Ga Tech Researchers Make Headway in Treating Spinal Cord Injuries

[lunasicc42]

If chondroitinase was discovered decades ago... Thats even worse, that a Treatment with it isn't available yet.

[Wise Young]

Originally Posted by boda

I dont get it, this is safe in humans and it has been shown to reduce scar tissue. Why cant doctors give someone an injection, like they prescribe 4AP? Then go on lithium or growth hormone, and ride the FES bike or locomat. Its not a controlled experiment but, all of these things have shown potential to stimulate growth. If it didnt work out it would not kill us or cause cancer. We would also have the not so exciting benefits of FES or Locomat (ie blood circulation,weight on the bones, etc) and reduced scar tissue. i am sure there are plenty of people that would sign up for something like this and pay for it if they needed to just to see if it might work or help a little.

Boda,

Let me try to explain. To my knowledge, while I think that it has been injected into the spinal discs of humans, chondroitinase has never been injected into the spinal cord of humans. It is a bacterial enzyme. In fact, one of the best sources of chondroitinase is Proteus vulgaris, probably the second most popular cause of urinary tract infections (Escherischia Coli is the first). Because of this, it is likely that most people, particularly people with spinal cord injury, have been exposed to the bacteria and probably have antibodies against chondroitinase ABC. There is apparently no equivalent enzyme in humans. Yes, there are other enzymes, such as hyaluronidase, that can carry out similar functions but not as efficiently as chondroitinase. One assumes that bacteria use chondroitinase for the same reason that we want to apply it to the spinal cord for regenerating axons, i.e. to migrate through the extracellular matrix proteins in the tissues.

So, phase 1 clinical trials are needed to get chondroitinase tested for safety in human spinal cord. Who makes it and who is responsible for ensuring that it is safe? For many years, Seikagaku in Japan was the only source of GMP (good manufacturing practice) quality chondroitinase for animal studies. It is not a trivial task to isolate and purify this protein from bacteria while maintaining its enzyme activity or excluding all impurities that may stimulate inflammation and immune responses. The other problem that has plagued experimental use of chondroitinase for many years is the instability of the enzyme when it is in solution. This was the reason why many experiments in the 1990's failed to show any beneficial effect of chondroitinase in animals, even though it was showing good results in cell culture, because people were applying the enzyme to the spinal cord through various implanted pumps.

Phase 2 clinical trials are necessary to establishing the best dose, duration, timing, and administration of chondroitinase. Does one really have to inject it into the spinal cord (thereby making every treatment into an operation). How often does one have to do this? Does it work in subacute and chronic spinal cord injury? How long should one give it? How often should it be injected, i.e. every day, every week, every month? What is the best route of giving it? Does it work when given intrathecally? Most of these questions have not been thoroughly answered in animals and none have been answered in humans.

Phase 3 trials are essential to show that the treatment works and is safe. Such trials, because they involve surgery and rehabilitation of hundreds of patients probably will cost a hundred million dollars or more. In addition, before these trials can start, a company probably will have to invest several hundred million dollars into developing and testing procedures for manufacturing chondroitinase, to scale the manufacturing so that one can get kg quantities as opposed to mg quantities, and to optimize the drug and delivery to maximize pharmacokinetics, pharmacodynamics, and shelf-life of the drug. In order to get this kind of money to invest into its development, a company must have strong intellectual property protection for chondroitinase.

I agree with you that there should be lots of people willing to go for a spin with chondroitinase. By the way, rather than saying the whole long word, some people simply call this Chase. The fact that there are academic laboratories that are continuing to work on this drug is very good news because these kinds of advances are providing intellectual property protection for the eventual product. This protection is necessary to convince companies to invest the kind of money to get an enzyme product on the market. The discovery of a new form of chondroitinase that is resistant to heat, for example, is important because it makes it easier to make the enzyme for treatment of spinal cord injury.

Wise.

[lunasicc42]

thanks wise. Your response was to someone else but answered some of my questions at the same time.

[malthouse]

So it looks like we're pushing shit up hill then!!!

[Wise Young]

Originally Posted by lunasicc42

thanks wise. Your response was to someone else but answered some of my questions at the same time.

I hope that you are beginning to understand why I have been saying that there are many promising therapies, the real bottleneck are the clinical trials, and we must get the therapies to trial as soon as possible. If the treatment works, that is great. If it doesn't we go on to the next treatment.

wise.

[Wise Young]

Some one just asked what is the difference between chondroitin and chondroitinase.

