A blind man sees his fiancée’s smile for the first time. Another walks around at night, navigating via streetlamps and headlights. Yet another reads his own name (and spots a typo). All three had lost their sight years before, as an inherited disorder destroyed the light-sensing cells of their retinas. But they had since been fitted with retinal implants that took over from the broken cells, sensing incoming light, and converting it into electrical impulses delivered to the brain. The devices are a long way from 20/20 vision, but they have nonetheless restored sight to those who had lived without it for years.
These retinal implants seem miraculous, but they have a major drawback: they rely upon a working optic nerve. This is the main communication line between the eye and the brain. If it’s damaged, no amount of retinal techno-wizardry will help. And that’s bad news for people with glaucoma, the world’s second leading cause of blindness, which wrecks the optic nerve.
But even for those people, there is hope. Silmara de Lima from the Children’s Hospital in Boston has found a way of regenerating the optic nerve in adult mice, partly restoring their vision. Although his techniques cannot be used directly in humans, they provide an important proof of principle that optic nerve injuries can be reversed. We just need to figure out how.
The retina consists of different layers of cells, signalling to one another in an electrical relay race. The first runners are the light-detecting rods and cones. The last ones are the retinal ganglion cells (RGCs), which extend long fibres (axons) into the brain. These axons form the optic nerve.
If retinal ganglion cells are damaged through injury or disease, their axons don’t grow back, leading to permanent blindness. But according to Larry Benowitz, they just lack the right encouragement. Over the years, his team has showed that inflamed eyes naturally accrue substances that shunt the retinal ganglion cells into an actively growing state. These substances include oncomodulin, a protein secreted by white blood cells.
Based on this discovery, Benowitz’s team has managed to persuade retinal ganglion cells into growing fresh axons using three steps. First, they inject an inflammatory substance that raises oncomodulin levels. Next, tey add a signalling molecule called cAMP that augments oncomodulin’s effect. Finally, they shut off a gene called PTEN that normally holds back the growing axons.
Now, de Lima, working in Benowitz’s lab, has shown that the growing neurons they go all the way. He delivered the three-step treatment to mice with damaged optic nerves. After 10 to 12 weeks, their freshly sprouting axons had completed the long trek to the brain. In 13 of the 15 mice, the fibres also connected to the right areas: the ones responsible for processing visual information.
As a result, they aced several tests designed to see if their vision partially returned. They were better able to adjust their body clocks to changing patterns of light and dark. Their pupils widened and narrowed in response to changing light levels. They fell for an optical illusion that mimicked a steep drop, preferring to stay in the ‘shallow’ end’.
“This paper presents a convincing and important step towards regeneration and reconnection of the optic nerve,” says Eberhart Zrenner, who works on retinal implants. However, he notes that the methods are a long way from clinical use.
De Lima is very clear on this point. “The methods used here cannot be applied in the clinic,” he says. Triggering inflammation in the eye could damage the lens and retina. Shutting off PTEN, which protects cells from cancer, could increase the risk of tumours. The risks, he says, are “unacceptable”.
But de Lima argues that subtler approaches might work. For example, some scientists have managed to correct genetic diseases of the eye by using viruses to deliver working copies of faulty inherited genes. The same approach could be used to shuttle in oncomodulin without inflaming the rest of the eye, or temporarily repress the PTEN gene, without permanently putting it out of commission.
Reference: De Lima, Koriyama, Kurimoto, Oliveira, Yin, Li, Gilbert, Fagiolini, Martinez & Benowitz. 2012. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviours. PNAS http://dx.doi.org/10.1073/pnas.1119449109
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