First light: Vision restored in blind mice

Regenerating nerve fibers from the retina (shown in red) are seen coming into the dorsal lateral geniculate nucleus, a principal visual relay area of the brain.

Some kinds of vision loss are reversible: Lucentis and Avastin can restore some visual acuity in macular degeneration, and gene therapy in the eye has had success in genetic forms of blindness like Leber’s hereditary neuropathy, affecting light receptors in the retina. But when the optic nerve is damaged – from a traumatic injury or from glaucoma — all bets are off. The eyes may take in visual information, but it can’t get to the brain. It’s the end of the road.

Larry Benowitz, PhD, and other neurobiologists at Boston Children’s Hospital and elsewhere have tried for years to rebuild that road. Regeneration of the optic nerve, and in the central nervous system in general, was once thought impossible. But through patient tinkering to coax natural growth signals and silence growth-inhibiting signals, neurons in the retina – known as retinal ganglion cells — began to grow a bit into the optic nerve. Then a bit more.

In a 2010 paper, Benowitz’s team combined their top three interventions, and showed a synergistic effect – the greatest growth of optic nerve fibers (axons) to date. But no one had been able to demonstrate recovery of vision after severe optic nerve damage – until now.

Axons extend the full length of the optic nerve in this treated mouse.
Axons extend the full length of the optic nerve in this treated mouse.

“Getting axons to grow down into the brain is the first hurdle,” says Benowitz. “In order for nerve signals to get propagated properly along nerve fibers, the fibers have to get sheathed – wrapped in myelin. Can these axons come into the brain and wire up properly? Can they form synapses again? Finally, most importantly, will this restore any kind of function?”

Benowitz’s team, with a few tweaks to the approach used in 2010, managed to do all of this in blind mice. Damaged optic nerve fibers not only regrew all the way from the retina to the visual areas of the brain, but restored some basic elements of vision: rudimentary motion detection, depth perception and light-based circadian rhythms.  Here’s specifically what happened:

>>>In this “visual cliff” experiment, mice were made to walk on clear plexiglass platforms above a checkerboard pattern that appeared to drop off abruptly. Untreated blind mice were just as likely to walk over either end of the platform, whereas mice with regeneration avoided the “deep” end, suggesting they’d gained at least some depth perception.


<<<In this experiment, blind mice were put on a platform surrounded by rotating vertical stripes. Those given the regenerative treatment moved their heads reflexively to follow the pattern; controls did not.



In circadian activity experiments, mice blinded by optic-nerve injury, kept in a room with an artificial day/night cycle (lights on at 7 a.m., off at 7 p.m.), drifted out of synch with that cycle when left untreated. In contrast, treated mice came back into synch with the light cycle, though their times of peak activity were still delayed compared with normal mice:

Circadian activity image

Benowitz doubts his team went so far as to restore the ability to discriminate objects. “What lies behind what we call seeing is very complicated – so many subsystems contribute to seeing,” he says. “We’re in a sense just scratching the surface about functional recovery.”

Plus, his approach in mice — detailed in the Proceedings of the National Academy of Sciences and in this press release – would need a lot of adaptation before it could be used in people.

That’s where gene therapy could come in again. “The eye turns out to be a feasible place to do gene therapy,” says Benowitz. “The viruses used to introduce various genes into nerve cells mostly remain in the eye, and retinal ganglion cells are easily targetable.”