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Major Recent Advances in Spinal Cord Injury Research
Wise Young
http://keck.rutgers.edu/
It is difficult to choose a few seminal articles that represent the entire field of spinal cord injury. Therefore, I will instead talk about five major advances that I consider to be the most hopeful.
1. Combination of embryonic stem cells and growth factors can produce motoneurons in the spinal cord that can reinnervate muscle. This work from Douglas Kerr and his colleagues at Johns Hopkins used the combination of embryonic stem cells pre-differentiated with retinoic acid and sonic hedgehog, and rolipram and db cAMP allowed the establishment of over 4000 motoneurons in rats and some of these motoneurons sent axons out of the spinal roots to reinnervate muscle and restore function. This is the first time that functional regeneration of motoneurons have been reported in muscle. It is a very exciting finding.
2. Combination therapies are producing better regeneration than monotherapy. Many examples of this now have been reported. I will only list the first three that come to mind. First, Xu from Louisville who reported several years ago that combination of Schwann cells, several neurotrophins, and chondroitinase are much better in stimulating spinal axonal regeneration. Second, Pearse and Bunge from the Miami Project reported that combination of Schwann cells with db cAMP and rolipram produced the best regeneration. Although these results have not yet been replicated by other groups yet, Kerr's work (cited above) used cAMP and rolipram to stimulate motoneuronal growth. Finally, there is the work by Yick, Wu, and So in Hong Kong University showing the combination chondroitinase and lithium work better than either of the therapies alone. The last is particularly exciting because lithium has long been used to treat manic depression and we recently found that it strongly stimulates expression of BDNF, NT-3, and GDNF, the combination of growth factors that Xu found to stimulate regeneration.
3. Myelination of spinal axons. Many cells have now been reported to remyelinate spinal axons. These include Schwann cells, oligodendroglial precursor cells obtained from embryonic or fetal neural stem cells, olfactory ensheathing glia, and even enteric glia (this latter is unpublished work from our laboratory). Remyelination is one of the crucial goals of spinal cord injury and multiple sclerosis research. So, the knowledge that not just one but four different kinds of cells can engage in robust remyelination of spinal axons is very hopeful indeed.
4. Reversal of axonal growth inhibitors. In the nearly two decades since Martin Schwab first reported that there is a protein called Nogo in myelin that inhibits axonal growth, we now have four different practical therapeutic approaches to reversing the effects of Nogo and other axonal growth inhibitors. This includes antibodies against Nogo itself (called IN-1, this is now in Phase 1 clinical trials in Switzerland), a bacterial toxin called Cethrin that blocks the intracellular messenger Rho mediating the inhibitory effects, Nogo receptor blockers (including Nogo-66 and antibodies against a co-receptor Lingo), and chondroitinase (a bacterial enzyme mentioned above that breaks down chondroitin-6-sulfate-proteoglycan). All these have been reported to regenerate the spinal cord in rats.
5. The discovery that over 90% of people with "incomplete" spinal cord injury can recover locomotion through intensive ambulatory rehabilitation after injury. For a long time, only about 40% of people who are "incomplete" after spinal cord injury recovered walking. Now, it seems that a vast majority of people with "incomplete" spinal cord injury can recover walking. The goal of regeneration is of course to make people more "incomplete". This suggests that the combination of regenerative therapies, remyelination, and rehabilitation will restore function to people. Finally, there may be some therapies that will help such rehabilitation along, including stimulation of the lumbar locomotor pattern generator and 4-aminopyridine.
We now of course must get these therapies into clinical trials and show that they are effective. Given the minimal funding of spinal cord injury clinical trials, few of the therapies have reached people so far. There is increasing interest from major pharmaceutical companies in spinal cord injury therapies. There is a lot of work to do but the path and direction is clear. We need to work fast and hard.
© 2006 Wise Young.
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