Regeneration evolving in steps

Chicago-Achieving optic nerve regeneration is far from becoming reality. However, there has been encouraging progress in recent years toward addressing the multiple challenges that must be overcome to reach this goal, said M. Francesca Cordeiro, MD, PhD, at glaucoma subspecialty day during the annual meeting of the American Academy of Ophthalmology.

"Successful optic nerve regeneration requires maintaining viability of the damaged neurons, promoting re-elongation of the surviving neurons' fibers and their penetration through scar tissue, as well as overcoming the influence of growth inhibitory signals that interfere with axonal fiber growth back to the brain," said Dr. Cordeiro, professor of retinal neurodegeneration and glaucoma studies, University College London Institute of Ophthalmology, England. "In addition, guidance signals are needed to ensure the nerve fibers re-form functional connections with their original target.

"Recent work from investigators around the world shows advances in the first three areas," Dr. Cordeiro continued. "However, achieving vision requires integrity of the long, complex pathway from the eye all the way to the occipital cortex. There are problems to surmount at each stage of the axon's transport path where unique sets of mediators are needed to allow nerve regrowth and guidance, and it takes a very long time to get a good functional synapse and to pass through the multiple synapses necessary to reach the occipital cortex. At present, encouraging axonal growth back to the cortex and maintaining a functionally intact pathway remain major barriers."

Reviewing recent literature on regenerative optic nerve strategies, Dr. Cordeiro cited a paper published in 2010 by Lloyd and co-workers that has shed insight on the signaling that directs regeneration of peripheral nerve axonal fibers. These investigators have focused on the idea that cross-talk is required between the Schwann cells, which dedifferentiate to a progenitor/stem cell and promote axonal growth, and fibroblasts.

"This has been a real step forward in understanding the molecular mechanisms involved in peripheral nerve regeneration," said Dr. Cordeiro, who also is honorary consultant ophthalmologist, Western Eye Hospital Imperial College Healthcare Trust, London.

Another paper from 2010 by Benowitz and coworkers reported success in achieving long-distance axon regeneration in a mouse model of optic nerve axotomy. These investigators reported axonal growth to the brain could be stimulated using a variety of strategies, including injury to the crystalline lens to induce an intraocular inflammatory response in the eye with intracellular elevation of cAMP and use of oncomodulin, a calcium-binding protein.

In 2008, Chen and Cho reported on use of a pharmaceutical approach to promote optic nerve regeneration in a mouse eye model of optic nerve crush injury. These investigators demonstrated pharmacological modulation delivered to the site of injury with the combination of lithium, which induces Bcl-2 expression (a protein important in nerve regeneration), and astrotoxin, which suppresses scar formation, promoted nerve fiber growth back to the brain.

A few years earlier, Ellis-Behnke et al. reported success using a peptide nanofiber scaffold for achieving brain repair and axon regeneration with return of functional vision in hamsters with a severed optic tract. In a paper in press, Dunlop and Harvey report that use of olfactory ensheathing glia at the site of the injury promoted axon regeneration into the optic chiasm.

Dr. Cordeiro also mentioned a 2010 paper by Field et al. that provided the first report of success in achieving good functional connectivity between photoreceptors and retinal ganglion cells.

"This is good news from research involving another area of the visual system," she concluded. "It suggests that, for now, research on nerve cell regeneration might be better to focus on the photoreceptor."

fyiM. Francesca Cordeiro, MD, PhDE-mail: m.cordeiro@ucl.ac.uk

Dr. Cordeiro has no financial interest in the subject matter.