data that has come out can be explained more readily in germs of relatively short distance sprouting of nerve fibers from surviving systems. That also correlates to the histology that’s being done.”
Blight said the notion that ch’ase has an effect closer in to the lesion area has implications for who would be a good candidate for this treatment. It appears cervical injuries might be best. “Here you have circuits related to control of upper limb,” said Blight. “You’re dealing with relatively short distance connections. It seems very possible you could enhance upper limb function in someone who was tetraplegic – but not necessarily affecting the lower limbs. It might be possible to stimulate the reconnection relay systems to pass signals from the brain to lower limb circuits. It’s all theoretical at this point. We don’t know what the limitations are.
“This is a tough one,” said Blight. “Right now, while it’s probably easier to study this in a cervical injury as opposed to thoracic injury, there’s certain reluctance on the part of the community of basic researchers in the field to use more invasive or biologic therapies in cervical complete injuries, or cervical incomplete for that matter, because there is the risk people could be made worse off.”
While a thoracic injury might be a safer model to try, it may not produce significant recovery of function and therefore won’t reveal as much. “It seems that thoracic injury is unlikely to be a good target for initial proof of principle. In that case you’d more or less have to have long distance growth to see anything useful out of it.”
So, what has to happen? More R&D? Funding?
Said Blight, “We are learning more and more. We’re also looking for other ways to deal with the proteoglycan issue other than using the enzyme. The enzyme, now, is the most obvious way but it’s something of a brute force method. As we learn more and more about the molecular inhibitions of growth by the proteoglycans, the likelihood is that we will come up other more subtle ways of working with that.”