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Gene therapy restores vision in blind dogs
By Bijal P. Trivedi

Scientists are using gene therapy to restore vision in blind dogs. A genetic defect in affected dogs causes the retina to degenerate, leading to permanent blindness.

A montage of images taken of the retina of the blind dog. The white arrow marks the site where the virus carrying the RPE65 gene was injected.

Jean Bennett, of the University of Pennsylvania, and colleagues studied Briards that have a mutation in both copies of their RPE65 gene. Without a healthy copy of RPE65, the dogs' retinal cells do not produce rhodopsin molecules, which detect light photons and translate them into electrical signals that are sent to the brain.

"We have rescued defective retinal cells that can now translate light into electrical impulses and send signals to, and communicate with, the brain," emphasizes Bennett. "This is not just a small local genetic change that we have made to a few cells in the retina."

Bennett's team used a virus to carry a healthy copy of RPE65 into a region of the retina containing light-sensing cells. The virus infected the retinal cells and released its therapeutic cargo, RPE65. Cells with a healthy copy of RPE65 produced rhodopsin, allowing the dogs to see.

The canine disease is similar to that seen in infants with Leber congenital amaurosis (LCA). "LCA is the most devastating form of retinal degeneration," says Bennett. "Children diagnosed with this form of blindness are sent to learn Braille, work with guide dogs and use a cane." The dogs may provide a useful model for studying retinal diseases in humans and developing therapies.

To measure the effects of gene therapy on the dogs' behavior, the animals were placed in a dimly lit obstacle course. "An untreated animal looks like a ball-bearing shot out of a pinball machine," explains Bennett. The animals are unable to avoid the obstacles and bump into things on the left and right. Animals that received therapeutic genes in the right eye avoided objects directly in front of them and on their right. They only bumped into objects on the left side.

"The dogs seem to prefer the treated eye and look in that direction," says Bennett. "They must be both thrilled and puzzled." She and her colleagues are confident the treated dogs are able to see, but they are not sure how well. The researchers will continue to monitor the dogs' visual acuity.

To test whether the modified retinal cells were transmitting signals to the brain, Bennett's team measured the electrical activity as the dogs were exposed to blue light. In healthy dogs the retinal cells showed increasing electrical activity, as the light became more intense. Treated dogs that had received a healthy copy of RPE65 showed a similar response. In untreated animals the light evoked barely any electrical activity.

Bennett's team also measured the diameter of the pupil after exposure to light. In healthy and treated animals the pupil diameter constricted in response to the light. In untreated affected animals the pupil diameter remained almost constant.

"This really shows us that we have restored communication between the retinal cells and the brain," says Bennett. "The cells were able to detect light and send a signal to the brain. And the brain responded telling the pupil to constrict."

The healthy RPE65 gene was present and active in retinal cells nine months after treatment. The dogs' ability to see appears to have remained constant.

Bennett and her team are interested in the potential of gene therapy to treat LCA in humans. This rare disease is usually diagnosed in infancy when parents notice that their child's eyes wander constantly. The roving eye movement occurs because the child is unable to focus on specific objects. Eventually the light-sensitive cells in the retina degenerate, eliminating the opportunity for repair.

The researchers are conducting tests to ensure that the gene therapy is not toxic. Clinical trials could begin in as early as two years.

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Acland, G.M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-95 (May 2001).

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