Gene Therapy Offers Hope for Rare Retinal Condition


by Kayt Sukel

December 7, 2009

Three years ago, when nine-year-old Corey Haas was first diagnosed with Leber’s congenital amaurosis (LCA), a rare form of retinal degenerative disease, his parents weren’t given a hopeful prognosis regarding his vision.

“The doctors basically told us there was nothing we could really do except help him adapt by teaching him to use a white cane and read Braille,” says Ethan Haas, Corey’s father. “And when we did more research on the disease, we saw that it was just going to get worse over time. People with Leber’s in their 30s and 40s can only really see shadows and can’t do much independently. It was really heartbreaking to know that the world was just going to get darker and darker for Corey—it was only a matter of when.”

But the sight in one of Corey’s eyes has now vividly improved as the result of a new single-shot gene therapy developed by an interdisciplinary team of researchers from the University of Pennsylvania School of Medicine and the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. Corey’s response to the therapy—as well as that of eleven other trial participants’—was published in the Nov. 7 issue of The Lancet.

A “perfect storm” gene therapy candidate

LCA is a rare single-gene defect that affects an estimated 3,000 people in the United States. People with the disease are missing a critical enzyme that helps retinal cells use Vitamin A. This results in a very low sensitivity to light—and inability to see in poorly lit environments.

“Unless the room is lit up like a light box, individuals with LCA have a real difficult time getting around. They have only a fraction of the sensitivity to light that you or I have,” says Albert Maguire, an ophthalmologist at the University of Pennsylvania School of Medicine. “It’s almost as if they’ve put on several sets of dark sunglasses and it’s almost pitch-black in a normally-lit room. So in a slightly dim environment that would be no problem for you or I to navigate, people with LCA have no function at all.”

Though rare, Maguire argues that a disease like LCA is a “perfect storm” disease to try to cure using gene therapy.

“It’s a very simple single gene effect resulting in the lack of one enzyme,” he says. “All the machinery is there. Think of it like a car in the garage. The tank’s full, it’s ready to go, but the key to turn on the machine is missing. The right gene therapy can provide that key.”

Furthermore, the area affected is a fraction of the size of a postage stamp, which makes it easier for scientists to know exactly where to deliver the treatment. And unlike other retinal degenerative disorders, the affected cells do not immediately die.

“There appears to be a long window of time where the cells we need to treat remain in the retina. They aren’t functioning, they aren’t super-healthy, but they are there,” says Jean Bennett, Maguire’s research partner. “And that gives us an opportunity to treat them and resuscitate them before they die off.”

How the therapy works

The therapy uses an adeno-associated virus (AAV), modified to include the missing Vitamin A enzyme gene, injected directly into each patient’s worst-performing eye.

“Adeno-associated viruses are small DNA viruses,” says Brian Bothner, a researcher who studies the viruses at Montana State University, “They are small in size and very simple. With their limited number of genes, they cannot replicate in a cell on their own. The cell has to be co-infected with another virus, an adeno-virus, to lead to disease. And that’s one of the reasons they make such good gene therapy—on their own, they won’t cause disease, but they can still get DNA into a cell.”

Once injected, the AAV brings the missing gene directly to the affected cells in the retina. With the new DNA blueprint, the cells can then produce the missing enzyme.

“Think of taking a capsule-like drug. You have this gelatinous outer coating that breaks down in the stomach, releasing the drug,” says Katherine High, director of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. “This therapy works in a similar way. You have this outer capsule that is configured to bind to the outside of a target cell, get inside and deliver the working gene to the nucleus.”

That’s exactly what occurred with the trial participants. A single shot into a single eye of each participant resulted in remarkable improvement in vision within 1–2 weeks of injection, reaching a stable level about three months later. The researchers could see improvement in all the test participants, who ranged in age from 8 to 44 years old. But the children treated showed much greater improvement than their adult counterparts. Now, two years after the trial, the effects remain.

Corey Haas, the trial’s youngest participant, has shown dramatic progress—near-normal pupil response to light in his treated eye.

“Corey doesn’t use his white cane anymore,” his father says. “His independence level has increased tremendously—he’s not always calling for my wife or me to come help him find something or do something. He can ride his bike all over the neighborhood. When he plays with his friends out back and it starts to get dark, he can still play out there and see. It’s pretty amazing.”

Earlier studies of the treatment using animal models suggests that the effect should last at least 9 years—perhaps even longer—without additional intervention.

“Our best data comes from dogs we injected in July 2000. We’ve been following them and their vision for over 9 years,” Bennett says. “They are still seeing well and doing well. We believe it bodes well for the individuals we injected in this trial.”

Applying AAV to other retinal disorders

Bennett, Maguire and High all hope that the success of the LCA trial will result in a licensed pharmaceutical treatment that ophthalmologists can prescribe to anyone with LCA—ideally, to infants and small children as soon as they are diagnosed. They also hope that the trial’s success will help researchers develop new therapies for other single-gene disorders.

“There are many single-gene defects that cause retinal degeneration. The latest figure shows that something like 192 different genes are involved in retinal function,” Bennett says. “There are certain technical challenges, but I really do think there is a good market for developing these therapies for single-gene disorders.”

Bothner believes we will see more of these kind of AAV therapies in the next 5 years—and that as we learn more about how they work, we’ll see more effective versions.

“I think we’ll have better versions of viruses for more specific cell targeting,” he says. “And with that, we’ll have much more efficient delivery of the genes within the cells using smaller doses. We may even be able to time the release of the gene we deliver. It’s pretty exciting.”

As for Ethan Haas, he has only one hope for the future—that the researchers will inject Corey’s other eye with the AAV-therapy.

“We’re hoping that Dr. Bennett will call us up and say that they are going to do it soon. We’re very hopeful for that,” he says. “And we look forward to it. Dr. Bennett, Dr. Maguire and Dr. High—they really are changing people’s lives forever. They’ve changed my son’s life forever.”