Chondroitin is a chemical group that attaches to a compound called chondroitin-6-sulfate proteoglycan (CSPG). Chondroitinase is the enzyme that breaks that chemical down. CSPG is normally present in the boundaries of tissues. It stops things from growing across tissues boundaries.

Wise.

[patecatl]

ScienceDaily (Nov. 5, 2009) — Researchers have developed an improved version of an enzyme that degrades the dense scar tissue that forms when the central nervous system is damaged. By digesting the tissue that blocks re-growth of damaged nerves, the improved enzyme -- and new system for delivering it -- could facilitate recovery from serious central nervous system injuries.

http://www.sciencedaily.com/releases...1102171217.htm

The enzyme, chrondroitinase ABC (chABC), must be supplied to the damaged area for at least two weeks following injury to fully degrade scar tissue. But the enzyme functions poorly at body temperature and must therefore be repeatedly injected or infused into the body.

In a paper published November 2 in the early edition of the journal Proceedings of the National Academy of Sciences, researchers describe how they eliminated the thermal sensitivity of chABC and developed a delivery system that allowed the enzyme to be active for weeks without implanted catheters and pumps. This work was supported by the National Institutes of Health.

"This research has made digesting scar clinically viable by obviating the need for continuous injection of chABC by thermally stabilizing the enzyme and harnessing bioengineered drug delivery systems," said the paper's lead author Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

At physiological body temperature, chABC enzyme loses half of its enzymatic activity within one hour and their remaining functionality within three to five days. To thermostabilize the enzymes, Bellamkonda, Emory University cell biology associate professor Robert McKeon and Georgia Tech graduate student Hyun-Jung Lee mixed the enzyme with the sugar trehalose. The result -- the enzyme's activity was stabilized at internal body temperature for up to four weeks during in vitro tests.

The researchers then used a lipid microtube-hydrogel scaffold system to deliver the thermostabilized enzymes into animals via a single injection. The scaffold provided sustained delivery of the enzyme for two weeks, with the microtubes enabling slow release and the hydrogel localizing the tubes to the lesion site. This delivery system also allowed the enzyme to diffuse deeper into the tissue than did catheter delivery.

In animal studies, the enzyme's ability to digest the scar was retained for two weeks post-injury and scar remained significantly degraded at the lesion site for at least six weeks. The researchers also observed enhanced axonal sprouting and recovery of nerve function at the injury site when the thermostabilized enzyme was delivered.

The delivery system also enabled the combination of therapies. Animals treated with thermostabilized chABC in combination with sustained delivery of neurotrophin-3 -- a protein growth factor that helps to support the survival and differentiation of neurons -- showed significant improvement in locomotor function and enhanced growth of sensory axons and sprouting of fibers for the neurotransmitter serotonin.

"These results bring us a step closer to repairing spinal cord injuries, which require multiple steps including minimizing the extent of secondary injury, bridging the lesion, overcoming inhibition due to scar, and stimulating nerve growth," added Bellamkonda, who is also deputy director of research for GTEC, a regenerative medicine center based at Georgia Tech and Emory University, and a Georgia Cancer Coalition Distinguished Cancer Scholar.

This research was funded by Award No. R01 NS043486 from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NINDS or the NIH.

[malthouse]

OK, Beaut, lets get on with it then!!

[GRAMMY]

kinda frustrating...here we have the "new and improved" version but nobody is using the old original stuff ...

[George78]

Originally Posted by Wise Young

I hope that you are beginning to understand why I have been saying that there are many promising therapies, the real bottleneck are the clinical trials, and we must get the therapies to trial as soon as possible. If the treatment works, that is great. If it doesn't we go on to the next treatment.

wise.

Dear Wise,
Thanks for the explanations. May be clinical trials are the real bottleneck, but we right here must all admit that we all be dead before we finished with clinicals trials and have a therapy available for us poor chronicals. As I previously said, I have been to an hospital in Washington DC in 1980 to be involved in a surgery consisting in autologous schwann cells graft into the spinal cord (Dr. Carl Kao). 30 years later where are we??.. May be we made a step forward in understanding the mechanisms of the injury, but we made a serious step backward too because it's harder than never for us to be involved in a surgery. To my point of view, the Establishment sentenced us to die in very bad conditions instead of giving us the right to do something before we die. That's a shame. I think the real bottleneck for us is to find places in the world where doctors can propose *today* something they believe hopeful and let us decide ourselves, with good advices, to go or not to go. What do you think?.. Concerning chondroitinase, do you know if there's a place in the wolrd where chondroitinase therapy is available for humans?..
Many thanks
George