Thursday, September 17, 2009

Gene Therapy Cures Color-Blind Monkeys

After receiving injections of genes that produce color-detecting proteins, two color-blind monkeys have seen red and green for the first time.

Except in its extreme forms, color blindness isn’t a debilitating condition, but it’s a convenient stand-in for other types of blindness that might be treated with gene therapy. The monkey success raises the possibility of reversing those diseases, in a manner that most scientists considered impossible.

“We said it was possible to give an adult monkey with a model of human red-green color blindness the retina of a person with normal color vision. Every single person I talked to said, absolutely not,” said study co-author Jay Neitz, a University of Washington ophthalmologist. “And almost every unsolved vision defect out there has this component in one way or another, where the ability to translate light into a gene signal is involved.”

The full-spectrum supplementation of the squirrel monkeys’ sight, described Wednesday in Nature, comes just less than a year after researchers used gene therapy to restore light perception in people afflicted by Leber Congenital Amaurosis, a rare and untreatable form of blindness.

Those results were stunning, but they were also achieved in children, whose still-growing brains can rewire themselves on the fly in response to new sources of visual stimuli. By contrast, adult brains were thought to be too fixed and static to develop new pathways. Even if gene therapy healed their eyes, the signals would stall inside them.

“I remember telling them that it was unlikely to work, but it was so exciting they had to try,” said David Williams, director of the University of Rochester’s Center for Visual Science. “It’s just an incredible milestone in the history of color vision. Looking back on this in 50 or 100 years, it will be a landmark paper even then.”

Neitz’s team injected their monkeys’ eyes with viruses carrying a gene that makes L-opsin, one of three proteins released when color-detecting cone cells are hit by different wavelengths of light. Male squirrel monkeys naturally lack the L-opsin gene; like people who share their condition, they’re unable to distinguish between red and green.

At first, the two monkeys behaved no differently than before. Though quick to earn a grape juice reward by picking out blue and yellow dots from a background of gray dots on a computer screen, they banged the screen randomly when presented with green or red dots.

But after five months, something clicked. The monkeys picked out red and green, again and again. At the biological level, Neitz can’t say precisely what happened — the monkeys, named Sam and Dalton, are alive and healthy, their brains unscanned and undissected — but their actions left no doubt.

Neitz thinks the monkeys’ brains didn’t grow new neural circuits. “That’s the way we were thinking about neural plasticity before,” he said. Instead, their brains may have reconfigured themselves, “learning how to use the same old circuits in a new way when the information coming over the lines changed.”

“It’s incredibly cool. It demonstrates a fascinating plasticity in the brain,” said Jeremy Nathans, a Johns Hopkins neurologist regarded as the father of modern color-vision genetics. “We presume that we have that same kind of plasticity as well.”

If so, then gene therapies for severe human forms of color blindness could be successful. So could gene treatments for age-related macular degeneration. Ultra-experimental hacks that confer light- and color-perceiving powers on cells used in other aspects of sight would be that much closer to reality.

Neitz was quick to caution that “there’s a lot of steps before we actually cure a real blindness in people.” Except for the LCA trials, proposed gene therapies for blindness are still in animal-testing stages, if they’ve even progressed that far. The monkeys appear free of any side effects, but safety still needs to be proven.

Williams, however, was quicker to speculate. “Ultimately we might be able to do all kinds of interesting manipulations of the retina,” he said. “Not only might we be able to cure disease, but we might engineer eyes with remarkable capabilities. You can imagine conferring enhanced night vision in normal eyes, or engineering genes that make photopigments with spectral properties for whatever you want your eye to see.”

“This study makes that kind of science fiction future a distinct possibility, as opposed to a fantasy,” continued Williams.

In the meantime, Sam and Dalton remain in Neitz’s lab, drinking grape juice, unable to communicate — at least to us — what it’s like to see color in what was once a gray-yellow wash. “One wonders what the internal representation of color is for them, and how it changed,” said Nathans. “At a certain level, that’s a very difficult question to answer.”

Neitz was less uncertain. “You go out and look at a rainbow, or the fall leaves, or sunset over the ocean, and it’s not something where you just say, ‘I can see colors.’ It has a deep effect on us,” he said. “These emotions are something we inherited from our evolutionary past. I think monkeys have that, too. I think these animals must have the real experience of, ‘Oh! Wow!’”

Citation: “Gene therapy for red–green colour blindness in adult
primates.” By Katherine Mancuso, William W. Hauswirth, Qiuhong Li, Thomas B. Connor, James A. Kuchenbecker, Matthew C. Mauck, Jay Neitz & Maureen Neitz.
Nature, Vol. 461, No. 7261, September 16, 2009.

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