Scientific Method —

See, blind mice? Mouse eyeball drug restores light sensitivity

Light-sensitive chemical triggers nerves even when rods and cones are absent.

In some forms of blindness, notably retinitis pigmentosa and macular degeneration, the loss of vision is caused by the death of the rod and cone cells that actually sense light; the rest of the eye and visual system remains largely intact. This allows electrode implants to activate the nerves that relay signals from the eye on towards the brain, providing some hope of restoring vision. Now, researchers have figured out a clever way to get rid of all the hardware. They've tested a light-sensitive chemical that sticks to proteins on nerve cells and causes them to fire off a nerve signal in response to light. When it's injected into the eye of otherwise blind mice, the chemical restores some light sensitivity.

The chemical in question is called AAQ (short for acrylamide-azobenzene-quaternary ammonium), and its activity on nerve cells was first described in 2008. In one of AAQ's forms, it binds to a protein that lets potassium ions into the cell, which makes nerve cells more likely to fire. In an alternate configuration, the molecule allows the ions to flow, causing nerve cells to shut down. The key feature of the molecule is that it's possible to switch AAQ between these two states using light: short wavelengths push it into the form that starts up potassium flow, while longer wavelengths cause it to switch back to shutting ion flows down.

To test whether this might work in the eye, the authors used mice that were engineered to carry mutations that cause the same defect that triggers retinitis pigmentosa in humans. (In addition, a second mutation knocked out an alternate pathway for sensing light.) Retinas obtained from these mice showed no response when exposed to light. But, once AAQ was added to them, there was a clear increase in activity when a light source was pointed at the retina.

There was a bit of confusion, in that the behavior they saw was the opposite of what they expected: short wavelengths seemed to activate the cells of the eye, when they should have been shutting them down. The researchers showed that AAQ was actually active in inhibitory nerves, those that shut down the activity of their neighbors. So, the short wavelength light was actually triggering nerve activity by blocking this inhibition. This isn't at all how normal vision functions, but it still seemed to get the job done.

In any case, it seemed like the switching on and off of the molecule was enough to have an effect, since broad-spectrum white light also produced a general increase in activity in the retinas.

With that success in hand, the authors turned to actual mice, injecting AAQ directly into the eye, and then exposing them to light. Mice are nocturnal, and generally do their best to avoid light, but the mutant mice were completely indifferent to it. Adding AAQ to the retinas restored their aversion. When exposed to light at one end of a tube, the mice quickly retreated to the middle of the tube. And the mice were much less active in a well-lit cage than they were in a cage left in the dark.

The authors don't perform any tests of visual acuity, and it's not possible to ask a mouse how well it sees, so it's impossible to say quite what was restored by the drug. But there are reasons to think that the performance should be pretty good. For example, the authors see a light response time that's on the order of a few dozen milliseconds, which is not too bad compared to the normal biology. And there appears to be decent spatial resolution, as experiments with a narrow beam of light showed that the response was triggered specifically in the area that was directly exposed to the light

The authors of the paper recognize that a number of research groups are testing alternate approaches to hacking into the remaining wiring in the eye, so they spend most of the discussion comparing and contrasting AAQ with alternatives like electronic implants and using viruses that encode light-sensing proteins. There are good and bad aspects to all of them, but the authors point out that a small chemical is the least invasive of them, in that you can simply stop the drug if anything odd happens. Plus, if better versions of the chemicals become available—like a cocktail that covers a broad spectrum of light—switching over to them should be simple.

That said, the drug is only effective for about 24 hours, and was directly injected into the eye, so it's not exactly the ideal solution.

In any case, as the authors note, the real test will be when this chemical is used in primates, where we can actually understand a bit about what this drug does in terms of restoring actual sight.

Neuron, 2012. DOI: 10.1016/j.neuron.2012.05.022  (About DOIs).

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