A complex road to finding a cure for blindness

Gustavo Aguirre, a professor of medical genetics and ophthalmology in the School of Veterinary Medicine, has taken giant steps toward conquering several forms of blindness. In his career, he’s played a role in developing gene therapies that halted or even reversed vision loss in dogs, with findings that have paved the way to treating blindness in humans.

Aguirre was recognized for these accomplishments earlier this month by the Kennel Club of the United Kingdom with their International Canine Health Award, which carries a prize of £40,000—funding that Aguirre intends to funnel back into his research and that of his colleagues.

One of Aguirre’s many areas of study advanced forward recently, in collaborative work among Penn Vet, the Scheie Eye Institute, Michigan State University, and the University of Florida. The research focused on a form of blindness called Leber congenital amaurosis (LCA), an inherited condition that robs children of their sight. The condition also affects dogs, and after years of work, in 2001, Aguirre and colleagues were the first team to report a gene therapy success in treating LCA in the canine model. The treatment involves injecting into the eye a functional version of a gene that is mutated in individuals with LCA. A sheepdog named Lancelot was among the first given the therapy.

“The first dog that had the treatment had a wonderful, social personality,” says Aguirre. “He visited Congress a few times and was really instrumental at the national level in raising funds for eye research.”

Dogs are useful models for investigating vision loss, as the size and structure of their eyes are similar to that of humans.

“That prompted this continued work and the concept that, if we can treat a dog, couldn’t human patients be treated for the same disease?” Aguirre says.

The hunt for a human treatment involved researchers from Scheie, the University of Florida, and several other institutions. By 2008, three groups reached their goal; they restored vision in human patients with LCA using gene therapy. Follow-up work showed that the patients had substantially improved vision, which lasted at least three years after treatment.

The most recent progress in LCA gene therapy was reported in the journal Proceedings of the National Academy of Sciences in January. For the first time, a key question was answered: Does the gene therapy prevent the progressive loss of cells in the retina?

Collaboration between Aguirre, longstanding Penn Medicine colleagues Artur Cideciyan, research professor of ophthalmology, and Samuel Jacobson, professor of ophthalmology, and others, demonstrated that, despite the visual benefit in human patients treated with gene therapy, cells continued to die at a rate similar to that seen in untreated patients. 

The study also underlined a little-known fact about LCA, which is that the disease in humans is a more aggressive form of the dog disorder. While children with the condition are born with ongoing cell loss, dogs may take roughly four or five years—the equivalent of 30 or more “human years”—to get to that stage.

Lancelot was the perfect example of this divergence between the dog and human versions of LCA. The gene therapy he received at a very young age restored his vision and stopped progressive retinal degeneration.

“Experimentally, you optimize your outcome by treating a disease in dogs at the earliest possible stage in the most optimal conditions,” says Aguirre, “and if that works well, it’s wonderful, and holds promise for treating human patients.”

But when Aguirre and his colleagues treated older dogs at stages of their condition that paralleled what is found in the youngest human patients, they discovered that visual function was restored but the retina continued to deteriorate.

Knowing that the treatment does not protect retinal cells from degenerating provides the researchers with valuable data they can use to develop more sophisticated approaches to helping LCA patients, as well as their four-legged counterparts.

“We may be able to tackle LCA with what we call combinatorial therapy; that is, gene therapy plus something else,” says Aguirre.

What that “something else” is remains to be determined; identifying it is the next step Aguirre and his team members plan to take to find a lasting cure for LCA. 

Gustavo Aguirre