Nerve Repair Pathways
When you get a cut on the tip of your finger, new peripheral nerves are usually able to develop and make connections with other nerves restoring the feeling to your fingertip. This process is known as nerve regeneration. However, this process does not occur in the case of stroke, brain or spinal cord injury, where useful function is often permanently lost because damaged nerve cells are unable to regrow their connections. Furthermore, uninjured nerve cells are often unable to form new connections to compensate for ones that have been lost.
For many years researchers have been investigating ways to improve outcome following injury to the CNS. Two such strategies are axon regeneration and neuroprotection. In acute CNS injuries such as spinal cord injury or stroke, neuroprotective strategies seek to minimize functional loss by preventing further tissue damage. Conversely, axon regeneration strategies seek to restore sensory and motor function lost as a result of injury by reconnecting the neural pathways through new axon growth.
Two opposing biological pathways seem to control the CNS's ability to regenerate its lost neuronal connections. In order to allow the axon regeneration process to progress, either activation of the pathways that stimulate axon growth (pro-regenerative) or inactivation of the pathways that normally prevent the growth of axons (anti-regenerative) must occur.
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The Pro-regenerative Pathway
Recent evidence shows that mature nerve cells can be stimulated to re-establish and grow new connections under certain circumstances. Axon re-growth can be stimulated by a variety of growth factors and other naturally occurring agents. Dr. Larry Benowitz and his team at Children's Hospital Boston have had success in re-growing axon connections with several naturally-occurring stimulators of axon regeneration: inosine (a purine nucleoside), mannose (a simple sugar) and oncomodulin (a small protein).
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The Anti-Regenerative Pathway
Inhibitors of regeneration, present in the cellular environment around the injury, are major obstacles to axon regeneration, particularly right after the injury. To date, three inhibitors in the myelin area of the neuron have been identified: Nogo, myelin-associated glycoprotein (MAG) and myelin-oligodendrocyte glycoprotein (OMgp). All three of these proteins exert inhibitory action by interacting with a receptor called the Nogo receptor (NgR). Other inhibitors of axon re-growth are P75/Troy, ephrin and compounds that interact with the Epidermal Growth Factor receptor (EGFR).
Promoting nerve cell growth by turning off or blocking these inhibitory signals is the focus of research conducted in the laboratories of Dr. Zhigang He, also at Children's Hospital Boston.
Acting as the master switch to these growth inhibitory interactions is Rho, a small GTPase. Turning off this switch using a molecule such as Cethrin, which is a Rho inhibitor, provides potential to promote nerve repair leading to functional recovery.
Therapeutic Possibilities for Axon Regeneration
The Rho-inhibitor Cethrin provides a potential "first-in-field" therapy for treatment of acute spinal cord injury. Cethrin is an investigational, recombinant fusion protein that may promote the regrowth of axons after a major injury to the spinal cord and is being evaluated in a Phase I/IIa Clinical Trial.
Alseres also has ongoing, sponsored-research programs for approaches to activate pro-regenerative pathways that stimulate axon regeneration led by Dr. Benowitz and for approaches to deactivate anti-regenerative pathways that inhibit axon regeneration led by Dr. He. This research would enable ALSE to identify other potential compounds that could promote axon regeneration following stroke, spinal cord or traumatic brain injury.
Recent research from these labs indicates that an approach that simultaneously stimulates the pro-regenerative pathway and inhibits the anti-regenerative pathway may provide much stronger regeneration than employing either one alone. The concurrent implementation of these sponsored research programs may open avenues for exploring combination therapies for intractable CNS disorders.
We believe these ground-breaking areas of research hold promise in advancing the development of "first-in-field" therapies targeted at restoring a variety of sensory and motor functions in patients after stroke, spinal cord, optic nerve and traumatic brain injuries.