Penn researchers report gain in using gene therapy to battle blindness

Gustavo D. Aguirre (left) and William A. Beltran worked with Penn colleagues, aided by University of Florida scientists.
Gustavo D. Aguirre (left) and William A. Beltran worked with Penn colleagues, aided by University of Florida scientists.
Posted: January 25, 2012

Four years ago, teams of researchers at the University of Pennsylvania and elsewhere made headlines by restoring some sight to blind people, though it was a form of blindness few had heard of.

Now some of the same researchers are making progress with a far more common kind of blindness, retinitis pigmentosa, which strikes many thousands.

This week, the scientists reported success in treating four dogs with forms of the disease. And they are optimistic that their findings will, like the earlier study, translate to humans.

As before, the new effort involved injecting healthy genes into the retina to compensate for mutated, malfunctioning genes. Known as gene therapy, this concept is fairly young but is starting to show promise with a few diseases, including a type of hemophilia.

In the dogs, the gene injections stopped the eye disease in its tracks - preventing the onset of severe symptoms and, to some extent, reversing early signs of damage, the scientists reported in Proceedings of the National Academy of Sciences.

The research was led by Gustavo D. Aguirre and William A. Beltran of Penn's School of Veterinary Medicine, along with ophthalmologists Artur V. Cideciyan and Samuel G. Jacobson of Penn's Perelman School of Medicine. Scientists at the University of Florida created the "vector" - a modified virus - that was used to deliver the corrective genes to the dogs' eyes.

While it isn't the first time researchers have used gene therapy to treat blindness, the latest effort is significant in that it tackled a disease that afflicts two kinds of cells - rods and cones, said a scientist in the same field who was not involved with the work.

"This is a big advance," said John G. Flannery, a professor of neurobiology at the University of California, Berkeley.

It's unclear just how many people have the kind of blindness that was treated in the dogs, but the number is apparently in the many thousands.

The animals were born with mutations in a gene called RPGR, which is a rare occurrence in dogs but relatively common in people. Such mutations account for most human forms of a kind of retinitis pigmentosa known as "X-linked" - meaning that the defective gene is located on the X chromosome.

X-linked retinitis pigmentosa is one of the most common kinds of retinitis pigmentosa, which has been estimated to affect tens of thousands of people in the United States, though Penn's Jacobson said a reliable total was not available.

Most patients with X-linked RP are males, though women have been known to have milder forms of the disease. Typically patients are unable to see at night, and by age 10 they start to lose their peripheral vision, eventually ending up with what is called tunnel vision. By age 40, most are legally blind.

In the dog study, the scientists could not measure the animals' vision directly, because animals cannot answer questions about what they saw.

Instead, the researchers anesthetized the animals and used lasers to measure the thickness of the layer of the retina that contains rods and cones. (Thicker is better, meaning the cells have not started to die.) This measurement is made with a sophisticated device also used on humans.

The scientists also shone lights into the animals' eyes and measured the electrical response of their rods and cones, finding that the replacement genes did indeed seem to maintain the health of these light-sensitive cells. They were able to show this because the healthy genes were injected only in one eye in each animal; in the untreated eye, the rods and cones deteriorated.

In some forms of gene therapy, the benefits decline over time, since the healthy gene is not inserted in the genome and is not copied as cells divide. But eye cells don't divide, and the dogs' improvement persisted many months later.

The study collaborators, led by William W. Hauswirth and Alfred S. Lewin at the University of Florida College of Medicine, created the gene-delivery vector from an adeno-associated virus, a kind of virus that does not cause disease.

For an added layer of safety, they modified the virus so it could not make copies of itself, lest it infect cells outside the targeted area.

The viruses were then loaded with a healthy form of the gene that was mutated in the dogs, along with a helper stretch of DNA called a promoter, which was specifically tailored to work in rods and cones.

Sometimes the role of a promoter is described as turning on or ramping up the activity of a gene.

Penn's Aguirre proposed another analogy, likening the process to a truck delivering boxes of cargo. The viral vector delivered its cargo to the correct cells, and then the promoter was needed to "open" it.

"You have the right tools to open the boxes in the right cell," Aguirre said.

And ultimately, to open up the world of sight.

Contact staff writer Tom Avril at 215-854-2430 or