There was a palpable air of excitement among spinal cord researchers at the conference, even with the news of Christopher Reeve’s death. A series of important findings from basic science has fueled newfound optimism that, finally, science is making some headway toward reconnecting the brain and the body.
Repairing and rewiring the injured spinal cord is a complex, multidimensional puzzle (see sidebar, “What Will It Take?”). In animal models, properly timed combinations of therapies have shown the greatest benefit, and that is the direction the field is taking. Still, one central problem must be solved in order to restore function from paralysis: getting nerve fibers to regrow.
The post-injury spinal cord is hostile territory to these nerve fibers, or axons. Proteins that repel and thwart their advance are abundant, in both the “glial scar” that forms after an injury, and, counterintuitively, in the myelin that normally supports axon functioning. In this battle between axon and “inhibitors,” the axon loses.
Scientists have been working on the “inhibition problem” for two decades, ever since it became clear that there was something in myelin that stopped axon growth. The eventual identification of three groups of inhibitory molecules in myelin—“Nogo” and its cousins—and the subsequent discovery of the Nogo receptor to which these molecules bind to do their dirty work set off a race to develop a drug that could block the receptor and remove the brakes on axon growth.
These efforts are beginning to come to fruition, with human clinical trials of the first “Nogo blockers” likely within a year or two.
The glial scar has its own army of inhibitory soldiers, and a growing body of research is providing clues about how to strike back at these targets as well. Many studies show that nerve regeneration is enhanced in the presence of an enzyme called chondroitinase, which promotes the cellular digestion of inhibitory molecules in the scar—essentially neutralizing the bad guys. Jerry Silver’s group at Case Western Reserve University has used chondroitinase in combination with a yeast carbohydrate (zymosan) to induce “the most robust nerve regeneration I’ve ever seen” in an animal model of spinal cord injury. The zymosan, he says, acts like “high-test fuel for nerve fibers.”
From these two arms of inhibition research, the need for multiple therapies becomes crystal clear, and combination therapies bring their own challenges for bioengineering and drug delivery. But what if there were a way to knock down all of the inhibitors with one blow?
According to Marie Filbin of Hunter College, who delivered a special lecture on spinal cord repair, it is likely that “all the inhibitory molecules converge somewhere. We just have to find where and block it.”
Going Where Nogo Has Not
Filbin’s team has looked beyond the Nogo receptor to search for just such a common pathway and has focused in particular on an important signaling molecule called cyclic AMP, or cAMP. Recent studies have shown that increasing the level of cAMP in nerve cells encourages axon regeneration. In two of these, reported separately by Filbin and Mary Bunge at the Miami Project to Cure Paralysis, dramatic functional improvement was achieved in animal models of spinal injury by ramping up cAMP as part of a combination therapy. Taken as a whole, the data provide convincing evidence that increasing cAMP is a strategy worth pursuing. (See sidebar: “The Rolipram Quandary.”)
Still, a fundamental question has remained: how does cAMP enhance nerve growth? Could it be acting on some final pathway that may hold the key to developing a kind of smart bomb that knocks out the operations base for the army of inhibitors? To find out, Filbin’s group and others are teasing apart the molecular pathways by which an elevation in cAMP leads to nerve regeneration. How is cAMP processed inside nerve cells? What genes are turned on or off, and how? What are the consequences of the protein those genes kick out into the nerve cell?
In the process of unraveling this cascade of molecular and genetic events, Filbin has identified a number of molecular targets where novel pharmaceutical compounds might be applied.
“Ten years ago, there was only one therapeutic target: what we now know to be Nogo,” says Filbin. “Now, we have a multitude of different molecular actions where we can intervene.”
In other words, current research may be the advance work for a new generation of “anti-inhibitory” drugs that go where Nogo has not.
|Scientists are working on ways to promote the regrowth of nerve fibers called axons after a spinal cord injury. They have identified various molecules that inhibit such regrowth and are now searching for drugs that can overcome these inhibitors.|
© Jill K. Gregory, CMI; firstname.lastname@example.org
WHAT WILL IT TAKE?
If it seems like new therapies to repair the injured spinal cord have been slow in coming, consider the enormity of the challenges:
1. Prevent cell death. In the immediate aftermath of an injury that severs or crushes the spinal cord, nerve cells and their fibers (axons) die off in the sur-rounding area. So, job number one in the case of an acute injury is to keep these cells from dying.
2. Stop the scar. Next, a scar or cyst forms around the injury site, as if the body were attempting to seal off the damage. The scar, comprised of brain support cells called glia, contains inhibitory proteins that form a biochemical barrier to block axons’ growth. So step two is to somehow prevent this "glial scar" from forming, or, barring that, to find a way through or around it.
3. Overcome the inhibitors. A slew of molecules within myelin, the fatty sheath that envelops axons and normally enhances their transmission of nerve signals, act like stop signs to growing nerves, thwarting their progress. These "myelin inhibitors" must therefore also be overcome.
4. Reconnect. Axons that do manage to regrow need guidance. They need to find their way past the point of injury and reconnect to the right nerve targets on the other side.
5. Re-establish communication. It is not enough for axons simply to grow in the right direction. They also have to form functional synapses with other neurons, re-establishing the biochemical and electrical signal-sharing that underlies all nervous system function.
6. Remyelinate. New axons, as well as any whose myelin coating was damaged as a result of the injury, must be resheathed to ensure optimal transmission of neural signals.
7. Rehabilitate. Finally, there remains the huge challenge of functional rehabilitation. The person with the injury will most likely need to relearn basic movements, such as reaching an arm toward a specific target, or putting one foot in front of the other to walk.