Glaucoma affects more than 4 million Americans and is the major cause of blindness. But repairing the damaged optic nerve, which is the underlying cause of this disease in most instances, has eluded researchers. This is due to the intrinsic inability of the adult nervous system to regenerate.
Working in animal models, Larry Benowitz, PhD, director of the Laboratories for Neuroscience Research in Neurosurgery at Children’s Hospital Boston, and his collaborators made a major discovery in optic nerve regeneration in 2006. Their research implicated the inflammatory response as having a stimulatory effect on nerve growth.
Benowitz’s team pinpointed oncomodulin, a factor secreted by immune cells that enter the eye, as responsible for activating this growth. They would later show that at elevated levels, the signaling molecule cyclic adenosine monophosphate (cAMP) improved oncomodulin’s ability to bind to receptors on retinal neurons, further promoting cell growth.
Two years later, Children’s researchers Mustafa Sahin, MD, PhD, and Zhigang He, PhD, BM, in parallel research, demonstrated that deleting the gene encoding an enzyme called PTEN promoted moderate regeneration of the optic nerve. This might be expected considering the gene’s critical role as a brake in cell growth.
To restore vision, substantial growth of the optic nerve, enough to reach the brain’s visual cortices, is necessary. But the addition of oncomodulin, elevation of cAMP or the removal of PTEN alone did not stimulate enough optic nerve growth to reach the brain. Benowitz’s team theorized that targeting the two pathways simultaneously would achieve more substantial growth, potentially enough to re-establish vision.
The results were better than expected. Not only did targeting both pathways stimulate the regrowth of injured retinal nerve fibers over long distances, but rare fibers even reached deep within the brain to the visual processing centers of the thalamus.
“This is really a massive change,” says Benowitz.
Many fibers grew the length of the optic nerve and crossed into the base of the brain, where nerve fibers from the left and right eyes intersect at the optic chiasm. Benowitz, his first author Takuji Kurimoto, MD, PhD, and their collaborators outlined the achievements in a recent study published in the Journal of Neuroscience.
Benowitz’s lab is now investigating whether this regeneration improves vision in mice. They also hope to further stimulate optic nerve growth by adding a third approach to their current strategy: attacking inhibitory growth factors located outside the cell.