January 2010




Gene therapy provides new palette of options for color blindness and beyond

by Maxine Lipner Senior EyeWorld Contributing Editor


Treated color-blind monkeys able to see red

A new treatment has made it possible for two previously color-blind adult monkeys to see the color red, according to results reported in the October 8, 2009 issue of the journal Nature. This is good news not only for the 8 million color-blind individuals who may some day benefit, but also for those with blinding cone-related diseases such as achromatopsia, as well as those with age-related macular degeneration, believes William W. Hauswirth, Ph.D., professor of ophthalmology and molecular genetics, University of Florida College of Medicine, Jacksonville, Fla. “Color blindness is the most common genetic defect in our species,” Dr. Hauswirth said. “However, many people would confirm that normal male color blindness is not a very debilitating disease and is often called a condition, not a disease, for that reason.”

Dr. Hauswirth was moved to undertake the research for its broader implications. “We’re interested in developing gene therapies for blinding diseases, not male color blindness,” he said. “However, once we found we had two color-blind monkeys, who belonged to the Neitz Laboratory [Seattle], it was a vehicle for demonstrating that we could actually treat cones using a gene therapy vector.” This would allow investigators to note a behavioral improvement in the patient or, in this case, the monkey.

Adding red-sensitive pigment

The two monkeys, named Sam and Dalton, were missing red-sensitive pigment in their cones. “The idea was simple—we were going to supply a gene for that red-sensitive pigment and deliver it to their cones,” Dr. Hauswirth said. Toward that end, investigators removed the majority of genes from a nonpathogenic AAV [adeno-associated virus] and replaced this with DNA for human red pigment. “We picked out all of the genes that the virus has, leaving just a few hundred bases at each end of the DNA that’s inside the virus,” Dr. Hauswirth said. “Then we put in the red-sensitive pigment.” Investigators also put in a “promoter” to regulate the expression of the gene. “We engineered a virus to deliver our red pigment and to express it,” Dr. Hauswirth said. This vector was then placed in the central retina, which was rich with cones.

Initially, investigators were disappointed with what they saw. “We observed the behavior of the monkeys to the color red and nothing happened—they still couldn’t see red at two weeks, at three weeks, or at four weeks,” Dr. Hauswirth said. “By 15 weeks I didn’t want to take the Neitz’s telephone calls anymore—I figured it didn’t work.”

Then between the 19- and 20-week marks, something changed for both monkeys with this x-linked genetic disorder. “Both of them went from not seeing red to very quickly seeing red about as well as their female relatives—basically we cured their color blindness,” Dr. Hauswirth said.

Taking time to adjust

Of course the question remains as to why it took five-and-a-half months for the monkeys to be able to see the red color. Dr. Hauswirth theorizes that it’s related to the time needed for the visual cortex to make the adjustment and begin to interpret red signals. “I would argue that the visual cortex part of the brain required that period of time to recognize this new signal coming from red-sensitive cones,” he said. “When that happens there is actually some remodeling of neural connections. I think that it takes about that amount of time because they’ve never seen red before.”

The fact that these adult monkeys were able to interpret red signals helps to negate the prevailing wisdom regarding the lack of plasticity of the adult visual system. “There have been a lot of opinions and some experiments that suggested that if the cortex isn’t rewired early in life, it can’t be done later in life,” Dr. Hauswirth said. “But apparently, at least for color vision, this isn’t true. It is very good news for individuals who haven’t seen color at all in their lives.”

This makes the work particularly promising for patients with achromatopsia, a severe form of color blindness. “They have never seen colors,” Dr. Hauswirth said. “Their whole lives they have had very poor visual acuity outside—it’s actually painful for them to be out in sunlight.” Such patients are effectively blind in bright light. “They have to be in dim light to see anything because they are only using their rods, which are only good in dim lighting conditions,” Dr. Hauswirth said.

The approach could also potentially work for age-related macular degeneration. “This is the most important blinding disease in people over 60,” Dr. Hauswirth said. In addition, those with traditional color blindness could of course gain. “There is a substantial subset of color-blind males from whom we’ve been getting emails saying, ‘Sign me up,’” Dr. Hauswirth said. However, since this is not considered a serious condition, genetic treatment for color blindness would go to the back of the line. Dr. Hauswirth estimates that it will take two to three years to complete safety studies in humans. He hopes that a clinical trial for more serious disorders will not be far behind. “Within five years there could possibly be an experimental clinical trial for cone diseases,” he said.

Editors’ note: Dr. Hauswirth has no financial interests related to his comments.

Contact information

Hauswirth: 352-392-0679, hauswrth@eye.ufl.edu

Gene therapy provides new palette of options for color blindness and beyond Gene therapy provides new palette of options for color blindness and beyond
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