In gene therapy first, scientists restore vision to dogs born blind

April 26, 2001

GAINESVILLE, Fla. --- During World War I, the French army dispatched ammunition-carrying Briard dogs to the front lines. The Red Cross turned to the shaggy-haired sheepdogs to haul first-aid supplies.

And now Briards once again have been called to service: For the first time ever, animals that were born blind gained the ability to see after undergoing gene therapy, according to research from the University of Florida, Cornell University and the University of Pennsylvania. The findings, published in the May issue of Nature Genetics, open the door to developing treatment in coming years for people with a rare, inherited eye disorder.

The scientists reported their success in three dogs with a condition closely resembling Leber congenital amaurosis, or LCA, a blinding disease caused by mutations in a gene important for eye function. About 2,000 people in the United States have LCA, a currently untreatable condition that typically results in blindness from birth or shortly thereafter.

"In gene therapy with other eye diseases, we've been able to prevent worsening of the condition in animals, but this is the first time we've been able to recover a lost function," said William W. Hauswirth a contributing author who is the Rybaczki-Bullard professor of molecular genetics and microbiology at UF's College of Medicine.

"This is also really the first study that shows you can use gene therapy to get a response in a human-sized eye, that you can effectively treat enough of the retina to have an effect on the animal's visual function."

Dr. Jean Bennett, a senior author of the Nature Genetics paper and a scientist at the F.M. Kirby Center for Molecular Ophthalmology at Penn's Scheie Eye Institute, said the study results expand the possible treatment strategies for degenerative retinal diseases.

"We have worked hard for many, many years trying to develop a treatment for retinal degeneration, and this is the biggest leap forward yet," she said.

UF researchers had established that the apparently harmless adeno-associated virus can carry healthy copies of a gene into the cells of the retina, which is composed of layers of light-sensitive nerve cells. The healthy gene's mission: to produce a protein critical to translating light waves into nerve impulses that can be interpreted as images by the brain.

Scientists from Cornell and Penn, where the experiment was conducted, had identified the eye disease in the dogs and the mutated RPE65 gene responsible. The mutated RPE65 gene causes an estimated 15 percent of LCA cases, with the rest attributed to other mutations.

Efforts are under way to develop gene therapy approaches to combat those other mutations. In the experiment, three Briard puppies had their right eyes treated late last year with a single injection of thousands of copies of the corrective gene in the virus provided by Hauswirth. Their left eyes were untreated as a control. The scientists planned to formally test eye function three months later, when the dogs were 6 months old.

"Well before those tests, the researchers thought the dogs could see because they kept turning their heads to the right to use the eye that had been treated," said Hauswirth, who also holds an appointment in the department of ophthalmology and is affiliated with UF's Genetics Institute and Powell Gene Therapy Center. "But then when the official tests were conducted, I got this very excited phone call, 'Bill, Bill, the dogs can see!'"

The tests showed that the treated eyes responded to light. The dogs also were able to navigate through a maze, even when the lighting was dim. "The dogs bumped into objects on the left side, but would always avoid the objects on the right," Hauswirth said.

Officials from the Foundation Fighting Blindness, which supported the study with grant funds, said the success in reversing blindness in dogs is an important advance. "With this study, gene therapy has overcome a major hurdle," said Gerald Chader the organization's chief scientific officer. "The Food and Drug Administration wants to see evidence that a treatment is safe and effective in a large animal model before granting permission to begin clinical trials in humans. Genetic medicine is now making things we could only once dream of a reality."

Hauswirth cautioned that it will take several years before the experimental treatment can be tested in people.

"This experiment showed us that this kind of therapy has potential to work, but now we need to go back and do very structured and rigorous tests to look for any signs of ill effects from the treatment," Hauswirth said. "And then in the early phase of testing in people, we also will be looking first at whether it causes any problems, rather than actually trying to reverse blindness."

LCA is an autosomal recessive disease, meaning that one copy of a mutated gene must be inherited from each parent to cause symptoms. Such mutations also occur in Briards and other dogs that have been inbred to preserve characteristics of their breed.

"The retina initially looks normal," Hauswirth said. "Over time, however, the retina starts losing part of its structure because there is no visual input. By the time a child is 10 or 15 years old, the light-sensitive photoreceptor cells are usually gone. At that point, putting in this gene isn't going to restore vision. So there almost certainly is going to be a window of treatability for LCA patients -- probably the younger the better."

In their next phase of animal testing, the scientists will try to pinpoint the time of life during which treatment might be effective. "That's such a critical question to deciding what populations in humans might benefit, although there's no guarantee that it will translate exactly to people," Hauswirth said. "No one really knows what dog years versus human years means in the eye."
The research effort continues to be supported by grants from the National Institutes of Health, the Foundation Fighting Blindness, Research to Prevent Blindness and the Macular Vision Research Foundation.

University of Florida

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