Dong Feng Chen

A Journey Towards Repairing a Damaged Optic Nerve 

The optic nerve is a cable of nerve fibers that carry electrical impulses, containing visual information, from the eye to the brain. In adult mammals, any damage to the optic nerve caused by injury or disease tends to be permanent, because the cells that form the optic nerve cannot regenerate or repair themselves.This is why glaucoma and other diseases that involve optic nerve damage, such as optic neuritis and optic nerve trauma, lead to permanent loss of vision.

Similarly, nerve fibers in the brain and spinal cord share this common tragic feature of not being able to regenerate. This is most unfortunate, as a capacity for successful nerve regeneration is a necessity for restoration of function following damage, through accident or disease, to the human brain and spinal cord. Success of optic nerve regeneration might also open the door to future strategies of eye transplantation.

Scientists around the world are working hard to find a way to regrow the optic nerve. In addition, because of its easy access, the optic nerve has long served as a standard model for the study of spinal cord injury and regeneration in lab animals.

Only recently has it become accepted that the failure of the optic nerve to regenerate is not a single-factor event. Successful restoration of vision after optic nerve injury can be divided into five necessary steps: (1) First, damaged neurons must be able to stay alive. (2) The surviving neurons have to be reprogrammed to turn on their growth machinery for nerve re-elongation. (3) The regrowing nerve fibers should be able to penetrate injury-generated scar tissue. (4) The regenerating fibers must overcome growth-inhibitory signals on the path they navigate. (5) Finally, the fibers also have to be guided back appropriately to their original target to re-form functional connections. Each of these steps presents a great challenge to our efforts to repair an injured optic nerve.

In the past, most attempts to promote optic nerve regeneration focused on only one of these steps. Some success in optic nerve regeneration, albeit very limited, was achieved: For example, Aguayo’s group [reference 1] performed a study using growth factors, such as brain-derived nerve growth factor, to support neuron survival (targeting step one). They demonstrated a significant increase in the number of neurons surviving after injury; however, disappointingly, they found little improvement in optic nerve regeneration beyond the site of the injury. To address step two, Monsul and Hoffman [2] in the Neuro-ophthalmology Laboratory at Johns Hopkins University injected cyclic adenosine monophosphate (cyclic AMP) into the vitreous of mice to boost the neurons’ intrinsic growth potential for nerve re-elongation. They found that cyclic AMP was effective in inducing a small number (less than 1 percent) of nerve fibers to regenerate, but only for a short distance (up to 1 mm), through the crush site. To target steps three and four, Lehman and colleagues [3] used an enzyme called C3 to enhance neurons’ ability to penetrate glial scars and, at the same time, block nerve-growth inhibitory signals. They found that about 0.5% of nerve fibers regenerated within the injured optic nerve. Similarly, in collaboration with a group at Children’s Hospital (part of Harvard Medical School), my lab [4] showed that blocking EGF-receptor signaling suppressed neurons’ responses to glial scars and to nerve-growth inhibitors. As a result, approximately 0.5% of severed optic nerve fibers regrew past the injury site and elongated up to 2 mm.

Recently, my laboratory achieved an important breakthrough by using combined approaches that simultaneously targeted the first three steps required for optic nerve regeneration. We demonstrated [5] that 40-70% of optic nerve fibers regenerated from the eye all the way into the brain (about 7 mm) in mice, at ages up to two weeks after birth; this is at a time when nerve-growth inhibitors have already appeared in the mouse brain. We are now planning further studies to overcome the fourth and fifth barriers to optic nerve regeneration, and we hope that functional restoration of sight after optic nerve injury may become possible in the near future, first in mice and then in people.

With recent progress in stem cell research, neural stem cell therapy is emerging as a new approach that may be promising for restoration of sight after optic nerve injury. Attempts have focused on activating dormant stem cells, already present in the eye, to participate in the repair process in response to injury. In addition, it may be possible to harvest and transplant donor stem cells into the eyes of patients whose optic nerves have been injured, to replace the neurons that have been lost or to provide a permissive environment for nerve regrowth. Although these studies are still in their infancy, the field is progressing rapidly and may soon turn the stem cell approach into a viable therapy.

References:

1. Mansour-Robaey S., Clarke DB, Wang YC, Bray GM, Aguayo AJ. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994; 91:1632-6.

2. Monsul NT, Geisendorfer AR, Han PJ, Banik R, Pease ME, Skolasky RL Jr., Hoffman PN. Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol. 2004;186:124-33.

3. Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G, McKerracher L. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci. 1999; 19:7537.

4. Koprivica V, Cho KS, Park JB, Yiu G, Atwal J, Gore B, Kim JA, Lin E, Tesser-Lavigne M, Chen DF, He Z. EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans. Science 2005; 310,106-10.

5. Cho KS, Yang L, Ma HF, Lu B, Huang X, Pekny M, Chen DF. Re-establishing the regenerative potential of CNS axons in adult mice. J Cell Sci. 2005; 118, 863-872.